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Vénal, L., E. Liozon, C. Brigaudeau, T. Papo, F. Chariotte, P. Soria, V. Loustaud, and E. Vidal. "Syndromes hyperéosinophiliques de présentation classique avec évolution clonale et transformation leucémique." La Revue de Médecine Interne 19 (June 1998): 118S. http://dx.doi.org/10.1016/s0248-8663(98)80187-2.
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Cardin, Lise, Daphné Bolz, and Jean Saint-Martin. "Nelson Paillou et la transformation du handball en France (1942–1982) : Entre discours et réalités." STADION 44, no. 2 (2020): 366–89. http://dx.doi.org/10.5771/0172-4029-2020-2-366.
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Nelson Paillou can be considered a major sports leader of the second half of 20th century France. He was president of the French Handball Federation from 1964 to 1982, vice-president and eventually president of the French National Olympic and Sports Committee (CNOSF) from 1971 to 1993, and a key person in the foundation of the French association for violence-free sport and fair play. Based on printed sources and on personal as well as institutional archives, this article questions the role Paillou played in the development of French sport. First, Paillou worked to introduce and disseminate handball in France, and he developed a policy to enable masses of people to learn to play handball across the country. As such, he targeted the French youth and founded a national executive for handball technique in order to structure the supervision of players of all levels, from initiation up to the elite level. Second, Nelson Paillou also contributed to the recognition and visibility of handball in France and at European and international levels. He developed a significant communication policy and assured a remarkable presence at all handball events in order to reinforce his choices in terms of management and diffusion of the game. Finally, it appears that during the second half of the 20th century, Paillou, who strongly supported the ideals of Pierre de Coubertin, emerged as a promotor of humanist values in sport and in handball. His position against sponsors and some kind of professionalism was overcome with difficulties but it was necessary to open French handball to the international field. Paillou presented himself as an ambiguous French sports leader who sometimes took contradictory decisions. However, Paillou’s resolutions reflected the choices of an opportunistic leader in front of the transformation of sport in a period marked by the arrival of show business and professionalism.
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Deschênes-Simard, Xavier, Yusuke Mizukami, and Nabeel Bardeesy. "Macrophages in pancreatic cancer: Starting things off on the wrong track." Journal of Cell Biology 202, no. 3 (August 5, 2013): 403–5. http://dx.doi.org/10.1083/jcb.201307066.
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Chronic inflammation drives initiation and progression of many malignancies, including pancreatic cancer. In this issue, Liou et al. (2013. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201301001) report that inflammatory macrophages are major players in the earliest stages of pancreatic cancer. They show that paracrine signals from the macrophages activate the nuclear factor κB transcriptional program in normal pancreatic acinar cells, resulting in acinar–ductal metaplasia, a dedifferentiated state that is poised for oncogenic transformation.
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Hassan, L. "Successful genetic transformation in date palm (Phoenix dactylifera)." Journal of the Bangladesh Agricultural University 11, no. 2 (August 4, 2014): 171–76. http://dx.doi.org/10.3329/jbau.v11i2.19841.
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The introduction of foreign genes into most of the Phoenix spp using recombinant DNA technology is not a straight forward task. In Phoenix spp application of this technology towards successful transformation proved to be a more difficult one so far no report on the successful regeneration of transgenic date palm plants has been published. We developed an efficient and reproducible variety-independent method for producing transgenic date palm (Phoenix spp) via Agrobacterium-mediated transformation. Agrobacterium rhizogenes strains LBA 9402 were used and for cotransformation experiments the strain LBA 9402 with the binary vector pBIN19 with the p35S GUS INT gene was used. Off-shoot segments from different Phoenix spp cultivars were infected with Agrobacterium rhizogenes. The development of hairy roots at a high frequency only on infected tissue pieces showed that transformation is possible. Various parameters like, effect of different genotypes on root initiation, root number and root length have been studied. Regeneration of transformed root cultures to plantlets was also attempted. Histochemical GUS assay and polymerase chain reaction analysis of hairy roots confirmed the presence of GUS gene. Agrobacterium tumifaciensmediated transformation was also performed using the leaves of off-shoot explants. Agrobacterium tumefaciens strains: I) GV3101 with the vir plasmid pMP90 the strain C58C1 ATHV with the vir-plasmid pTiBo542 (=pEHA101; Hood et al. 1986) was used. The nptII gene (neomycin phosphotransferase) was used as a selectable marker gene. The ?-Glucuronidase-gene (GUS-Gene: Jefferson et al. 1987) under control of the Ubi- and 35S-Promotors, with an Intron (Vancanneyt et al. 1990), was used as the reporter gene. We also used the genetically engineered Agrobacterium tumefaciens strain LBA4404 as a vector for infection in the transformation experiment, which contains plasmid pBI121 of 14 KDa (binary vector). This binary vector contains following genes within the right border (RB) and left border (LB) region of the construct: The udiA gene (Jefferson, 1986) predetermining GUS (?-glucuronidase), driven by CaMV promoter and NOS terminator. This reporter gene can be used to assess the efficiency of transformation. The nptII gene (Herrera-Estrella et al., 1983) encoding neomycin phosphotransferase II (nptII) conferring kanamycin resistance, driven by NOS promoter and NOS terminator. The bacterium also contains plasmid pAL4404 which is a disarmed Ti plasmid (132 KDa) containing the virulence genes. For the confirmation of transgenes, calli were taken from the growing callus mass for DNA isolation. PCR- and Southern analysis was performed to determine the integration and the copy number of the transgene. The GUS-test was performed to demonstrate ß-glucuronidase expression. The transgenic plantlets were kept in a hardening room for four weeks and they will be transferred to a growth chamber with controlled environment for further establishment. DOI: http://dx.doi.org/10.3329/jbau.v11i2.19841 J. Bangladesh Agril. Univ. 11(2): 171-176, 2013
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Cai, Xiongwei, Yoshihiro Hayashi, Mark Wunderlich, Nancy A. Speck, James C. Mulloy, Gang Huang, and Yi Zheng. "Loss of Function RUNX1 Mutations Restrict Protein Biosynthesis during Pre-Leukemia and MDS Transition but Not after Leukemic Transformation." Blood 128, no. 22 (December 2, 2016): 3860. http://dx.doi.org/10.1182/blood.v128.22.3860.3860.
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Abstract Runx1, a DNA binding subunit of core binding factors, is found frequently mutated in hematological malignancies. Runx1 mutation can be an early event in leukemogenesis endowing pre-leukemic stem cells with a selective advantage in the bone marrow, and is associated with an unfavorable outcome. In mouse models, loss of function (LOF) Runx1 mutations cause a broad decrease of ribosome biogenesis in hematopoietic stem and progenitor cells (HSPCs) by directly binding to ribosomal related genes essential for protein synthesis, and confers resistance to genotoxic stress (Cai et al. 2015 Cell Stem Cell 17(2):165-77). Paradoxially, leukemia cells generally require higher biosynthetic activity, and AML patients with LOF Runx1 mutations show upregulated ribosome signatures compared with those without Runx1 mutations (Silva et al., 2009 Blood 114:3001-3007). It remains unclear whether RUNX1 plays a role in regulating protein synthesis in leukemogenesis as in normal HSPCs, and if LOF Runx1 mutations are important for leukemia initiation, transformation and/or maintenance. To examine such mechanistic roles of RUNX1 in AML progression, we have used a previously reported MLL-PTD; Mx Cre; Runx1 Flox/Flox (Double mutant -DM) mouse model (Hayashi et al., 2015 Blood 126:303 ) that allows experimental tracking of the step-wise transition of HSPCs from pre-disease stage to a MDS-like stage, prior to full blown AML. Various subpopulations of the HSPCs, including genotypic HSCs, MPP, GMP, CMP, MEP, were isolated from the mice at pre-disease, MDS-like, and AML full-blown stages, and were assayed for protein synthesis rates by O-propargyl puromycin incorporation, DNA synthesis rates by BrdU labeling, and FACS analysis. At the pre-disease state, DM HSCs, as well as all the progenitor populations, had lower protein biosynthesis activity compared with similar populations of wild-type control or MLL-PTD mutant mice, consistent with LOF Runx1 mutations providing stress-resistance and survival advantage. As disease progressed, the DM mice developed MDS-like phenotypes including severe anemia and bone marrow fibrosis, with the HSCs (LSK CD34-Flt3- cells) showing increased protein synthesis rate compared with the pre-disease DM mice. Upon the onset of full-blown leukemia, the protein translation rates in all subpopulations of DM HSPCs were significantly faster than the control non-leukemic cells, regardless of the Runx1 mutant status. Importantly, preliminary analyses of two human AML samples found that CD34+ cells with LOF Runx1 mutations displayed a similarly enhanced protein synthesis rates than CD34+ leukemia bone marrow cells carrying wild type Runx1, as seen in the mouse model. Our results show that at early initiation, LOF Runx1 mutation supresses protein biosynthesis; during transition to MDS, the inhibitory regulation was bypassed in LT-HSCs (LSK CD34-Flt3-), suggesting that Runx1-controlled protein translation is involved in the early clonal selection of disease progression. In full-blown leukemia cells including the primitive subpopulations, however the protein synthesis rate appears to become uncoupled from Runx1 regulation possibly due to an activation of compensatory machineries. This study of the role of Runx1 mutation in pre-leukemia cell progression to full blown leukemia raises the question that while some tumor initiating mutations such as LOF Runx1 mutations contribute to the tumor initiation and transformation process, they may not be essential for maintaining certain crucial leukemia cell phenotypes such as protein biosynthesis. Disclosures No relevant conflicts of interest to declare.
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Hurtz, Christian, Huimin Geng, Gang Xiao, Mignon L. Loh, B. Hilda Ye, Ari Melnick, and Markus Muschen. "BCL6 Enables RAS-Mediated Pre-B Cell Transformation in Childhood Acute Lymphoblastic Leukemia." Blood 124, no. 21 (December 6, 2014): 3570. http://dx.doi.org/10.1182/blood.v124.21.3570.3570.
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Abstract Background & Hypothesis: The transcriptional repressor and proto-oncogene BCL6 has recently been identified as a therapeutic target in subtypes of diffuse large B cell lymphoma (DLBCL) and as mediator of a novel for of drug-resistance in Ph+ acute lymphoblastic leukemia (ALL; Duy et al., Nature 2011). A previous senescence rescue screen identified BCL6 as a key factor that bypassed senescence and thereby enabled RAS-mediated transformation of mouse embryonic fibroblasts (Shvarts et al., Genes Dev 2002). Since ~50% of pediatric cases of ALL carry genetic lesions that result in hyperactivation of the Ras-Erk pathway (Zhang et al., Blood 2012), we tested the role of Bcl6 in this large subgroup of childhood leukemia. Results: Mutations leading to hyperactivation of the Ras-Erk pathway are found in about 50% of childhood ALL cases (Zhang et al., 2012). Among 26 ALL xenografts, we found 9 cases with constitutive Erk-T202/Y204 phosphorylation, which was paralleled by elevated expression levels of BCL6 in these cases. Studying mouse pre-B cells that were engineered with a doxycycline-inducible NRASG12D mutant, we were able to directly measure the consequences of acute activation of the Ras-Erk pathway on BCL6 expression levels. First we incubated the cells with doxycycline to induce the expression of NRASG12D and then harvested the cells at different times point to test for BCL6 protein and mRNA expression levels. Interestingly, after 24h NRASG12D-TetO pre-B cells cells showed strong upregulation of BCL6 at the mRNA (352-fold) and protein level (15-fold). Upregulation of BCL6 in response to NRASG12D-activation was sensitive to treatment with the MEK kinase inhibitor PD325901, upstream of Erk, suggesting that BCL6 expression is a consequence of Erk activation in pre-B cells. Likewise, treatment of patient-derived pre-B ALL cells with the MEK inhibitor PD325901 reversed BCL6 expression, as demonstrated by quantitative RT-PCR and Western blot. From one patient, a diagnostic (KRAS wildtype) and a relapse sample with an acquired KRASG12V mutation were available. Consistent with specific expression of BCL6 in the KRASG12V relapse ALL sample, only KRASG12V ALL cells from the relapse but not wildtype cells from the diagnostic sample were sensitive to a retro inversoBCL6 peptide inhibitor (RI-BPI; Cerchietti et al., 2009). Development of a genetic mouse model for inducible ablation of Bcl6. These findings suggest an important role of BCL6 as a cofactor of RAS-driven pre-B cell transformation, comparable to previous findings in mouse embryonic fibroblasts. To directly test a mechanistic role of Bcl6 in RAS-mediated pre-B cell transformation, we generated a novel mouse model for inducible Cre-mediated deletion of Bcl6 exons 5-10, flanked by loxP sites. For lineage-specific deletion in vivo, we crossed these mice with an Mb1-Cre deleter strain, in which Bcl6 was deleted in pro-B cells, resulting in a differentiation block at the pre-B cell stage. Interestingly, Mb1-Cre x Bcl6fl/fl B cell lineage cells could be transduced with NRASG12D retroviral vectors, however these cells did not give rise to leukemia when injected into congenic recipients, whereas NRASG12D-transduced Bcl6fl/fl pro-B cells that retained Bcl6 function developed B cell lineage leukemia in all transplant recipients. In a second experiment, we transformed Bcl6fl/fl pro-B cells with NRASG12D and induced Cre with a second, tamoxifen-inducible vector in full-blown leukemia cells. Acute ablation of Bcl6 in NRASG12D ALL cells completely abrogated the ability of NRASG12DALL cells to form colonies in methylcellulose and resulted in rapid apoptosis and depletion from the cell culture. We conclude that BCL6 is not only required for the initiation of RAS-driven ALL in vivo but also for the maintenance of fully established RAS-driven leukemia. Conclusion: These findings provide genetic evidence for BCL6 function as a critical cofactor of RAS-mediated transformation in childhood ALL. Inhibition of BCL6 in RAS-driven ALL may be useful to prevent leukemia relapse after initial remission (Bcl6-dependent leukemia-initiation) and also to achieve profound remission by combining conventional cytotoxic therapies with BCL6 inhibition (e.g. RI-BPI). Disclosures No relevant conflicts of interest to declare.
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Aivalioti, Maria M., Tushar D. Bhagat, Aditi Paranjpe, Boris Bartholdy, Kith Pradhan, Mario Pujato, Amit Verma, and Britta Will. "PU.1-Dependent Enhancer Decommissioning Drives Transformation of Tet2 deficient Hematopoietic Stem and Progenitor Cells." Blood 136, Supplement 1 (November 5, 2020): 40. http://dx.doi.org/10.1182/blood-2020-142070.
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Acute myeloid leukemia (AML) is the most frequent leukemia in elderly individuals with a median age at diagnosis of 67 years (Juliusson et al., Blood 2009). It arises in a step-wise process and originates from hematopoietic stem cells (HSC) (Jan et al.,Sci Transl Med. 2012). Genetic and epigenetic alterations drive the formation of pre-leukemic HSC clones with altered function, which can gain dominance and eventually give rise to AML upon the acquisition of cooperating lesions (Jan et al.,Sci Transl Med. 2012). However, it is currently impossible to predict which healthy elderly individuals with clonal hematopoiesis will eventually develop myeloid malignancies, as the pathways to leukemia are unknown. Heterozygous inactivating mutations of the epigenetic regulator Ten-Eleven Translocation-2 (TET2) are commonly found in patients with AML, yet also in a remarkable fraction of healthy elderly individuals in whom it is associated with clonal hematopoiesis (Busque, et al Nat Genet. 2012). These observations and studies in Tet2-deficient mice strongly suggest that TET2 inactivation is an early event in the pathogenesis of myeloid malignancies, but is not sufficient to fully transform HSC (Moran-Crusio et al., Cancel Cell 2011). TET2 cooperates with several transcription factors to regulate hematopoiesis (Rasmussen et al., Genome Res 2019), one of which is PU.1 (de la Rica et al., Genome Biol. 2013), an essential transcription factor governing normal hematopoiesis (Iwasaki et al., Blood 2005). In humans, PU.1 activity or expression is only moderately impaired in the majority of AML patients, and remarkably, also in aged HSC (Will et al., Nat Med. 2015), underscoring the essentiality of PU.1. Importantly, PU.1 target genes are frequently found hypermethylated in AML (Sonnet et al., Genome Med. 2014, Kaasinen et al., Nat Commun. 2019), suggesting a profound epigenetic inactivation of the PU.1 network. We hypothesized that moderate impairment of PU.1 abundance, as found in AML, can cooperate with loss-of-function mutations of Tet2 to initiate malignancy. We developed a novel tissue-specific compound mutant mouse model carrying heterozygous deletion of an upstream regulatory element (URE) of Pu.1 along with Tet2 deletion (Vav-iCre+ PU.1URΕ∆/+Tet2+/flox; Vav-iCre+ PU.1URΕ∆/+Tet2flox/flox). While none of the single mutant mice developed AML, compound mutant mice developed aggressive myeloid leukemia whose penetrance and latency exhibited Tet2 dose dependency. The disease presented with leukocytosis, anemia and splenomegaly. By cell morphology analysis of the peripheral blood, bone marrow and spleen, the leukemic mice exhibited accumulation of differentiation-blocked myeloblasts, myelocytes and/or metamyelocytes, that was confirmed using detailed myeloid differentiation markers, distinguishing the disease in immature or mature AML. Furthermore, gold standard in vitro and in vivo assays, assessing both self-renewal and differentiation capacity of double mutant mice-derived cells, revealed that the expanded differentiation-blocked stem and progenitor cells bear aberrant self-renewal and disease-initiating capacities. Comprehensive molecular profiling by next generation sequencing of disease-initiating cells uncovered a substantial overlap with human AML, such as functional GF1b loss with concomitant overexpression of CD90/Thy1 (Thivakaran et al., Haematologica 2018). Importantly, our analyses also revealed transcriptional dysregulation, hypermethylation of PU.1 regulated enhancers with concomitant loss of enhancer activity and alterations in chromatin accessibility of particularly genes co-bound by PU.1 and TET2. Current efforts focus on identifying key effectors of the dysregulated PU.1/TET2 sub-network driving malignant transformation in clonal hematopoiesis. Our collected data provide proof of concept that moderate PU.1 dose impairment can functionally cooperate with the inactivation of Tet2 in the initiation of myeloid leukemia and uncovers a likely unifying AML pathomechansim. Disclosures Will: Novartis Pharmaceuticals: Other: Service on advisory boards, Research Funding.
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Gouzi, Fares, François Bughin, Lucie Barateau, Agathe Hubert, Savine Volland, Dalila Laoudj-Chenivesse, Emilie Passerieux, et al. "Utilisation d’outils numériques dans le cadre d’un dispositif hybride pour l’apprentissage par problème de la physiologie en deuxième année des études médicales. Étude de faisabilité du recours au laboratoire numérique de physiologie « e-ϕsioLab »." Pédagogie Médicale 19, no. 2 (2018): 77–90. http://dx.doi.org/10.1051/pmed/2019007.
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Contexte : À l’Université de Montpellier, l’enseignement de la physiologie passe par une initiation à la démarche expérimentale, effectuée sous forme d’un apprentissage par problème (APP) au cours d’enseignements dirigés (ED) ou travaux pratiques (TP). Actuellement, les ED/TP de physiologie en 2e année de Diplôme de formation générale en sciences médicales (DFGSM2) posent un problème de faisabilité. But(s) : Nous avons évalué la faisabilité d’un dispositif hybride « Laboratoire numérique de physiologie (e-ϕsioLab) » combinant ED présentiels (EDP) au tableau blanc interactif (TBI) + supports multimédias, et ED dématérialisés (EDD) sur plate-forme pédagogique Moodle, pour la résolution de problèmes de physiologie en DFGSM2. Méthodes : Pour les EDP, nous avons évalué les travaux des étudiants et comparé la participation des étudiants ayant bénéficié de ces ED e-ϕsioLab vs. ED classique. Pour les EDD, nous avons évalué les travaux et la participation des étudiants. Résultats : Les travaux ont révélé que les étudiants avaient effectué les tâches d’apprentissage visées pour l’APP (élaboration d’hypothèses, manipulation de paramètres, interprétation, retour sur problème) à l’aide du dispositif hybride. Durant les EDP, la participation et les échanges entre les étudiants étaient supérieurs aux ED classiques. Etudiants et enseignants ont utilisé les fonctionnalités de l’e-ϕsioLab, permettant la production de travaux originaux et en phase avec les objectifs pédagogiques. Conclusion : Notre dispositif hybride e-ϕsioLab à forte hybridation présentiel/à distance apparaît faisable pour l’APP en physiologie. Son utilisation a révélé une forte participation des étudiants, et poussé à la transformation de l’enseignement de physiologie vers les pédagogies actives.
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Yan, Dongqing, and Golam Mohi. "Critical Role for Stat5 in the Initiation and Maintenance of Polycythemia Vera in a Jak2V617F Knock-In Mouse Model." Blood 118, no. 21 (November 18, 2011): 121. http://dx.doi.org/10.1182/blood.v118.21.121.121.
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Abstract Abstract 121 Version:1.0 StartHTML:0000000207 EndHTML:0000006199 StartFragment:0000002599 EndFragment:0000006163 SourceURL:file://localhost/Users/mohim/Desktop/ASH%202011/Dongqing%20Yan%202011%20ASH%20Abstract.doc The JAK2V617F mutation has been identified in most cases of Ph-negative myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). Expression of JAK2V617F results in constitutive activation of multiple signaling molecules/pathways. However, the key signaling downstream of JAK2V617F required for transformation, induction and maintenance of MPNs remains elusive. Using a mouse genetic strategy, we found that Stat5 is absolutely required for the pathogenesis of PV induced by Jak2V617F. Whereas inducible expression of Jak2V617F in mice resulted in all the features of human PV, including increase in red blood cells, hemoglobin, hematocrit, white blood cells, platelets, and splenomegaly, deletion of Stat5 in the Jak2V617F knock-in mice normalized all the blood parameters and the spleen size. Histopathologic analyses revealed that Stat5 deficiency blocked the development of PV in mice expressing Jak2V617F. In addition, deletion of Stat5 completely abrogated erythropoietin (Epo)-independent erythroid colony formation evoked by Jak2V617F, a hallmark feature of PV. Flow cytometric analysis revealed that concomitant deletion of Stat5 reduced the Jak2V617F-induced expansion of LSK (lin−Sca-1+c-kit+) and MEP (megakaryocyte-erythroid progenitors) as well as CD71+Ter119+ and Gr-1+Mac-1+ populations to normal levels. Unlike Jak2V617F knock-in mice, which developed myelofibrosis at old age, Stat5-deficient Jak2V617F-expressing mice failed to develop myelofibrosis. Re-expression of Stat5 in Stat5-deficient Jak2V617F knock-in mice bone marrow by retroviral transduction completely rescued the defects in transformation of hematopoietic progenitors and the PV phenotype. Furthermore, deletion of Stat5 after establishment of PV disease in the transplanted animals expressing Jak2V617F by injection with polyinosine:polycytosine (pI:pC) normalized the blood parameters and inhibited the progression of the disease. Together, these results indicate a critical function for Stat5 in the induction and maintenance of PV. Biochemical analyses revealed that Stat5 deficiency significantly inhibited constitutive phosphorylation of p70S6 kinase and markedly reduced expression of Bcl-xL, Cyclin-D2 and Pim-1 mediated by Jak2V617F. These suggest that p70S6 kinase, Bcl-xL, Cyclin-D2 and Pim-1 are downstream targets of Jak2V617F-Stat5 signaling, and they may play a role in hematopoietic transformation induced by Jak2V617F. These findings provide strong support for the development of Stat5 inhibitors as targeted therapies for the treatment of PV and other JAK2V617F-positive MPNs. Disclosures: No relevant conflicts of interest to declare.
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Arora, Sankalp, Jayastu Senapati, Naveen Pemmaraju, Prithviraj Bose, Lucia Masarova, Guillermo Montalban-Bravo, Abhishek Maiti, et al. "Five-Year Follow up Results of Phase II Clinical Trial Evaluating Ruxolitinib (RUX) and Azacitidine (AZA) Combination Therapy in Patients (pts) with Myelodysplastic Syndrome/Myeloproliferative Neoplasms (MDS/MPNs)." Blood 142, Supplement 1 (November 28, 2023): 1861. http://dx.doi.org/10.1182/blood-2023-187035.
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Introduction: MDS/MPN represent a distinct category of Philadelphia chromosome negative myeloid neoplasms that share pathological and morphological characteristics with both MDS and MPN. Very few prospective studies have been conducted in pts with MDS/MPN, with currently available data showing a median overall survival (OS) of less than two years in this challenging subset. We conducted a phase 2 clinical trial evaluating the combination of JAK-inhibitor RUX with demethylating agent AZA in pts with MDS/MPN. The interim analyses (Assi et al, AJH 2018) showed objective responses in 57% pts and a median duration of response (DOR) of 8 months (mos). Herein we report the long-term follow up of a larger cohort of pts treated on this prospective ongoing clinical trial. Methods: We conducted an open label single-arm phase 2 clinical trial (NCT01787487) at the MD Anderson Cancer Center, Houston, evaluating the use of RUX-AZA in newly diagnosed or previously treated MDS/ MPN. Adults aged ≥ 18 years with MDS/MPN categorized as Intermediate 1-2 or High-risk by Dynamic International Prognosis Scoring System (DIPSS) (Passamonti et al, Blood 2010) were included. Pts previously exposed to RUX and/or AZA were excluded. RUX 5-20mg twice daily (per RUX label depending upon platelet counts at initiation) was given in 28-day cycles, and AZA 25mg/m2 (SQ or IV) Days 1- 5 was added starting cycle 4. Cycles were repeated every 4-6 weeks depending on count recovery. Response assessment was carried out using the 2015 International Consortium Proposal of response MDS/MPN criteria (Savona M et al, Blood 2015) and best objective response was tabulated. Progression free survival (PFS) included treatment change because of disease progression or inadequate response, transformation to acute myeloid leukemia (AML) or death and calculated from the time of therapy initiation. Results: From May 2013 to August 2022, 52 pts with a median age of 68 years (range, 39-82 years) were treated on trial. The data cutoff was July 15, 2023 ( Table 1). 32 pts (61%) were males, and 9 (75%) pts were white. 50 pts (96%) had ECOG PS<2. Baseline median bone marrow (BM) blasts were 4.5% (range 0-19%), with 19 (37%) carrying JAK2 mutations, and 16 (31%) with an abnormal karyotype. Intermideate-2 DIPSS was the most prevalent risk category, seen in 23 (44%) pts. At least one cytopenia was present in 32 (61%) pts, and three (6%) pts had bicytopenia. 24 of 49 (49%) had palpable splenomegaly, and 3 pts had undergone prior splenectomy. After a median follow up of 60 months (mos) (95% CI: 50.0-71.3) from therapy initiation, 18 (35%) pts are alive, and 1 pt is on active trial therapy. Objective responses per the MDS/MPN international consensus response criteria were observed in 28 (54%) pts and included clinical improvement in 14 (50%) pts, partial marrow response in 12 (43%) pts, optimal marrow response and cytogenetic complete remission in 1 (4%) pt each. The DOR in the 28 pts with objective response to therapy (censored for death in pts who died without evidence of progression) was 35 mos (95% CI: NE-73.5). The median OS in this group of responders was 36.4 mos (95% CI: NE-77.2). Five of these pts died without confirmed disease progression at the time of death. For the full cohort the median PFS was 13.4 mos (95% CI: 7.9-18.8) and median OS was 31.8 mos (95% CI: 18.5-44.9 ) (Figure 1). Transformation to AML occurred in 12 (23%) pts, with the median time to transformation being 13.2 mos (range 2.9-71.3) and all of them have died at the time of last follow-up. 8 (15%) pts underwent allogenic stem cell transplant (ASCT) as subsequent therapy following treatment with AZA-RUX amongst whom 6 (75%) had shown objective responses prior to transplant. For the pts who underwent ASCT, median PFS from the initiation of AZA-RUX was 40.8 months and median OS was not reached. Conclusion: Long term follow up from this phase II prospective clinical trial demonstrates durable disease responses with the RUX-AZA combination in MDS/MPN, with the responses translating into improved survival outcomes.
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Hurtz, Christian, Lai N. Chan, Erica Ballabio, Cheryl L. Willman, William L. Carroll, Scott A. Armstrong, Patricia Ernst, Ari Melnick, Thomas Milne, and Markus Müschen. "Oncogenic Feedback Activation Between BCL6 and MLL Promotes Malignant Transformation in MLL-RearrangedAcute Lymphoblastic Leukemia." Blood 128, no. 22 (December 2, 2016): 907. http://dx.doi.org/10.1182/blood.v128.22.907.907.
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Abstract Background: BCL6 is known as a protooncogene and transcriptional repressor in diffuse large B cell lymphoma, where it is frequently involved in chromosomal rearrangements. We recently identified BCL6 as a novel mediator of drug resistance to tyrosine kinase inhibitors (TKI) in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloid leukemia (Duy et al., Nature 2011; Hurtz et al., J Exp Med 2011). In addition,BCL6 directly competes with the tumor suppressor BACH2 for p53 promotor binding to protecting cells from p53-mediated apoptosis in multiple ALL subgroups (Swaminathan et al., Nature Medicine 2013). Based on this, our current study is focusing on the function of BCL6 in different subtypes of human ALL. Results: Analysis of gene expression data from 207 children with high-risk B cell precursor ALL (COG P9906) showed that high expression levels of BCL6 at the time of diagnosis correlated with a poor overall and relapse-free survival (p=0.007). Furthermore, 49 matched sample pairs from patients at diagnosis and relapse showed increased BCL6 levels at relapse compared to diagnosis (p=0.003). To test whether or not there are specific subtypes of leukemia with high BCL6 expression levels, we studied BCL6 expression via western blot and immunohistochemistry staining in Non-Ph+ cell lines and ALL patient samples (n=76). Interestingly, BCL6 levels are particularly elevated in MLL-rearranged (MLLr) ALL cases. In addition, patients from the clinical trial that had high BCL6 levels and had MLL rearrangements had the worst clinical outcome (p=0.0009). We next tested if MLLr oncogenes drive aberrant BCL6 expression. First, we performed a ChIP-analysis using antibodies against MLL, AF4, and ENL, which provided evidence for direct binding to the BCL6 promoter. We then performed a BCL6 Western blot analysis of inducible MLL-AF4-transgenic and retrovirally transduced MLL-ENL pre-B cells, demonstrating that both oncogenes are sufficient to induce ~10-fold upregulation of BCL6 protein levels. Additionally, we used a newly developed conditional BCL6 knock out/reporter mouse model to decipher the function of BCL6. We transduced B cell progenitor cells from BCL6fl/fl mice with MLL-ENL and either with a control or Cre-expression vector. Using the BCL6 reporter capability of the mouse we found that BCL6 is significantly higher expressed in MLL-ENL transduced cells. To test if MLL is required for BCL6 upregulation, we used a conditional MLL knock out mouse and found that after Cre-mediated deletion of MLL, pro-B, mature-B, and MLL-AF4 transduced ALL cells almost lost the ability to upregulate BCL6. Interestingly, using inducible BCL6 transgenic and knockout as well as retrovirally transduced pre-B and ALL cells showed that overexpression of BCL6 leads to higher expression levels of MLL and deletion of BCL6 results in lower expression levels of MLL. Therefore, we conclude that MLL and BCL6 both cooperate and activate each other's expression in an activating feedback loop. Strikingly, Cre-mediated BCL6- deficiency results in apoptosis of MLL-ENL transduced cells. Clinical relevance: To verify if the high BCL6 expression levels in MLL-AF4 patients are important for the disease progression, we transduced primary human ALL xenografts with a dominant-negative BCL6-mutant (BCL6-DN). Expression of BCL6-DN rapidly induced cell cycle arrest and cell death. To test if pharmacological inhibition of BCL6 is of potential use for patients with MLLr leukemia, we treated multiple MLL-AF4 rearranged human xenograft cases with a RI-BPI a BCL6 peptide inhibitor. Strikingly, treatment with RI-BPI not only compromised colony formation in methylcellulose it also prevents leukemia-initiation in transplant recipient mice. RI-BPI also had a strong synergistic effect when combined with the chemotherapy drug Vincristine, which represents the backbone for most high risk regimen in pediatric ALL. Conclusions: These findings identify BCL6 as a central factor in leukemia initiation and survival and its pharmacological inhibition as a novel strategy to treat MLL-rearranged ALL. Aberrant expression of BCL6 in MLLr ALL is the direct consequence of the MLLr oncogenic activity in these cells. Based on these findings, we propose combinations of BCL6 inhibitors with currently used chemotherapeutics as potential approach to reduce the risk of ALL relapse and improve overall outcome. Disclosures Armstrong: Epizyme, Inc: Consultancy. Ernst:Amgen: Other: stocks. Melnick:Janssen: Research Funding.
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Ozpolat, Bulent, Ugur Akar, Magaly Barria, and Gabriel Lopez-Berestein. "PKCδ Regulates Eukaryotic Initiation Factor eIF2α through PKR during Retinoic Acid-Induced Myeloid Cell Differentiation." Blood 108, no. 11 (November 16, 2006): 1928. http://dx.doi.org/10.1182/blood.v108.11.1928.1928.
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Abstract Dysregulation of mRNA translation can contribute to malignant transformation. Translation initiation is a rate limiting step of mRNA translation and protein synthesis and plays a critical role in regulation of cell growth, proliferation and differentiation. We previously reported that ATRA induces translational suppression through multiple posttranscriptional mechanisms during terminal cell differentiation detected by proteomic analysis (Harris et al, Blood, 104 (5) 2004). Here we investigated the regulation of translation initiation and the role of eIF2α during terminal differentiation of myeloid leukemia cells. We found that ATRA and other granulocytic differentiation inducing agents, such as dimethyl sulfoxide (DMSO), arsenic trioxide (ATO) induce phosphorylation of eIF2α on serine 51 in promyelocytic leukemia (NB4) cells, indicating the suppression of translation initiation. However, monocytic/macrophagic differentiation of NB4 cells by phorbol 12-myristate 13-acetate (phorbol ester, PMA), or by ATRA in U937 and THP-1 myelomonoblastic myeloid leukemia (AML) cells, was not accompanied with induction of eIF2α phosphorylation. ATRA, ATO or DMSO-induced granulocytic differentiation closely correlated with induction of expression and phosphorylation/activation of protein kinase C-delta (PKCδ) on threonin 505 and serine 643 in NB4 cells. The specific PKCδ inhibitor, rottlerin, markedly inhibited ATRA-induced expression and phosphorylation (serin 51) of eIF2a in NB4 cells. Rottlerin reduced phosphorylation of eIF2α expression not only in the leukemia cells but also in solid tumor cells such as breast (MCF7) and pancreatic (Panc28) cancer cells. Because protein kinase R (PKR) has been shown to inhibit mRNA translation by inducing phosphorylation of eIF2α, we also examined whether this pathway is involved in ATRA-induced phosphorylation of eIF2α and whether it is downstream of PKCδ. We observed that ATRA induces expression and phosphorylation/activation of PKR in NB4 cells. Rottlerin inhibited ATRA-induced expression and activity of PKR , suggesting that activity of PKR is regulated by PKCδ in response to ATRA in NB4 cells. Overall, our data suggest that retinoic acid suppresses translation initiation through PKCδ/PKR/eIF2α pathway during granulocytic but not monocytic differentiation of acute myeloid leukemia cells. These results revealed a novel role of ATRA in granulocytic cell differentiation of myeloid cells. Because malignant cells usually have hyperactivated mRNA translation, targeting translational factors/regulators of initiation may offer new strategies for the treatment of myeloid leukemia cells.
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Minami, Yosuke, Scott A. Stuart, Tomokatsu Ikawa, Akihiro Abe, Tomoki Naoe, Catriona H. M. Jamieson, and Jean Y. J. Wang. "Transformation of E2A-Deficient Pluripotent Progenitors by BCR-ABL Generates Imatinib-Resistant Leukemic Stem Cells." Blood 112, no. 11 (November 16, 2008): 1342. http://dx.doi.org/10.1182/blood.v112.11.1342.1342.
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Abstract Chronic myeloid leukemia (CML) is effectively treated with imatinib (imatinib mesylate, IM), a small molecule inhibitor of the BCR-ABL tyrosine kinase that is expressed in the entire hematopoietic compartment including stem cells (HSC) and progenitors. However, it is still unclear whether IM-therapy is able to eradicate BCR-ABL-positive HSC and progenitors. By transforming murine E2A-deficient pluripotent hematopoietic cells (Ikawa, et al., Immunity 04) with p210BCR-ABL, we determined that as few as 50 granulocyte macrophage progenitors (GMP)-like cells were sufficient to induce a transplantable CML-like disease in congenic mice, and that the leukemogenic GMP displayed higher levels of β-catenin activity than either the non-transformed GMP or the transformed nonGMP (most of which were myeloid differentiated cells), both in culture and in transplanted mouse bone marrow (Proc Natl Acad Sci USA 08, in press). The initiation of transformation required BCR-ABL kinase activity; however, whereas transformed nonGMP were sensitive to IM-treatment, expansion and survival of the leukemogenic progenitors in ex vivo-culture or in mice were not completely inhibited by IM-treatment. The drug resistance did not correlate with higher levels of BCR-ABL, mutations at ABL-kinase domain, induction of quiescence, stromal support or drug efflux. Additionally, the differential responses between the transformed progenitors and differentiated cells to IM-treatment were not affected by the restoration of E2A-function. These results imply that leukemic progenitors possess innate resistance to IM and that eradication of these cells with other drugs is required to cure CML. We are also investigating BCR-ABL-positive residual disease in HSC and progenitors of chronic phase CML patients on IM-therapy.
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Chan, Lai N., Christian Hurtz, Gang Xiao, Seyedmehdi Shojaee, Rebecca Caeser, Huimin Geng, Ari Melnick, and Markus Müschen. "BCL6 Is Critical to Overcome Oncogene-Induced Senescence in RAS-Mediated B Cell Transformation." Blood 128, no. 22 (December 2, 2016): 438. http://dx.doi.org/10.1182/blood.v128.22.438.438.
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Abstract Background and Hypothesis: The transcriptional repressor and proto-oncogene BCL6 is a therapeutic target in subtypes of diffuse large B cell lymphoma (DLBCL) and modulates drug-resistance in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL; Duy et al., Nature 2011). BCL6 was shown to be a critical factor that bypasses p53-dependent senescence and thereby enables RAS-driven transformation of mouse embryonic fibroblasts (Shvarts et al., Genes Dev. 2002). Given that ~50% of pediatric ALL cases carry genetic lesions that lead to hyperactivated RAS-ERK signaling (Zhang et la., Blood 2012), we examined the role of BCL6 in RAS-driven pre-B ALL and identified a novel mechanism by which RAS-ERK signaling can mediate BCL6 expression. Results: Using a doxycycline-inducible TetOn- NRASG12D vector system, we found that inducible activation of RAS-ERK signaling strongly upregulated BCL6 expression at both the mRNA (~350-fold) and protein (~50-fold) levels in murine pre-B cells. Increases in BCL6 expression were abrogated upon treatment with a MEK inhibitor (PD325901). In addition, Cre-mediated deletion of Mapk1 suppressed upregulation of BCL6 expression upon imatinib treatment in BCR-ABL1-driven pre-B ALL cells. These findings suggested that elevated expression of BCL6 is a consequence of ERK activation. Previously, we demonstrated that BCL6 expression is negatively regulated by STAT5 in BCR-ABL1 pre-B ALL (Duy et al., Nature 2011). Interestingly, oncogenic NRASG12D inhibited phosphorylation of STAT5-Y694 by activating the inhibitory protein tyrosine phosphatase Ptpn6. Cre-mediated deletion of Ptpn6 induced STAT5 activity. Furthermore, loss of Ptpn6 function abrogated upregulation of BCL6 expression induced by imatinib in BCR-ABL1 pre-B ALL. Taken together, RAS-ERK signaling induces BCL6 expression by suppressing STAT5 activity. To directly test the role of BCL6 in RAS-transformed pre-B ALL, we generated a novel mouse model for inducible Cre-mediated deletion of Bcl6 exons 5-10, flanked by loxP sites. Inducible deletion of Bcl6 in NRASG12D-transformed pre-B ALL cells led to rapid depletion from the cell culture and reduced colony forming ability in vitro. These findings suggested that BCL6 is required for maintenance of fully established RAS-transformed ALL. Notably, we found that initiation of NRASG12D-driven leukemia in vivo depends on BCL6 as NRASG12D ALL failed to give rise to leukemia in the absence of Bcl6 in transplant recipient mice. Studying a diagnostic (KRAS wild-type) and a relapsed (KRASG12V) sample from one pre-B ALL patient revealed increased BCL6 expression in KRASG12V relapsed ALL cells. In addition, selective sensitivity to PD325901 and a retro inverso BCL6 peptide inhibitor (RI-BPI) was observed in KRASG12V relapsed ALL cells. Finally, RI-BPI prolonged overall survival of recipient mice transplanted with KRASG12V relapsed ALL cells in vivo. Conclusions: In summary, we demonstrated a novel mechanism by which oncogenic RAS signaling induces expression of BCL6, and showed that BCL6 is critical for RAS-driven transformation in pre-B ALL. Importantly, ALL clones often acquire drug resistance and activating mutations in the RAS pathway (Bhojwani and Pui, Lancet Oncol. 2013). Our findings suggest that pharmacological inhibition of BCL6 may provide a novel therapeutic avenue to overcome drug-resistance and prevent leukemia relapse after initial remission in RAS-driven ALL. Disclosures Melnick: Janssen: Research Funding.
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Lee, Christine Shu Mei, Kristen L. Estabrooks, Kaitao Lai, Agnibesh Dey, Jonathan Cheng, Shane Whittaker, Chuen Wen Tan, et al. "Procoagulant Platelet Subpopulation As a Novel Predictive Biomarker of Poor Outcomes in Essential Thrombocythemia." Blood 138, Supplement 1 (November 5, 2021): 3622. http://dx.doi.org/10.1182/blood-2021-152075.
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Abstract Background: Patients with essential thrombocythemia (ET) remain at risk of significant thrombotic complications, despite use of validated risk stratification and treatment pathways. Procoagulant platelets, a platelet subpopulation which supports thrombin generation, are elevated in prothrombotic conditions. We hypothesize that ET patients exhibit high procoagulant platelet potential and the procoagulant platelet subset may be a biomarker for risk of poor disease outcomes, enabling identification of patients for therapeutic escalation. Methods: 70 ET patients, 20 polycythemia vera (PV) patients and 32 age-matched healthy controls were recruited at Concord Hospital, Australia and Singapore General Hospital (development cohort). Outcome data including thrombosis, death and transformation to myelofibrosis and acute leukemia were prospectively collected. Procoagulant platelets were measured by uptake of a tripeptide trivalent arsenical (GSAO) combined with P-selectin expression by flow cytometry, with or without stimulation with increasing thrombin concentrations (0.5-5 U/mL) ± 10 µg/mL collagen, in whole blood samples. a Flow cytometry data were analyzed using both standard and a multiparameter clustering approach (FlowSOM) with FlowJo software. A hypergate algorithm based on fluorescence intensity of six parameters was developed using R programming language to enumerate a novel GSAO+ platelet subpopulation in each patient flow cytometry dataset. Time to event analysis was performed on cohorts defined by receiver operating characteristics (ROC) analysis identified cut-off for the subpopulation, with clinician adjudication of outcomes blinded to biomarker data. 25 consecutive ET patients were subsequently recruited from Concord Hospital outpatient clinics in a prospective validation study for an independent time to event analysis. Results: ET (n=70) and PV (n=20) patients in the development cohort demonstrated marked increased GSAO+/P-selectin+ procoagulant response to thrombin±collagen compared to healthy controls (n=32), segregating according to JAK2 V617F mutation status (Figure 1). Multivariate analysis (age, sex, thrombosis history, cardiovascular risk factors, hydroxyurea, platelet and leukocyte counts and mutation status) demonstrated that only male sex (p=0.013) and JAK2 V617F mutation (p=0.004) were independent predictors of thrombin response in ET. FlowSOM analysis identified a high GSAO+ platelet subpopulation significantly overexpressed in ET patients with thrombosis history (p=0.001). A ROC curve to evaluate the high GSAO+ platelet subpopulation as a predictor of disease transformation and/or death yielded a higher predictive value than the total GSAO+/P-selectin+ population (AUC of 0.9022, p=0.0081, Figure 2A). Prospective follow up with time to event analysis (development cohort) showed a ROC derived cut-off of 2.09% GSAO+ subpopulation at time of recruitment (100% sensitivity, 73.9% specificity) was predictive of death and/or disease transformation (p=0.0006, Figure 2B) or new thrombotic events (p=0.0026, Figure 2C) in patients already on primary or secondary prevention therapy. In the validation cohort, time to event analysis (n=25, median time to census 20 months, range 2.7-30) demonstrated a hazard ratio of 7.3 (95% CI: 1.4 to 37.4, p=0.02, Figure 2D) for new thrombotic events with GSAO+ subpopulation of >2.09%, independent of potential covariates (mutation status, IPSET score, historical thrombosis, anti-platelet therapy). In 3 of 3 patients in which biomarker bloods were collected at clinical review for thrombosis prior to initiation of therapy, the GSAO+ subpopulation was markedly increased and then reduced following disease modification therapy. Conclusion: This study, including validation in a small prospective cohort with pre-specified outcomes, identifies a high GSAO+ platelet flow cytometry subpopulation as a potential novel risk stratification marker for transformation and/or recurrent thrombotic events in ET. The biomarker can be collected at multiple timepoints during a patient's clinical course for dynamic risk assessment and early data suggests utility in monitoring response to therapy. Larger multisite studies to evaluate the hypergate performance as a biomarker for poor outcomes in patients with ET appear warranted. aPasalic et al. J Thromb Haemost. 2018 Jun;16(6):1198-1210. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Li, Qiang, Christian Hurtz, Seyedmehdi Shojaee, Zhengshan Chen, Huimin Geng, Gang Xiao, Mignon L. Loh, B. Hilda Ye, Ari Melnick, and Markus Muschen. "Identification of BCL6 As a Therapeutic Target in RAS-Driven Acute Lymphoblastic Leukemia." Blood 126, no. 23 (December 3, 2015): 556. http://dx.doi.org/10.1182/blood.v126.23.556.556.
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Abstract Background & Hypothesis: In ~50% of cases of acute lymphoblastic leukemia, activating lesions in RAS pathway are found. These lesions are particularly frequent in relapse ALL and specifically acquired in the relapse clone (Irving et al., 2013). A previous study of senescence rescue screens identified the transcriptional repressor BCL6 as a key factor to overcome p53 dependent senescence and enable RAS-mediated transformation of mouse embryonic fibroblasts (Shvarts et al. 2002). Using peptide inhibitors and small molecules that interfere with the ability of BCL6 to recruit essential corepressors, we and others recently demonstrated that therapeutic targeting of BCL6 in BCL6-dependent malignancies is feasible. Here we tested the hypothesis that BCL6 represents a therapeutic target in multiple subsets of ALL, including ALL with RAS pathway lesions. Results: In support of this hypothesis, we found that inducible expression of oncogenic NRASG12D increased BCL6 mRNA levels by ~350-fold (qRT-PCR) and protein levels by ~50-fold (Western blot). Upregulation of BCL6 in response to NRASG12D activation was sensitive to treatment with the MEK kinase inhibitor PD325901 and correlated with levels of phospho-ERK downstream of MEK. These findings suggest that BCL6 expression is a result of ERK activation downstream of oncogenic NRASG12D and MEK in ALL cells. To verify this observation in patient-derived cells, we compared ALL cells that were isolated at the time of initial diagnosis (D), and at the time of relapse (R) from the same patient. Interestingly, the patient had acquired a KRASG12V mutation at the time of relapse. As a likely consequence, we found both hyper-phosphorylation of ERK and overexpression of BCL6 in the relapse cells (KRASG12V), but not in diagnosis sample (KRAS wild-type). R-ALL cells harboring the KRASG12V mutation were more sensitive to the treatment with the MEK inhibitor PD325901 and the BCL6 peptide inhibitor RI-BPI than D-ALL cells. BCL6 inhibition also markedly increased survival rate of NOD/SCID mice xenografted with R-ALL cells. These results suggested BCL6 served as an important contributor to RAS -mediated transformation. To further study the mechanistic role of BCL6 in RAS-mediated pre-B cell transformation, we tested its function in a mouse ALL model. Pre-B cells from both Bcl6+/+ and Bcl6-/- mice could be transduced by NRASG12D and achieved growth-factor independence under cell culture conditions. However, Bcl6-/- NRASG12D ALL cells failed to initiate fatal leukemia in NOD/SCID transplant recipient mice, whereas Bcl6+/+ NRASG12D ALL cells gave rise to lethal leukemia in all transplant recipients. Studying Cre-mediated deletion of Bcl6-fl/fl alleles in a complementary mouse model revealed that continuous presence of Bcl6 function is required for normal proliferation of ALL cells. Cre-mediated ablation of BCL6 in NRASG12D driven ALL induced rapid cell death and completely abrogated the ability of NRASG12D ALL cells to form colonies. Conclusion: These results support that BCL6 is not only required for the initiation of RAS-transformed ALL in vivo but also for the maintenance of fully established RAS-driven leukemia. The findings provide genetic evidence for BCL6 function as a critical cofactor of RAS-mediated transformation in human ALL. Inhibition of BCL6 in RAS-driven ALL may be useful to prevent leukemia relapse after initial remission (Bcl6-dependent leukemia-initiation) and also to achieve remission by combining conventional cytotoxic therapies with currently available BCL6 inhibitors (e.g. RI-BPI peptide inhibitor or FX-1085 small molecule inhibitor). Disclosures No relevant conflicts of interest to declare.
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Maura, Francesco, Even H. Rustad, Niccolò Bolli, Venkata Yellapantula, Daniel A. Leongamornlert, Ferran Nadeu, Nicos Angelopoulos, et al. "Timing the Initiation of Multiple Myeloma." Blood 134, Supplement_1 (November 13, 2019): 573. http://dx.doi.org/10.1182/blood-2019-124357.
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INTRODUCTION: Cancer pathogenesis is usually characterized by a long evolutionary process where genomic driver events accumulate over time, conferring advantage to distinct subclones, allowing their expansion and progression. METHODS: To investigate the multiple myeloma (MM) evolutionary history, we characterized the mutational processes' landscape and activity over time utilizing a large cohort of 89 whole genomes and 973 exomes. To improve the accuracy of mutational signatures analysis, we analyzed both the 3' and 5' nucleotide context of each mutation and we developed the novel fitting algorithm mmSig, which fits the entire mutational catalogue of each patient with the mutational signatures involved in MM pathogenesis. The contribution of each mutational signature was then corrected based on the cosine similarity between the original 96-mutational profile and the reconstructed profile generated without that signature. To reconstruct the genetic evolutionary history of each patient's cancer, we integrated two approaches. First dividing all mutations into clonal (early) or subclonal (late), then subdivided the clonal mutations into duplicated mutations (present on two alleles and therefore acquired before the duplication) or non-duplicated mutations (detected on a single allele), reflecting either pre-gain and post-gain mutations on the minor allele, or post-gain mutations acquired on one of the duplicated alleles. RESULTS Eight mutational signatures were identified, seven of which showed significant similarity with the most recent mutational signature catalogue (i.e SBS1, SBS2, SBS5, SBS8, SBS9, SBS13 and SBS18). The new mutational signature (named SBS-MM1) was observed only among relapsed patients exposed to alkylating agents (i.e melphalan). The etiology of this specific signature was further confirmed by analyzing recent whole genomes public data from human-induced pluripotent stem cells exposed to melphalan (Kucab et al, Cell 2019). Reconstructing the chronological activity of each mutational signature, we identified four different routes to acquire the full mutational spectrum in MM based on the differential temporal activity of AID (SBS9) and APOBEC (SBS2 and SBS13). Our data indicate that AID activity is not limited to the first contact with the GC, but persists in the majority of patients, behaving similarly to a B-memory cells, capable of re-entering the germinal center upon antigen stimulation to undergo clonal expansion several times before MM diagnosis. Next, we confirmed the clock-like nature (i.e constant mutation rate) of SBS5 in MM and other post-germinal center disorders such as chronic lymphocytic leukemia and B-cell lymphomas. Based on the SBS5 mutation rates and the corrected ratio between duplicated and non-duplicated mutations within large chromosomal gains, we could time the acquisition of the first copy number gain during the life history of each MM patient. Intriguingly, the first MM chromosomal duplication was acquired on average 38 years (ranges 11-64) before sample collection. In 23/27 (85%) cases the first multi gain event occurred before 30 years of age, and in 13/27 (48%) before 20 years reflecting a long and slow process potentially influenced and accelerated by extrinsic and intrinsic factors. DISCUSSION Our analysis provides a glimpse into the early stages of myelomagenesis, where acquisition of the first key drivers precedes cancer diagnosis by decades. Defining the time window when transformation occurs opens up for new avenues of research: to identify causal mechanisms of disease initiation and evolution, to better define the optimal time to start therapy, and ultimately develop early prevention strategies. Disclosures Bolli: CELGENE: Honoraria; JANSSEN: Honoraria; GILEAD: Other: Travel expenses. Corradini:Janssen: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria; KiowaKirin: Honoraria; Servier: Honoraria; Takeda: Honoraria, Other: Travel Costs; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Gilead: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; BMS: Other: Travel Costs. Anderson:Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Other: Scientific Founder; Oncopep: Other: Scientific Founder; Amgen: Consultancy, Speakers Bureau; Sanofi-Aventis: Other: Advisory Board. Moreau:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Papaemmanuil:Celgene: Research Funding. Avet-Loiseau:takeda: Consultancy, Other: travel fees, lecture fees, Research Funding; celgene: Consultancy, Other: travel fees, lecture fees, Research Funding. Munshi:Adaptive: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Oncopep: Consultancy; Abbvie: Consultancy. Landgren:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Theradex: Other: IDMC; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
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Ropa, James, Nirmalya SAHA, and Andrew G. Muntean. "SETDB1 Represses Hox Gene Expression and Suppresses Acute Myeloid Leukemia." Blood 132, Supplement 1 (November 29, 2018): 1320. http://dx.doi.org/10.1182/blood-2018-99-117690.
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Abstract Epigenetic regulators play an important role in normal and malignant hematopoiesis. Epigenetic deregulation of the HOXA gene cluster drives transformation of about 50% of acute myeloid leukemia (AML), including those harboring MLL rearrangements and NPM mutations, as well as others. Expression of Hoxa9 and its co-factor Meis1 is sufficient to transform bone marrow into a lethal AML in mouse models. We previously demonstrated that the pro-leukemic genes Hoxa9 and Meis1 are critically regulated by the histone H3 Lysine 9 (H3K9) methyltransferase SETDB1. Recent studies show that SETDB1 is required for normal hematopoiesis and MLL-AF9 mediated leukemia (Koide, et al. Blood 2016). Our lab recently demonstrated that SETDB1 negatively regulates the expression of HoxA9 and Meis1 through deposition of promoter H3K9 methylation in MLL-AF9 AML cells (Ropa et al. Oncotarget 2018). Consistent with these data, HOXA9 and MEIS1 expression negatively correlates with SETDB1 expression in AML patient samples. Therefore, we investigated the biological impact of SETDB1 on AML. We first noted that expression of SETDB1 in AML patient samples is significantly lower compared to normal hematopoietic cells. Further, higher SETDB1 expression correlated with a significantly better overall survival (p=0.003) and lower expected hazard (HR=0.9/100RSEM; p=0.009) in AML patients compared with lower SETDB1 expression. These data are consistent with SETDB1 negatively regulating pro-leukemic genes and suggests that SETDB1 expression may be correlated with AML patient prognosis. We tested this directly by expressing high levels of SETDB1 in AML cells. Ex vivo assays show that retroviral overexpression of SETDB1 in MLL-AF9 AML cells leads to cell differentiation, decreased leukemia colony formation, and decreased cell proliferation. Consistent with the AML patient data, overexpression of SETDB1 significantly delays MLL-AF9 mediated leukemogenesis in vivo (p=0.01). Further, we observed a strong selective pressure against exogenous SETDB1 expression in moribund mice. Transcriptome analyses demonstrate that SETDB1 globally represses Hox and pluripotency gene programs. Strikingly, we found that SETDB1 represses many of the same genes that exhibit reduced promoter H3K9me3 in AML patient samples relative to CD34+ cells. These data point to a role for SETDB1 in negatively regulating pro-leukemic target genes and suppressing AML. We also explored how chemical and genetic inhibition of H3K9 methylation and Setdb1 affects AML initiation and maintenance. We first confirmed the previously reported requirement for Setdb1 in AML cell lines by genetically deleting both alleles of Setdb1 in MLL-AF9 cells, which resulted in a complete arrest of proliferation (Koide, et al. Blood 2016). Combined with our data presented above, these results suggest a narrow window of SETDB1 expression is maintained in AML cells. To achieve reduced (but not complete loss of) activity, we investigated how small molecule inhibition of H3K9 methylation (UNC0638) or shRNA mediated knock down of Setdb1 affects AML initiation. We observed increased ex vivo colony formation of normal ckit+ bone marrow cells upon shRNA mediated knockdown of Setdb1 or upon UNC0638 treatment. We hypothesized that this expansion of colony forming unit potential of hematopoietic cells may translate to increased transformation potential by leukemic oncogenes. Indeed, cells pretreated with UNC0638 followed by retroviral transduction with MLL-AF9 exhibit significantly higher capacity for leukemic colony formation than vehicle treated cells. These data are consistent with H3K9 methylation repressing genes required for AML transformation. Our data identified a narrow window of expression of SETDB1 in AML patient samples. SETDB1 expression is reduced in AML patients relative to normal cells and chemical inhibition of H3K9 methylation expands the pool of cells amenable to MLL-AF9 mediated transformation ex vivo. While inhibition of SETDB1 and other H3K9 methyltransferases has been suggested as a possible therapeutic strategy, our data suggests this may also prime bone marrow cells for transformation by inhibiting epigenetic processes that repress pro-leukemic target genes. Further investigation of the roles of SETDB1 and H3K9 methylation levels is necessary to determine the value of these epigenetic modifiers as therapeutic targets in AML and is currently ongoing. Disclosures No relevant conflicts of interest to declare.
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Chan, Lai N., Christian Hurtz, Etienne Leveille, Kohei Kume, Mark E. Robinson, Huimin Geng, Kadriye Nehir Cosgun, and Markus Müschen. "Identification of BCL6 As Synthetic Lethality in RAS-Driven B-Cell Transformation." Blood 138, Supplement 1 (November 5, 2021): 792. http://dx.doi.org/10.1182/blood-2021-148653.
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Abstract Background: Genetic lesions in the RAS-ERK pathway (NRAS, KRAS, RAF1, MAP2K1, PTPN11, NF1) are oncogenic drivers in ~40% of B-cell acute lymphoblastic leukemia (B-ALL) cases and are associated with chemoresistance and relapse. During normal B-cell development, persistent activation of RAS-ERK-signaling induces negative B-cell selection and cell death (Yasuda et al., 2011). The deleterious effect of persistent RAS-ERK signaling is mainly caused by PRDM1-mediated repression of BCL6 (Setz et al., 2018). Hence, the tumor suppressor PRDM1 and the proto-oncogene BCL6 are reciprocal antagonists during B-cell development (Shaffer et al., 2002). Genetic lesions that cause permanent activation of the RAS-ERK pathway in B-ALL would be expected to cell death as in normal B-cell development. Here we examined the mechanistic basis of how oncogenic activation of RAS-ERK signaling in B-ALL not only avoids cell death but also promotes malignant transformation. Results: Strikingly, doxycycline-inducible expression of NRAS G12D in murine B-cell precursors, resulted on dramatic increases of BCL6 mRNA (~390-fold) and protein (~50-fold) levels, which came at the expense of PRDM1. For these reasons, we explored mechanisms underpinning transactivation of BCL6 and tested whether RAS-dependent induction of BCL6 represents a mechanism to oppose PRDM1-mediated cell death. Consistent with transactivation of BCL6 downstream of ERK-activation, ChIP-seq analysis revealed binding of ERK-dependent transcription factors (CREB1, ELK1, EGR1, JUND and C-JUN) to the BCL6 promoter in human B cells. Highlighting an essential role of Erk-signaling in RAS-mediated upregulation of Bcl6 expression, pharmacological ERK-inhibition abrogated NRAS G12D-mediated Bcl6 induction. Likewise, Erk2-deletion abolished the ability of B-ALL cells to induce expression of Bcl6. Furthermore, pharmacological activation of ERK (BCI-215) markedly induced BCL6 expression. Together, these findings reveal a new pathway of BCL6-activation in B-ALL cells that depends on oncogenic RAS-ERK-signaling. To address the mechanistic role of BCL6 in RAS-driven B-ALL, we established a genetic model for Cre-mediated deletion of Bcl6 in NRAS G12D B-ALL cells. Genetic ablation of Bcl6 resulted in rapid depletion of B-ALL cells and compromised colony formation. Notably, Bcl6-deletion prevented leukemia-initiation in transplant recipient mice (P=0.007). Furthermore, patient-derived RAS-driven B-ALL cells were highly sensitive to pharmacological inhibition of BCL6 using peptide (RI-BPI) and small molecule (FX1) inhibitors. Importantly, treatment with RI-BPI delayed onset of fatal disease and prolonged survival of transplant recipient mice (P=0.009). We then tested whether targeting BCL6 can be leveraged in combination with existing treatment regimen and found that RI-BPI potentiated the effects of vincristine on killing patient-derived RAS-driven B-ALL cells. Hence, BCL6 represents a previously unrecognized therapeutic target in RAS-driven B-ALL that can be leveraged to sensitize to conventional chemotherapy. Mechanistically, genetic ablation or pharmacological inhibition of BCL6 increased expression of PRDM1 in RAS-driven B-ALL cells. shRNA-mediated knockdown of Prdm1 rescued Bcl6-deficiency in RAS-driven B-ALL cells. While Bcl6-deletion resulted in cell death of B-ALL cells, this was largely reversed by loss of Prdm1. Altogether, our findings suggest that compromised leukemogenesis was a result of aberrant PRDM1 expression in BCL6-deficient RAS-driven B-ALL cells. Conclusions: While permanent activation of the RAS-ERK pathway induces negative selection and cell death in normal B-cell precursors owing to excessive activation of the PRDM1 tumor suppressor, B-ALL cells carrying RAS-activating lesions have evolved a mechanism to evade PRDM1-mediated cell death by massive (>300-fold) upregulation of BCL6. In RAS-driven B-ALL, oncogenic expression of BCL6 suppresses PRDM1 and enables malignant transformation. Importantly, BCL6 expression in RAS-driven B-ALL represents a previously unrecognized synthetic lethality. Hence, peptide and small molecule inhibition of BCL6 de-represses PRDM1, reconstitutes PRDM1-dependent tumor suppression and represents a selective vulnerability in RAS-driven B-ALL cells that can be leveraged to overcome conventional mechanisms of drug-resistance in refractory B-ALL. Disclosures No relevant conflicts of interest to declare.
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Freeman, Ciara Louise, Kerry J. Savage, Diego Villa, David W. Scott, Alina S. Gerrie, David J. Ferguson, Fergus Cafferty, et al. "Frontline Therapy with Bendamustine and Rituximab (BR) in Follicular Lymphoma: Prognosis Among Patients with Progression of Disease By 24 Months (POD24) Is Poor with Majority Having Transformed Lymphoma." Blood 132, Supplement 1 (November 29, 2018): 2873. http://dx.doi.org/10.1182/blood-2018-99-113675.
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Abstract Background: Bendamustine and rituximab (BR) has been a preferred regimen for frontline therapy of patients (pts) with advanced stage follicular lymphoma (FL) since randomized trials demonstrated both favorable efficacy and toxicity profiles (Rummel et al 2013, Flinn et al 2014). However, the incidence of transformation and outcomes of pts with early progression within 24 months (POD24) after BR remain poorly documented. Since 2013, BR has been the recommended frontline therapy for all pts with advanced stage, symptomatic FL in British Columbia (BC). We report this population-based analysis evaluating outcomes following the introduction of BR, including the incidence of transformation and POD24, compared to a historical cohort of pts treated with frontline RCVP. Methods: The BC Lymphoid Cancer Database was used to identify all FL pts treated with frontline BR prior to April 1st 2018. A period of observation prior to systemic therapy was permitted, but pts were excluded if they received prior radiation or single-agent rituximab. All pts had pathologically confirmed FL grades 1-3A and symptomatic advanced stage disease (Ann-Arbor I/II if too bulky/not amenable to radiation or stage III-IV). Pts were excluded if they were HIV positive or had documented discordant/composite lymphoma. Event-free survival (EFS), overall survival (OS), and time-to-transformation (TTTF) were calculated from the date of initiation of systemic therapy. Early progression (POD24) was defined as relapse or progression, death from lymphoma or treatment toxicity within 24 months of initiation of systemic therapy. Outcomes were compared with a historical cohort of pts treated with frontline RCVP, which was the recommended induction prior to BR. All pts were eligible to receive rituximab maintenance, which is standard of care for responding pts post-induction therapy in BC. Results: A total of 296 BR-treated pts were identified with a median age of 61 years (range 24-86) and baseline characteristics as outlined in Table 1. Only 34 (11%) had been previously observed and 239 (81%) received rituximab maintenance. A historical cohort of 347 RCVP-treated pts was identified, with comparable clinical characteristics but longer duration of follow-up (median 8.4y, range 0.6-12.6). With a median follow-up for living pts of 2.8y (range 0.2-7.6), estimates for 2-y EFS and OS were 85% (95% CI 80-89%) and 92% (95% CI 88-95%), respectively, for BR-treated pts. As expected, use of BR was associated with an improvement in EFS compared with RCVP (2-y EFS 76% [95% CI 71-80%], p=0.001), but no difference in OS with current follow-up. A total of 28 (9%) transformations have occurred in BR-treated pts, 68% of which were documented histologically. Only elevated LDH was associated with increased risk of transformation (p<0.001). Compared with RCVP-treated pts, the incidence of transformation over time appears similar with current follow-up (Figure 1). Post-transformation outcome in BR-treated pts was poor, with 2-y OS 39% (95% CI 18-59). Early progression (POD24) has occurred in 35/296 (12%) of BR-treated pts. The majority of these, 27 (77%), had transformed lymphoma. Five POD24 pts (14%) died of lymphoma or treatment toxicity without documented transformation and 3 (9%) had relapse with FL and are still alive at last follow up. By comparison, POD24 occurred in 77/347 (22%) of RCVP-treated pts: comprising 31 (40%) transformed lymphoma, 27 (35%) died of lymphoma or treatment toxicity without documented transformation and 19 (25%) relapsed with FL and are still alive at last follow up. Outcome in BR-treated pts with POD24 was poor, with post-progression 2y OS 38% (95% CI 20-55%) compared to non-POD24 BR-treated patients (Figure 2). Conclusion: This population-based analysis demonstrates that in the absence of transformation or POD24, pts with advanced stage FL have excellent outcomes after frontline BR. The use of BR has not changed the rate of transformation compared with that seen after frontline RCVP, with limited follow-up. The occurrence of early progression (POD24) may be decreasing following the introduction of BR, but the majority of POD24 pts now have transformed lymphoma. As a consequence, only a small proportion of POD24 pts following BR have FL-only relapse that may be considered for novel approaches specific for FL. A greater impact on outcome for POD24 pts after BR will require early prediction and improved treatment of transformed lymphoma. Disclosures Freeman: Seattle Genetics: Honoraria; Abbvie: Honoraria. Scott:NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding; Janssen: Research Funding; Celgene: Consultancy, Honoraria; Roche: Research Funding. Connors:Merck: Research Funding; Janssen: Research Funding; Bristol Myers-Squibb: Research Funding; Cephalon: Research Funding; NanoString Technologies: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding; Bayer Healthcare: Research Funding; Genentech: Research Funding; Lilly: Research Funding; Seattle Genetics: Honoraria, Research Funding; F Hoffmann-La Roche: Research Funding; Roche Canada: Research Funding; Takeda: Research Funding; Amgen: Research Funding. Sehn:Karyopharm: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.
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Bojko, Peter, Wolfgang Abenhardt, Susanne Schnittger, and Torsten Haferlach. "Analysis of the V617F Mutation of the JAK2- and the W515 Mutation of the MPL Gene in Patients with Chronic Myeloproliferative Disease (CMPD) Treated in an Outpatient Practice." Blood 110, no. 11 (November 16, 2007): 4631. http://dx.doi.org/10.1182/blood.v110.11.4631.4631.
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Abstract Background: Patients (pts) treated in a private oncology practice for various subtypes of CMPD were studied for the V617F mutation of the JAK2 gene and the W515 mutation of the MPL gene to compare clinical and hematological data with mutational status. Results: 51 pts (29 female; 22 male) were screened and 46 pts were analyzed. Median age was 62 ± 13.7 yrs. 27 pts. are diagnosed with Essential Thrombocytemia (ET), 21 pts with Polycythemia vera (PV), 2 pts with Osteomyelofibrosis (CIMF), 2 pts with Chronic Myelo-Monocytic Leukemia (CMML), 1 pt with Hypereosinophilic Syndrome (HES) and 1 pt was not further specified. 3 pts were diagnosed with both ET and PV. 48 pts are currently treated with cytoreductives (hydoxyurea, anagrelide, oral melphalan) phlebotomy or both, and recent irradiation of the spleen, respectively. The mean time from diagnosis to start of treatment was 10.9 ± 23.5 months (range, 0–120 months) for all pts. The median duration of treatment at the time of analysis was 39 months (range, 0–198 months). The median number of treatment regimens is 1 per pt (range, 1–3). Overall, 25 pts (49%) had a JAK2- and 1 pt with ET (2%) a MPL gene mutation. Among pts with PV 12/18 pts (67%; 3 pts not analysed) had mutated JAK2. For ET pts the corresponding number was 15/25 (60%, 2 not analysed). Among the remaining pts, 1 pt with CIMF showed the JAK2 mutation, too. There was no significant difference of the hematocrit at the time of diagnosis in JAK2 mutated and unmutated pts with PV (mean 56.1% ± 7.0% vs 52.7% ± 3.4%, p=0.377). Similar, pts with ET had similar platelet counts at the time of first diagnosis, irrespective of their mutational status (925/nl ± 245/nl vs 790/nl ± 153/nl, p=0.168). The time from first diagnosis to initiation of any specific treatment was 10.1± 25.2 months (range, 0–120 months) and 11.9 ± 21.7 months (range, 0–84 months) for pts with- and without JAK2 mutation, respectively (p=0.795). In summary, our results with 67% JAK2 mutations in PV pts and 60% in ET pts differ from those of other studies (90- and 30%, respectively). In addition to the limited pt number, difficulty in accurate diagnosis of subtypes of MPD, especially in the early course of the disease, could be another explanation. There was no significant difference in clinical relevant parameters as hematocrit, platelet count and time to initiation of any specific treatment in pts with or without mutation of the JAK2 gene. Thus, prognostic relevance of this mutation is still not clear and should be correlated in those pts that undergo transformation to acute leukemia, for example. One potential issue, however, is the development of drugs targeted at this mutated cytoplasmic tyrosine kinase. There was only 1 pt with ET showing the W515 mutation of the MPL gene, which is in accordance with published data, describing mutations in about 1% of pts with ET. No pt with PV could be identified with this mutation, however. Thus, the clinical relevance of this mutation seems to be low in this setting.
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Fruehwirth, Margareta, Alexander J. A. Deutsch, Philipp B. Staber, Ariane Aigelsreiter, Werner Linkesch, Christine Beham-Schmid, and Peter Neumeister. "Aberrant Somatic Hypermutation of Follicular Lymphoma Transformed To Diffuse Large B-Cell Lymphoma." Blood 108, no. 11 (November 1, 2006): 2413. http://dx.doi.org/10.1182/blood.v108.11.2413.2413.
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Abstract Follicular Lymphoma (FL) accounts for approximately 20–30% of all malignant lymphomas and the frequency of histological transformation (HT) into diffuse large B-cell lymphomas (DLBCL) varies from 10% to 70%. Many genetic lesions have already been described in histological transformation, but a mechanism of genome-wide instability during histological transformation (HT) has not been reported. We have shown that the somatic hypermutation process (SHM) physiologically aimed at mutating the immunoglobulin variable gene (IgV) aberrantly targets multiple proto-oncogenes in >50% of DLCBL (Pasqualucci et al., Nature 412:341, 2001). Consequently, multiple mutations are introduced in the 5′ region of genes including known proto-oncogenes such as PIM-1, PAX-5, Rho/TTF and c-MYC. To further investigate whether aberrant somatic hypermutation (ASHM) also occurs in histological transformation of follicular lymphoma in DLBCL we studied the mutational profile of these genes in a total of 26 cases consisting of 10 paired samples of follicular lymphoma together with the corresponding DLBCL and 6 single cases of transformed DLBCL. Genomic DNA from histologically confirmed, macrodissected tissue obtained from formalin fixed and paraffin embedded tissue or cryoconserved samples was directly sequenced. Mutations in one or more genes were detected in 6 of 10 (60%) cases of pre-HT follicular lymphoma and in 13 of 16 (81.2%) post-HT cases. Two ore more genes were affected in 1 of 10 (10%) of FL and in 7 of 16 (43.7%) cases with DLBCL. Mutations in PIM-1 occurred in 3 of 10 (30%) cases of follicular lymphoma and in 9 of 16 (56.2%) in DLBCL. For PAX-5, the distribution of the mutated cases between FL and DLBCL was 2 of 10 (20%) and 7 of 16 (43.7%), for RhoH/TTF 2 of 10 (20%) and 3 of 16 (18.7%) and for c-MYC none of 10 (0%) FL and 2 of 16 (12.5%) DLBCL. A total of 38 single base pair substitutions were found in 19 cases, 10 sequence variants in 6 FL cases and 28 sequence variants in 13 DLBCL cases. The mutations were of somatic origin and share features of the IgV SHM process including bias for transition over transversion, elevated ratio of G+C over A+T substitutions and restriction to the first 1-2Kb from the promoter initiation site. The mean mutation frequency in mutated follicular lymphoma was with 0.024 ×10−2/bp 1.4 fold lower compared to 0.032 ×10−2/bp in the transformed DLBCLs. Further in PIM-1 and c-MYC some of the mutations were found to affect coding exons, leading to amino acid exchanges, thus potentially altering gene function. These data support a role of aberrant SHM in the histological transformation of FL to overt DLBCL.
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Gupta, Shikha, Ana Filipa Domingues, Oliwia Cyran, George Giotopoulos, Sudhakaran Prabakaran, Brian J. P. Huntly, Oliver M. Dovey, George S. Vassiliou, and Cristina Pina. "Transcriptional Heterogeneity Governs Cell Fate Diversification during Pre-Leukemia to Leukemia Progression." Blood 136, Supplement 1 (November 5, 2020): 31–32. http://dx.doi.org/10.1182/blood-2020-136504.
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Acute myeloid leukemia (AML) is a heterogenous clonal disorder of hematopoietic progenitor cells with a dismal survival. It has a strong reliance on epigenetic and transcriptional factors for disease progression. Accordingly, we have previously identified KAT2A, a histone acetyl-transferase, as a requirement for AML maintenance; where chemical inhibition of KAT2A promotes differentiation of AML cell lines (Tzelepis et al., 2016, Cell Reports 17, 1193-1205). More recently, using a conditional knockout mouse model for Kat2a we showed that it sustains KMT2A/MLLT3 AML stem cells. Kat2a is a classical regulator of transcriptional variability, it's loss leads to cell-to-cell heterogeneity in transcription levels specifically from genes involved in ribosomal biogenesis and translation (Domingues et al., 2020, eLife 9:e51754). No recurrent mutations in the KAT2A gene have been described in AML, and it is unclear if and how it participates in pre-leukemia-to-AML progression. Herein, we use our conditional Kat2a knockout mouse model to analyze the effects of Kat2a loss in biology of RUNX1-RUNX1T1(9a) and Idh1R132H-initiated AML. These models represent forms of human disease with a prolonged pre-leukemia phase that typically require additional mutations for leukemia progression. We observed that loss of Kat2a accelerates leukemia initiation and progression in vivo. This acceleration was a consequence of fixation of transformed Kat2a KO cells in vivo which reflects as enhanced self-renewal capacity in vitro as measured by serial re-plating colony forming assay. Given the central role of Kat2a in limiting cell-to-cell transcription heterogeneity, we interrogated a potential link between loss of Kat2a, its consequent increase in transcriptional heterogeneity and pre-leukemia progression. For this, we performed single-cell RNA sequencing (scRNA-seq) of early-stage Kat2a WT and Kat2a KO RUNX1-RUNX1T1(9a) pre-leukaemia. Compatible with our previous observation, we observed that Kat2a KO cells were more heterogenous transcriptionally. Interestingly, this was accompanied by diversification of cell fates towards B-lymphocytes and monocytes. Furthermore, pseudo-temporal ordering of single Kat2a KO cells revealed highly branched trajectory heavily populated with intermediate stages of transformation; including accumulation of leukemia progenitors with RUNX1-RUNX1T1 signature. In contrast, Kat2a WT cells have linear normal hematopoiesis trajectory with minimal branching and an abrupt transition towards candidate leukemia progenitor state. Pathway analysis of Kat2a KO leukemia progenitor cells indicated perturbation of ribosomal biogenesis and translation associated genes. In order to test how these changes contributed to transformation, we performed S6K1 inhibition on Kat2a WT cells which transiently promoted transformation in vitro in both RUNX1-RUNX1T1(9a) and Idh1R132H cells, thus, phenocopying the effects of Kat2a loss. This suggested a mechanistic contribution of observed transcriptional changes in protein synthesis machinery towards leukemia progression. Taken together, our work suggests that loss of Kat2a results in diversification of cell fates, including with increased accessibility to cell states prone to transformation. Furthermore, these cells, prone to transformation, may benefit from a low biosynthetic activity that promotes their progression to leukemia state. We hypothesize that Kat2a loss may function similarly in the context of other malignancies. In the future, this knowledge may aid in development of early diagnostic tools and suggest bespoke therapeutic interventions. Figure Disclosures Prabakaran: Noncodomics: Consultancy. Vassiliou:Kymab Ltd - Monoclonal antibody company. Currently not working in myeloid cancers or clonal haematopoiesis.: Consultancy.
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Naqvi, Syed Arsalan Ahmed, Irbaz Bin Riaz, Manal Imran, Muhammad Daim Bin Zafar, Kunwer Sufyan Faisal, Zaryab Bin Riaz, Parminder Singh, and Alan Haruo Bryce. "Deep prostate-specific antigen response and overall survival in patients with metastatic castration-sensitive prostate cancer: A systematic review and meta-analysis." Journal of Clinical Oncology 41, no. 6_suppl (February 20, 2023): 195. http://dx.doi.org/10.1200/jco.2023.41.6_suppl.195.
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195 Background: Preliminary data suggests that patients with metastatic castration-sensitive prostate cancer (mCSPC) who achieve deep prostate-specific antigen (PSA) response may have improved survival. This finding may have implications for developing treatment de-escalation strategies. Thus, we assessed the overall survival by deep PSA response in mCSPC patients receiving intensified treatments. Methods: MEDLINE and EMBASE were systematically searched from each database’s inception through 1st October 2022. Trials assessing androgen deprivation therapy intensification (doublets, triplets) and reporting overall survival (OS) by deep PSA response were considered eligible for inclusion. Deep PSA response was defined as the PSA level of less than 0.1 or 0.2 ng/ml within eight months after initiation of intensified treatment. Precomputed effect estimates of OS (deep PSA response vs no deep PSA response) were pooled using an inverse-variance approach after logarithmic transformation; a random-effects meta-analysis was conducted within the Bayesian framework using empirical informative priors for heterogeneity parameter as specified by Turner et al. Summary effect was expressed as hazard ratios (HR) with the corresponding 95% credible intervals (CrI). A sensitivity analysis was conducted using the Der Simonian-Lairds random-effects meta-analysis with Hartung-Knapp (HK) adjustment. Results: Five RCTs (PEACE-1, ARASENS, CHAARTED, LATITUDE, TITAN) with 2533 patients were included in this systematic review. A total of 1335 patients experienced a deep PSA response, while 1218 did not achieve a deep PSA response after the initiation of intensified treatment. The pooled incidence of deep PSA response was 49.45% (95% confidence interval: 37.75-61.18). Bayesian meta-analysis showed significantly improved OS in overall mCSPC patient population who achieved a deep PSA response after intensified treatment with either triplet or doublet therapy as compared to those who did not achieve a deep PSA response (HR: 0.39; 95% CI: 0.30-0.50) as shown. The results were consistent with HK adjustment. Conclusions: Excellent overall survival in patients with deep PSA response may offer an opportunity to guide treatment de-escalation trials in carefully selected mCSPC patients. [Table: see text]
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Jeannet, Robin, Qi Cai, Hongjun Liu, Hieu Vu, and Ya-Huei Kuo. "Alcam Mediated Interaction Regulates Normal Hematopoietic Stem Cell Function and Cbfβ-SMMHC Induced Leukemogenesis." Blood 120, no. 21 (November 16, 2012): 4091. http://dx.doi.org/10.1182/blood.v120.21.4091.4091.
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Abstract Abstract 4091 The inv(16) acute myeloid leukemia (AML)-associated CBFβ-SMMHC fusion protein impairs hematopoietic differentiation and predisposes to leukemic transformation. Alcam, which encodes the activated leukocyte cell adhesion molecule (CD166), is a cell surface immunoglobulin superfamily member mediating homophilic adhesion as well as heterotypic interactions with CD6. We found that Alcam expression marks long-term repopulating HSCs (LT-HSC), multipotent progenitors (MPP), a subset of granulocyte-macrophage progenitors (GMP), and that Alcam expression is lost or reduced in subsets of pre-leukemic and leukemic progenitors expressing the Cbfβ-SMMHC fusion protein. We characterized the role of Alcam in HSC differentiation and self-renewal using an Alcam-null (Alcam−/−) mouse model (Weiner et al. 2004 Mol Cell Neurosci 27:1, 59–69). We show that Alcam is highly expressed in LT-HSCs where its level progressively increases with age. Young adult Alcam−/− mice had normal homeostatic hematopoiesis, and normal numbers of phenotypic HSCs. However, Alcam−/− HSCs had reduced long-term replating capacity in vitro and reduced long-term engraftment potential upon transplantation. We show that Alcam−/− BM contain a markedly lower frequency of long-term repopulating cells than wild type (WT). Further, the long-term repopulating potential and engraftment efficiency of Alcam−/− LT-HSCs was greatly compromised despite a progressive increase in phenotypic LT-HSC numbers during long-term serial transplantation. In addition, an age-associated increase in phenotypic LT-HSC cellularity was observed in Alcam−/− mice. This increase was predominately within the CD150hi fraction, and was accompanied by significantly reduced leukocyte output. Moreover, Alcam−/− LT-HSCs display premature elevation of Selp expression, a hallmark of HSC aging. To understand the role of Alcam in leukemic transformation, we generated conditional Cbfb-MYH11 knock-in (Cbfb56M/+/Mx1-Cre), Alcam-deficient (Alcam−/−) mice. Interestingly, we found that loss of Alcam drastically delayed or reduced leukemia incidence. Transplantation of Alcam−/−/Cbfb56M/+/Mx1-Cre pre-leukemic bone marrow cells into WT recipients also led to delayed and reduced incidence of leukemia development. These results suggest that Alcam contributes to leukemia transformation in a cell-intrinsic manner. Collectively, our study reveals that Alcam regulates the functional integrity and self-renewal of LT-HSCs, and contributes to leukemia initiation induced by CBFβ-SMMHC. Disclosures: No relevant conflicts of interest to declare.
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Laffey, Kimberly G., Robert J. Stiles, Melissa Ludescher, Tessa Davis, Shariq S. Khwaja, Richard J. Bram, Peter J. Wettstein, et al. "A New Mechanism for T-ALL Leukemogenesis: Early Expression of Alpha-Beta TCR Occurs in a Natural Subset of CD4-CD8- Double Negative (DN) Thymocytes Where MHC Engagement May Drive NOTCH Mutation and Tumor Initiation." Blood 134, Supplement_1 (November 13, 2019): 1463. http://dx.doi.org/10.1182/blood-2019-131897.
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T cell lymphoblastic leukemia (T-ALL) is an aggressive cancer arising from transformed thymocytes. Most human T-ALL involves hyperactive NOTCH signaling that is often caused by activating NOTCH mutations. However, the identification of specific molecular signals that might induce or select for mutation and transformation are incompletely understood. We report that an understudied low-frequency, natural thymocyte subset expresses αβ T cell antigen receptor (TCR) earlier than most cells in mice and humans; engagement of the early αβTCR by major histocompatibility complexes (MHC) can cause outgrowth of NOTCH1 mutant clones and T-ALL leukemogenesis in a mouse model of T-ALL. Assessment of 5 recent human T-ALL cases found one to present this unique CD4-CD8- double- negative (DN) stage as the earliest identifiable developmental stage. These studies present a model of T-ALL leukemogenesis that identifies (i) a natural cell stage of origin susceptible to transformation, (ii) a matching mouse model showing that a signaling receptor (αβTCR) and its ligand (MHC) drive leukemogeneis and outgrowth of tumors bearing activating NOTCH1 mutations, and (iii) a human case that presents with a tumor consistent with this model and mechanism. In past work, the pre-TCR has been shown to impact T-ALL development in mice (Campese et al, Blood 2006), but an oncogenic role for the mature αβTCR is less well characterized and somewhat surprising. This is because, although T-ALL tumor cells may express variable levels of surface αβTCR/CD3, the earliest cell stages that are thought to transform are also thought to precede stages with αβTCR expression. Most conventional αβ thymocytes rearrange TCRβ and TCRα loci in separate, ordered developmental stages. However, some thymocytes in the conventional pathway rearrange both at DN stage thus exhibiting 'precocious' αβTCR (PAT) expression. Importantly, these PAT cells are indeed part of the conventional αβ lineage, being a 'subset' only due to early αβTCR expression but without known distinction in ultimate immune function (Aifantis et al, JEM 2006). We found that ~0.01% of mouse and human thymocytes are such PAT cells at steady state. To interrogate the PAT thymocyte surface phenotype, we performed multi-parametric flow cytometry with Spanning-tree Progression Analysis of Density-normalized Events (SPADE). This revealed that PAT thymocytes constitute a DN subset that is not associated with other well-described unconventional DN thymocytes known to express αβTCR, consistent with as the expectation that PATs are part of the conventional developmental pathway. We observed that the OT1 TCR transgene is expressed in mice with parallel timing and level to the natural PAT subset, allowing use of this model to study antigen-dependent signaling and oncogenesis. In a cohort study, no T-ALL was observed in wild-type C57BL/6 or OT-1.β2M-/- mice (deficient in endogenous antigen presentation), but MHC-sufficient OT-1 mice developed PAT-stage-specific T-ALL with activating NOTCH1 mutations. Transplant experiments corroborated a requirement for antigen presentation and TCR signaling for tumor maintenance as transplanted tumors grew in MHC+ but not MHC-deficient mice. This predicted that PAT thymocytes might have an unusual ability to signal through αβTCR even without coreceptor expression. When cultured in the presence of either exogenously added β2M or antigen presenting cells, both untransformed and neoplastic PAT cells upregulated CD69 in response to the OT-1 antigenic peptide, OVA. Furthermore, ex vivo analysis of PAT cells from polyclonal C57BL/6 versus MHC-deficient mice showed intrinsic upregulation of TCR-signaling-dependent Nur77 in an MHC-dependent manner. These data revealed a unique ability of PAT cells to engage in co-receptor independent but antigen-dependent signaling. Microarray analysis showed that the gene expression profile of neoplastic PAT cells from OT-1 T-ALL most closely resembled that of conventional post β-selection DN thymocytes, in agreement with the natural PAT stage during normal T cell development. These data support a model in which transformation occurred in the naturally occurring αβ PAT thymocyte subset as cell-of-origin. Collectively, our data suggest that precocious αβTCR expression and coreceptor-independent antigen engagement can cause activating NOTCH mutation and T-ALL development. Disclosures No relevant conflicts of interest to declare.
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Quere, Ronan, Göran Karlsson, Falk Hertwig, Marianne Rissler, Beata Lindqvist, Thoas Fioretos, Peter Vandenberghe, et al. "SMAD4 Sequestrates HOXA9 to Protect Hematopoietic Stem Cells Against Leukemia Transformation." Blood 116, no. 21 (November 19, 2010): 3153. http://dx.doi.org/10.1182/blood.v116.21.3153.3153.
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Abstract Abstract 3153 Leukemia stem cells (LSCs) are capable of limitless self-renewal and are responsible for the maintenance of leukemia. Since elimination of LSCs will be of therapeutic benefit, it is important to identify regulatory pathways that control their development. We studied LSCs in a Smad4-/- mouse model of acute myelogenous leukemia (AML) induced either by the HOXA9 gene or by the fusion oncogene NUP98-HOXA9. We first serially replated hematopoietic colonies from BM cells transduced with these oncogenes to analyze if loss of SMAD4 can increase immortalization of HSPCs. We observed that the immortalizing function of HOXA9 and NUP98-HOXA9 was increased in Smad4-/- HSPCs. The enhanced immortalization of SMAD4 deficient cells should be related to their incapacity to activate TGFβ signaling. However when we administrated a TGFβ receptor kinase inhibitor, the immortalization of Smad4-/- cells was still increased, compared to TGFb receptor-blocked Wt cells. Thereby, we conclude that the activation of the canonical TGFb signaling pathway is not required for the growth-reducing effect of HOXA9/NUP98-HOXA9 transduced progenitors mediated by SMAD4. We discovered that HOXA9/SMAD4 complexes accumulate in the cytoplasm of normal HSPCs transduced with HOXA9 or NUP98-HOXA9. In contrast there is no cytoplasmic accumulation of HOXA9 in SMAD4-/- HSPCs and as a consequence increased levels of HOXA9 accumulate in the nucleus leading to increased immortalization of HSPCs. Next, we investigated whether Smad4-/- HSPCs might exhibit increased frequency of BM transformation to induce leukemia in mice. Smad4 deficiency induces expansion of primitive LSK hematopoietic cells expressing HOXA9 or NUP98-HOXA9 in vivo, increases the frequency of leukemia stem cells and bone marrow transformation in mice. Accordingly, a larger fraction of mice transplanted with Smad4-/- transduced-HSPCs succumbed more rapidly to AML. Next, we developed an approach to activate the TGFβ pathway by restoring the subcellular distribution of the endogenous SMAD4 protein accumulated in the cytoplasm of HSPCs transduced with HOXA9 or NUP98-HOXA9. To this end, we first identified the best competitor by generating different constructs that enable expression of diverse portions of the MH1 domain of SMAD4 that bind HOXA9 (Wang et al., EMBO, 2007). All the retroviral vectors (RFP+) were tested by co-expression together with the NUP98-HOXA9 oncogene (GFP+). Co-transduced GFP+ RFP+ cells were sorted by FACS to assess the effect of MH1 overexpression by CFC assay. Interestingly, one specific portion of SMAD4 (MH1-c encoding a peptide of 20aa) dramatically reduced immortalization capacity of NUP98-HOXA9. The insensitivity of Smad4-/- cells shows notably that the specificity of this effect is SMAD4 dependent. Compared to the other truncated MH1 portions tested, the increased effect of MH1-c was correlated to its capacity to bind HOXA9 and to induce apoptosis. To understand the mechanism behind the effect of MH1-c, we looked at the localization of SMAD4 by immunostaining and confocal microscopy. Expression of MH1-c was observed to induce a robust nuclear translocation of the SMAD4 protein, while SMAD4 remained accumulated in the cytoplasm of cells transduced with the empty control vector (MH1-e). This clearly shows that MH1-c disrupts the physical interaction between HOXA9 and SMAD4. The SMAD4 subcellular distribution pattern was altered and the nuclear translocation clearly activated the TGFβ pathway and apoptosis of cells. Next, we asked whether MH1-c might affect the development of leukemia in vivo. When HSPCs were co-transduced with HOXA9 and the empty control vector and transplanted into the tail vein of lethally irradiated recipient mice, the transduced HSPCs developed AML. In contrast, HSPCs co-transduced with HOXA9 and MH1-c remained healthy over one year, without any detectable GFP+ RFP+ cells in BM when they were sacrificed. Taken together, these findings show that active SMAD4 that can freely translocate to the nucleus of HSPCs in vivo can prevent or profoundly delay the initiation of malignant transformation. In conclusion, targeting the association between SMAD4 and HOXA9 prevents/reduces immortalization in vitro and transformation to leukemia in vivo. These findings demonstrate how activation of a negative regulatory pathway that prevents leukemogenesis may be a feasible approach to improve leukemia treatment. Disclosures: Slovak: PerkinElmer: Employment.
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Linton, Kim, Cristina Julian, Adam Gibb, Ellie White, Emma-Frances Armstrong, Yun Li, Yutong Liu, Ashwini Shewade, and John Radford. "Treatment Patterns and Outcomes in Patients with Relapsed/Refractory Follicular Lymphoma Who Received Third Line Therapy at the Christie NHS Foundation Trust in the UK." Blood 138, Supplement 1 (November 5, 2021): 5011. http://dx.doi.org/10.1182/blood-2021-148490.
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Abstract Background: There are limited data on real-world treatment patterns and outcomes for follicular lymphoma (FL) in the relapsed/refractory (r/r) setting, with shorter response durations reported after each relapse (Link et al, 2019; Rivas-Delgado et al, 2019 and Batlevi et al, 2020). We examined treatment patterns for patients with FL initiating third line (3L) therapy at a single institution by time period in the post-rituximab era (2004-2010 and 2011-2020), and clinical outcomes for the overall cohort receiving therapy between 2004 and 2020. Methods: This is a retrospective, observational study of patients with FL who initiated 3L therapy between 2004 and 2020 in routine clinical practice at The Christie NHS Foundation Trust, UK. We selected patients aged ≥18 years at 3L initiation, with histologically documented FL Grade 1−3a treated with two prior lines of systemic therapy including an anti-CD20 monoclonal antibody and an alkylating agent, and at least one year of follow-up after initiating 3L therapy; follow-up ended June 2021. We excluded patients with grade 3b FL or transformation to high grade lymphoma any time before 3L treatment. Overall response rate (ORR) and complete response (CR) to 3L therapy was calculated, and overall survival (OS), progression free survival (PFS) and time to next treatment (TTNT) were estimated using the Kaplan-Meier (KM) method with 3L therapy initiation date as the index date. Results: Overall, 41 patients met all eligibility criteria; 11 and 30 patients received 3L therapy between 2004-2010 and 2011-2020, respectively. Median age at index date was 59 years and 53.7% were male; 73.2% had grade 1 or 2 FL; 78.1% had advanced stage (III/IV) FL at diagnosis. Median follow-up was 33.9 (IQR: 14.5, 63.0) months, and median time from diagnosis to 3L treatment was 60.2 (IQR: 29.4, 89.1) months. The most common regimen in 3L was rituximab plus bendamustine (R-benda) followed by rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and rituximab used as a single agent (R-mono). Treatment patterns differed by time period (Table 1). R-benda was more commonly used between 2011 and 2020. The most common sequence was rituximab plus cyclophosphamide, vincristine and prednisone (R-CVP) followed by R-CHOP and R-benda (Figure 1). ORR to 3L treatment was 61.0%, CR 29.3%. Median OS, PFS and TTNT with 95% confidence interval (CI) were 70.0 (30.2-NR), 19.2 (9.5-34.7) and 11.8 (9.0-27.6) months after 3L initiation, respectively. Two- and five-year OS rates were 79% and 50%, and two-year PFS rate was 37%. Conclusions: Patients with r/r FL treated in the routine 3L setting have highly variable treatment patterns and unfavorable outcomes, representing a continued unmet medical need. This study is limited by its small size and evolving treatments, warranting a larger study of more recently treated 3L patients to evaluate the impact of modern treatment pathways and novel therapies on clinical outcomes for r/r FL. Figure 1 Figure 1. Disclosures Linton: University of Manchester: Current Employment; BeiGene: Research Funding; Hartley Taylor: Honoraria; Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aptitude Health: Honoraria; Celgene: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Julian: Genentech, Inc.: Current Employment, Current holder of stock options in a privately-held company. Gibb: The Christie NHS Foundation Trust: Current Employment; Takeda: Honoraria, Research Funding, Speakers Bureau. Li: Genesis Research: Current Employment. Liu: Genesis Research: Current Employment. Shewade: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Radford: BMS: Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; ADC Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria, Speakers Bureau; AstraZeneca: Current holder of individual stocks in a privately-held company.
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Kingsley, Edwin C., Shannon Fabre, Motohisa Takai, Aileen Cleary Cohen, Jingjing Schneider, Jessica Li, and James D'Olimpio. "A Phase 4, Observational Study Evaluating the Efficacy and Safety of the Bruton Tyrosine Kinase Inhibitor (BTKi) Zanubrutinib in Patients with Waldenström Macroglobulinemia (WM)." Blood 142, Supplement 1 (November 28, 2023): 6171. http://dx.doi.org/10.1182/blood-2023-172881.
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Background and Significance:Zanubrutinib, a next-generation, selective BTKi, is approved for treatment of WM based on data from the phase 3 ASPEN study (NCT03053440), in which zanubrutinib showed a favorable benefit-risk profile vs ibrutinib, a first-generation BTKi, in patients with symptomatic WM (Tam CS, et al. Blood. 2020;136:2038-2050). In ASPEN, zanubrutinib showed consistent efficacy across patient subgroups, including prior treatment status (treatment naive or relapsed/refractory) and MYD88 mutational status (shown to affect prognosis and response to treatment). This registry study will contribute to a more inclusive evidence base for zanubrutinib treatment in populations underrepresented in previous clinical studies, specifically patients who are treatment naive, have non-L265 MYD88 mutations, orare from racial and ethnic minority groups. Study Design and Methods:This is a hybrid (retrospective and prospective), multicenter (US only), noninterventional registry study (NCT05640102) in adult patients (aged ≥18 years) with a histologically confirmed diagnosis of WM who are either receiving or planning to initiate zanubrutinib treatment (Figure). Patients with measurable disease (immunoglobulin M level >0.5 g/dL) at zanubrutinib initiation are eligible. Patients with disease transformation prior to zanubrutinib initiation, other non-Hodgkin lymphoma subtypes, or other malignancies (active or in the past ≤1 year) are excluded. Patients will be assigned to 1 of 2 cohorts based on MYD88 status determined using bone marrow specimens. Cohort 1 will include patients with MYD88L265P mutations who are treatment naive (arm A) or have relapsed/refractory disease (arm B). Arm A will enroll mostly patients from racial and ethnic minority groups (Black/African American, Asian, Indigenous/Native American, Native Hawaiian/Other Pacific Islander, and Hispanic/Latino), and arm B will only enroll patients from racial and ethnic minority groups. Cohort 2 will include patients with non-L265P MYD88 mutations or MYD88 wild type who are treatment naive or have relapsed/refractory disease in a single arm (arm C). The dose and duration of zanubrutinib treatment is at the discretion of the prescribing physician. Data collection will occur at screening, every 3 cycles during year 1 of zanubrutinib treatment, and every 6 cycles thereafter (28-day cycles). The primary endpoint is the major response rate (MRR) per investigator using Sixth International Workshop on Waldenström Macroglobulinemia response criteria (Owen RG, et al. Br J Haematol. 2013;160:171-176). Secondary endpoints are very good partial response or better (VGPR+) rate, overall response rate (ORR), duration of response (DOR), and treatment-emergent adverse events. Efficacy and safety analyses will be conducted descriptively for each study arm. MRR, VGPR+ rate, and ORR will be presented with 95% CIs, and median DOR will be estimated with the Kaplan-Meier method. The study is currently open for enrollment.
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Hurtz, Christian, Katerina Hatzi, Leandro Cerchietti, Eugene Park, Yong-Mi Kim, Parham Ramezani-Rad, Hassan Jumaa, et al. "BCL6-Mediated Repression of p53 Is Critical for Leukemia Stem Cell Survival in Chronic Myeloid Leukemia." Blood 118, no. 21 (November 18, 2011): 446. http://dx.doi.org/10.1182/blood.v118.21.446.446.
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Abstract Abstract 446 Background: Chronic myeloid leukemia (CML) is induced by the oncogenic BCR-ABL1 tyrosine kinase and can be effectively treated for many years with tyrosine kinase inhibitors (TKI). However, unless CML patients take TKI-treatment life-long, leukemia will eventually recur, which is attributed to the failure of TKI-treatment to eradicate leukemia-initiating cells (LIC; Corbin et al., J Clin Invest 2011). Persistence of LIC in CML can result in acquisition of secondary events eventually leading to TKI-resistant blast crisis, which is fatal within months. Recent work demonstrated that FoxO factors are critical for maintenance of CML-initiating cells (Naka et al., Nature 2010), however the mechanism of FoxO-dependent leukemia-initiation remained elusive. Results: Here we identified the BCL6 protooncogene as a critical effector downstream of FoxO in self-renewal signaling of CML-initiating cells. ChIP-seq analysis demonstrated that BCL6 directly binds to and represses Arf and p53 promoters in human CML cells. Genetic deletion of the BCL6 gene in a mouse model of CML results in progressive depletion of Lin- Sca-1+ c-Kit+ LIC. BCL6-deficient LIC exhibit excessively high expression levels of Arf and p53 and propensity to cellular senescence and apoptosis. As a consequence, BCL-deficient CML cells lack the ability to form colonies and to initiate leukemia in transplant recipient animals. To investigate whether these effects are indeed owing to the role of BCL6 as repressor of Arf/p53, we induced activation of a dominant-negative BCL6-mutant in p53+/+ and p53−/− CML cells. While dominant-negative BCL6 compromised colony formation and self-renewal in p53+/+ CML cells, BCL6 inhibition only had minor effect on p53−/− CML cells. We conclude that BCL6 enables survival of LIC in CML mainly through transcriptional repression of p53. To test potential clinical relevance of these findings, we used a recently developed retro-inverso BCL6 peptide inhibitor (RI-BPI, Cerchietti et al., 2009), which inhibits BCL6 function as transcriptional repressor. RI-BPI is currently under clinical trial for the treatment of BCL6-dependent diffuse large B cell lymphoma (Dr. Ari Melnick, LLS TAP Program). Importantly, peptide inhibition of BCL6 in human CML cells compromises colony formation and leukemia-initiation in transplant recipients and selectively eradicates CD34+ CD38− LIC in patient-derived CML samples. Conclusions: These findings identify pharmacological inhibition of BCL6 as a novel strategy to eradicate LIC in CML. Clinical validation of this concept could limit the duration of TKI-treatment in CML patients, which is currently life-long, and substantially decrease the risk of blast crisis transformation. Based on these findings, we propose a dual targeting strategy, in which (1) tyrosine kinase inhibitors (e.g. Imatinib) to target the transient amplifying pool of CML cells are coupled with (2) BCL6 inhibition that will target quiescent LIC. Disclosures: Hochhaus: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Shah:Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy; Ariad: Consultancy, Research Funding. Druker:Novartis: ; Bristol-Myers Squibb: ; ARIAD Pharmaceuticals: ; OHSU patent #843: Mutated ABL Kinase Domains: Patents & Royalties; MolecularMD: Equity Ownership.
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Ludvigsen Al-Mashhadi, Ahmed, Mikkel Runason Runason Simonsen, Chan Yoon Cheah, Rose-Marie Amini, Bente Arboe, James R. Cerhan, Iman Chanchiri, et al. "Favorable Outcomes of Splenic Marginal Zone Lymphoma in an International Study of 934 Patients with Long Follow-up." Blood 142, Supplement 1 (November 28, 2023): 4396. http://dx.doi.org/10.1182/blood-2023-173247.
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Introduction: Splenic marginal zone lymphoma (SMZL) is a rare, indolent disease. There is no universally accepted standard therapy and long-term outcome data are limited. Rituximab monotherapy is increasingly used over splenectomy in the first-line setting despite a paucity of comparative studies. In the absence of randomized trials, large-scale international real-world data studies are critical to evaluate outcomes of different treatment interventions and to understand the natural history of SMZL in the rituximab-era. Methods: Adult patients with SMZL diagnosed between Jan 1 st 2000 and Dec 31 st 2018 were identified using regional/nationwide population-based registries or hospital registries in Europe, the UK, North America, and Australia. Medical records and pathology reports from eligible patients were reviewed locally by clinicians with specialty experience in hemato-oncology. SMZL cases were required to meet the diagnostic criteria by Matutes et al. Detailed data on clinico-pathological features, comorbidities, treatments (including treatment intention), treatment responses and survival outcomes were entered in a central study database. Overall survival (OS) was defined as time from diagnosis until death from any cause or censoring at last follow-up unless stated otherwise. Event-free survival (EFS) was defined as the time from diagnosis until histological transformation, initiation of new chemotherapy or death from any cause. Survival probabilities were estimated using the Kaplan-Meier estimator. Cumulative risk of transformation was estimated with death as a competing risk. Primary endpoints were 10-year OS and 5-year EFS respectivly. Results: A total of 934 patients from 25 sites were included. Median age at diagnosis was 68 years (IQR 60-76) and 54% were female. Bone marrow involvement was present in 96% (564/590) of those assessed, anemia (Hb <12g/dL for women or <13g/dL for men) in 58%, LDH >UNL in 46%, lymphocytosis (>5 x10 9/L) in 34%, and B-symptoms in 34%. Treatment data were available for 97% of patients. Median follow-up was 9.1 years (range 0-23). Watch and wait was the initial strategy in 28% and 88% of patients received at least one line of treatment during follow-up with the most common being splenectomy (45%), immuno-chemotherapy (19%) or rituximab monotherapy (8%). Fifteen percent received “other” treatments (i.e., combinations of listed therapies and/or radiation). The overall response rate to first-line treatment was 88% (95%CI: 85-90%) with 61% (95%CI: 57-64%) achieving CR. Second line (2L) therapy was needed in 34% during follow-up, 3L in 20% and 4L+ in 9%. The 5-year EFS and OS for all patients were 61% (95%CI: 57-65%) and 77% (95%CI: 74-80%) respectively. The 10-year OS and lymphoma-specific mortality (with non-SMZL deaths as competing risk) estimates were 60% (95%CI: 57-64%) and 11% (95%CI: 9-14%) respectively. The 5-year OS after 2L and 3L were 61% (95%CI: 55-68%) and 51% (95%CI: 42-61%) respectively (figure 1). The 10-year cumulative risk of histological transformation was 17% (95%CI: 13-21%), with 5-year post-transformation OS of 42% (32-54%). At the time of transformation, 60% were chemo-naive and 52% had never been treated for SMZL. The 5-year OS for chemo-naive patients with transformation was 54% (95%CI: 41-71%) versus 24% (95% CI: 13-44%) for transformations after (immuno)chemotherapy (p = 0.01). When comparing patients intended for treatment in first line with splenectomy (n=312) versus rituximab (n=70), patients treated with splenectomy more frequently presented with extra-hilar lymphadenopathy (35% vs 18%), splenomegaly (92% vs 87%) and anemia (64% vs 48%). OS was similar for the two groups (Figure 2, p = 0.53). The 5-year EFS were 63% (95%CI: 57-68%) and 64% (95%CI: 54-77%), respectively (p = 0.31). Conclusions: To date, this is the largest real-world study of SMZL with detailed treatment and outcome data. The study shows that histological transformation was not uncommon with 10-year risk of 17%. However, outcomes for the entire cohort were excellent irrespective of initial treatment and both OS and EFS were similar after first line rituximab versus splenectomy. Long-term survival remained relatively high even following multiple lines of therapy.
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Haaga, John, Hilary Coller, Hung-Ying Kao, and Richard T. Lee. "Conversion of nontumorigenic dormant MOLT3 by lactate into a glycolytic cancer via epigenetic changes and lymphangiognesis." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e23176-e23176. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e23176.
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e23176 Background: Lactate considered a "waste product" lactate is a multifunctional modulator. Processes modulated by lactate are: 1. initiation of the transformation of the microenvironment 2.production of hyaluronan which interacts with RHAMM to cause cell motility, stabilize mitotic spindle, and supports stem cells. With these many processes, we hypothesized that lactate might interrupt the dormant state of the MOLT3 dormant cell line. Previous authors Indraccola et al, PNAS, 2006 reported that the dormant MOLT3 cell line implanted in SCID mice could be interrupted to become tumorigenic by co-implantation with VEGF,FGF, or irradiated (dead) Kaposi Sarcoma. We used this model to determine if lactate could stimulate tumorigenesis in a similar manner. Methods: In multiple cohorts of SCID mice, lactate was coimplanted with MOLT3 cells. In approximately 40 days, tumors grew rapidly in an exponential manner. Arterial perfusion was measured by contrast enhanced dual energy CT and MRI perfusion. Immunohistochemistry was performed for vascular stains CD21,VEGFR3, Notch 1, Ephrin B, VEGFA,VEGFD, Macrophages, VEGFD. Rna sequencing was performed on six samples, 3 Molt3 cell plugs, 3 MOLT3/lactate tumors (sequencing done at UCLA, data processed at Broad Street Institute MIT). Results: The data confirmed lactates's modulator role. Perfusion studies showed no arterial flow. The IHC showed many cancer cell with many mitotic figures and apoptosis.IHC confirmed presence of numerous macrophages, increased VEGFD, lymphatics and no arteries. Indraccola's reported their tumors showed no mitotic figures. 1114 genes were up/down regulated. In general rna showed: 1.mitochondrial dysfunction 2.Down regulated tumor suppressors 3) Up regulated oncogenes 4)Increased Stem cell markers 5) increased NFK-b and other pathways. Conclusions: Lactate induced an avascular "cancer" with features similar to natural pancreatic ductal and triple negative breast cancer. Results question the universality of the angiogenic switch. We hypothesize Lactate from marophages may be the cause of inflammation induced cancer.
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Mossner, Maximilian, Johann-Christoph Jann, Evi Lauinger-Lörsch, Daniel Nowak, Uwe Platzbecker, Aristoteles Giagounidis, Katharina S. Götze, et al. "TP53 Mutations Detected By Next-Generation Deep-Sequencing In Patients With Myelodysplastic Syndrome and Isolated Deletion (5q): Results From a German Multicenter Trial." Blood 122, no. 21 (November 15, 2013): 2759. http://dx.doi.org/10.1182/blood.v122.21.2759.2759.
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Abstract Background Beside cytogenetic aberrations, additional gene mutations are powerful predictors of outcome in myeloid diseases. Moreover, myelodysplastic syndromes with isolated deletion (5q) (MDS del(5q)) have been regarded as one of the most favorable entities among MDS. However, a substantial proportion of MDS del(5q) patients experience transformation into AML soon after diagnosis (Germing et al. Leukemia. 2012;26:1286-1292). Mutations of TP53 gene have early been recognized as an unfavorable prognostic biomarker in MDS in general and recent data suggest a role of TP53 mutations in the transformation of MDS del(5q) into AML. Lenalidomid (Len) is now approved in the US as well as in Europe for the treatment of MDS del(5q) it is of particular interest whether Lenalidomide can alter the course of pretreatment TP53 mutated MDS del(5q). Methods The Le-Mon-5 trial investigated the safety and efficacy of Len in patients with MDS and isolated deletion (5q). All patients gave their written informed consent to the clinical trial and to additional molecular genetic analyses. Bone marrow aspirates were performed at screening prior treatment initiation and during follow-up every 6 months. Only freshly extracted, high-quality DNA from ficollized mononuclear cells was used for next-generation deep-sequencing analysis. For generation of PCR amplicon libraries TP53 oligonucleotide primer plate assays were used and technically validated within the IRON-II (Interlaboratory Robustness Of Next generation sequencing) research study network. Amplicon deep-sequencing of TP53 (exons 4-11) was performed on a Roche 454 GS Junior system. Mean coverage of sequenced exons was about 800-fold allowing an approximate detection sensitivity of 2% mutational burden. Results Central cytological, histological and cytogenetic review was performed in all patients establishing the diagnosis of MDS with isolated deletion (5q). A total of 68 patients (male: n=9) were analyzed with a median age of 71 years (range 41-88 years). TP53 mutations prior to treatment initiation with Len were found in 7 patients (10%). Mean mutation frequency was 38%. Notably, we did not find mutation frequencies lower than 15%. Of 4 evaluable patients, three patients became transfusion independent within 4 months of Len treatment. Of 2 patients we had follow-up samples available. Both patients showed no difference with regard to the mutation frequency after a follow-up of 4 and 17 months on Len treatment (27% and 51%, respectively). Noteworthy, one the two patients achieved a complete cytogenetic remission despite maintaining his TP53 mutation frequency. Conclusion Using freshly extracted DNA we achieved high-quality NGS results with a high mean coverage of the relevant coding region of TP53. However, prevalence of TP53 mutations in our patient cohort was lower as compared to previously published data and we did not find low-level allele burdens as published by other groups, which might be due to the different sample sources used. Transfusion independence as well as cytogenetic remissions can be achieved in patients with TP53 mutations who are treated with Lenalidomide. Disclosures: Platzbecker: Celgene: Honoraria. Giagounidis:Celgene: Consultancy, Honoraria. Götze:Celgene Corp.: Honoraria. Haase:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Bug:Celgene: Honoraria, Research Funding. Hofmann:Celgene: Research Funding. Germing:Celgene: Honoraria, Research Funding. Nolte:Celgene: Honoraria, Research Funding.
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Akar, Ugur, Bulent Ozpolat, Nancy Colburn, and Gabriel Lopez-Berestein. "p38 MAPK Signaling Mediates Retinoic Acid-Induced Expression of a Novel Tumor Suppressor Protein Programmed Cell Death 4 (PDCD4) in Acute Promyelocytic Leukemia Cells." Blood 108, no. 11 (November 16, 2006): 1942. http://dx.doi.org/10.1182/blood.v108.11.1942.1942.
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Abstract Programmed-cell-death-4 (PDCD4) is a novel tumor suppressor protein that suppresses tumor promoter-induced neoplastic transformation. PDCD4 specifically inhibits the helicase activity of eukaryotic translation initiation factor 4A (eIF4A) and translation initiation and cap-dependent mRNA translation in vitro and in vivo. Loss or underexpression of PDCD4 is associated with carcinogenesis and chemoresistance in solid tumors. The role and regulation of PDCD4 in the the hematopoietic system and myeloid leukemia cells are not known. We previously reported that ATRA induces translational suppression through multiple posttranscriptional mechanisms during terminal cell differentiation (Harris et al, Blood, 104 (5) 2004). Therefore, in this study, we investigated the expression and regulation of PDCD4 during myeloid cell differentiation. All-trans-retinoic acid (ATRA) induces terminal differentiation in acute myeloid leukemia (AML) and promyelocytic (APL) cells, a well established model for myeloid cell differentiation. We found that treatment of HL60 (M2 type AML) and NB4 APL (M3 type AML) cells with ATRA (1 mM) induced PDCD4 protein and mRNA expression during granulocytic differentiation detected by western blot and RT-PCR analysis, respectively. We also demonstrated that inhibition of PDCD4 by siRNA reduced granulocytic differentiation induced by ATRA, suggesting that PDCD4 plays a role in granuliocytic differentiation. To determine mechanisms regulating PDCD4 we investigated the role of pP38 MAPK (Mitogen activated protein kinase) in reugulation of PDCD4 expression. ATRA induced PDCD4 expression correlated with activation of p38 MAPK (Mitogen Activated Protein Kinase) pathway in NB4 cells. To test the hypothesis that p38 MAPK signaling pathway mediates retinoic acid induced PDCD4 expression we treated cells with a specific p38 MAPK inhibitor, SB203580, ATRA or combination with ATRA. We observed that p38 inhibitor inhibited ATRA-induced expression of PDCD4 in NB4 cells. Basal level of PDCD4 expression was also markedly downregulated in the presence of p38 inhibitor when compared to untreated control cells, suggesting that p38 pathway is involved in ATRA-dependent and independent PDCD4 expression. Currently we are investigating whether inhibition of p38 by small interfering RNA (siRNA) will prevent expression of ATRA induced PDCD4 in APL cells. We are also trying to identify whether ATF2 transcription factor, a downstream of p38, is involved in PDCD4 expression. p38-mediated induction of PDCD4 pathway reveals a novel mechanism of PDCD4 regulation and ATRA action, providing a new insight into understanding terminal differentiation of myeloid cells. Better understanding the role of PDCD4 and posttranscriptional control of gene expression may offer targets for the differentiation therapy and chemo preventive strategies.
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Komrokji, Rami S., Najla H. Al Ali, Eric Padron, Jeffrey E. Lancet, and Alan F. List. "Azacitidine Treatment of Lenalidomide-Resistant Myelodysplastic Syndrome with Deletion 5q." Blood 118, no. 21 (November 18, 2011): 2774. http://dx.doi.org/10.1182/blood.v118.21.2774.2774.
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Abstract Abstract 2774 Background: Lenalidomide is a highly effective treatment for lower risk transfusion dependent myelodysplastic syndrome (MDS) patients with deletion 5q [del(5q)]. Approximately two thirds of patients become transfusion independent for a median duration of 2 years or longer (List et al, NEJM). Effective treatment alternatives after lenalidomide treatment failure are limited. We examined the response to treatment with azacitidine in del(5q) MDS patients after lenalidomide treatment failure. Methods: MDS patients with del(5q) who were treated with azacitidine after lenalidomide failure were identified through the Moffitt Cancer Center (MCC) MDS database and individual charts reviewed. Data collected included demographics, disease baseline characteristics, duration of response to lenalidomide, responses to azacitidine by international working group (IWG) 2006 criteria, transformation to acute myeloid leukemia (AML), and overall survival (OS). Descriptive statistics were used for analysis and Kaplan Meier estimates were used for OS and AML transformation. All analysis was conducted using SPSS version 19.0 statistical software. Results: Between July 2005 and June 2011, 18 del(5q) MDS patients treated with azacitidine were identified. The median age was 66 years (50–83), all patients were Caucasian, and male predominance (67%; 12 patients). ECOG performance status was 0–1 in 94% of the patients. The median duration of follow up from date of azacitidine initiation was 645 days. According to the WHO classification, 7 patients (38.9%) had MDS with isolated del(5q), 7 patients (38.9%) refractory cytopenia with multilineage dysplasia (RCMD), 2 patients (11.1%) refractory anemia with excess blasts 1 (RAEB-1), and 2 patients (11.1%) refractory anemia (RA).The international prognostic scoring system (IPSS) risk category was low in 2 (11.2%), intermediate 1 (int-1) in 14 (77.8%), and int-2 in 2 (11.2%) patients. Based on karyotype, 7 patients (38.9%) had isolated del(5 q), 9 (50%) del 5q +1 abnormality, and 2 (11.2%) with del 5q +2 or more cytogenetic abnormality. All patients were transfusion dependent. The median number of lenalidomide cycles prior to azacitidine was 12 (1–38), with median duration of response 319 days (17–1169). The median number of azacitidine cycles administered was 6 (2–23). The median duration of treatment was 183 days (43–592). The best response to azacitidine by IWG 2006 criteria was one (7.1%) complete response (CR), 2 (5.6%) marrow CR (mCR), 7 (38.9%) hematological improvement (HI), 4 (22.2%) had stable disease, and 4 (22.2%) had progressive disease (PD). The overall response rate was 56%.The HI cell lineage responses were 9 out of 18 (50%) erythroid, 3 out of 13 (23%) HI-P (Platelets), and 2 out 9 (22.2%) HI-N (neutrophils). The median OS was 749 days (95%CI 435–1063) from the time of starting azacitidine. The rate of AML transformation was 27.8% (n=5); median time to AML transformation from azacitidine start was 864 days (95%CI 360–1368). Conclusion: To our knowledge this is the first report demonstrating the activity of azacitidine in patients with del(5q) MDS after lenalidomide treatment failure. Response rates are similar to those reported in non-del(5q) patients providing azacitidine as an effective option for salvage treatment. Larger cohort of patients is needed to confirm these findings. Disclosures: Komrokji: Celgene: Honoraria, Research Funding, Speakers Bureau. Lancet:Celgene: Research Funding. List:Celgene: Consultancy.
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Lin, Kevin H., Lynn Huynh, Xiaoqin Yang, Enrico Zanardo, Lisa Matay, Megan Pinaire, Daria Liborski, et al. "Clinical Characteristics, Treatment Patterns, and Outcomes of Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Refractory to Covalent Bruton's Tyrosine Kinase Inhibitor (BTKi) and Exposed to B-Cell Lymphoma 2 Inhibitor (BCL2i)." Blood 142, Supplement 1 (November 28, 2023): 1910. http://dx.doi.org/10.1182/blood-2023-182188.
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Introduction: CLL/SLL patients who failed BTKi and are treated with BCL2i represent a growing population with few standard-of-care treatment options after discontinuing both therapies. Patients who fail both BTKi and BCL2i have poor prognosis, with a median overall survival (OS) of 3.6 months (Lew et al., Blood Advances, 2021). However, real-world evidence for these patients is limited. This study described the characteristics, treatment patterns, and outcomes of CLL/SLL patients who were relapsed or were resistant/refractory/intolerant (R/R/R/I) to BTKi and who were exposed to BCL2i. Among patients who discontinued BCL2i, responses to the treatment immediately after BCL2i were reported. Methods: This retrospective chart review study evaluated Dana-Farber Cancer Institute patients with CLL/SLL (≥18 years old) who were R/R/R/I to BTKi and received BCL2i (in any order). Abstraction took place from 12/2021 to 07/2023. Patients were required to have records available from 6 months before to 12 months after first BTKi initiation. Patients who received non-hormonal antineoplastic therapy for other primary malignancies in the period between CLL/SLL diagnosis and receipt of their first BTKi treatment were excluded. Demographic and clinical characteristics at or before BCL2i initiation were described. Lines of treatment (LOTs) and responses to BCL2i were summarized. Time to treatment discontinuation, real-world PFS (rwPFS) and OS were estimated by Kaplan-Meier analysis. Patients were considered doubly refractory if they were R/R/R/I to BTKi and BCL2i. Overall response rate to first treatment after BTKi and BCL2i was summarized among doubly refractory patients. Results: Among 104 patients who were R/R/R/I to BTKi, 61 (58.7%) received a BCL2i. The patients exposed to both BTKi and BCL2i were observed for a median (interquartile range [IQR]) time of 2.6 (1.1,4.4) years after BCL2i initiation. 57 (93.4%) patients received BCL2i after BTKi and 4 (6.6%) received BCL2i before BTKi. BCL2i was most commonly (23 [37.7%] patients exposed to BCL2i) received in the fourth LOT and all patients received their first BCL2i after their first LOT. Median (IQR) age at BCL2i initiation was 68.4 (63.3-74.4) years. Among patients who were assessed for cytogenetic abnormalities (n=58), the most common abnormalities were del(13q) (55.2%) and del(17p) (36.2%). 36 (61.0%) patients had TP53 mutation. 45 (73.8%) patients discontinued their first BCL2i treatment. IGHV mutation was assessed for 49 patients and 8 (16.3%) had mutation rates ≥ 2%. Median (IQR) time to BCL2i discontinuation for patients receiving BCL2i was 1.5 (0.4, 3.1) years. 40 (76.9%) of the 52 patients with a known first response to BCL2i achieved clinician-assessed complete (CR) or partial response (PR) at first assessment. 25 (41.0%) patients were R/R/R/I to BCL2i at the time of abstraction. Of them, 21 (84.0%) progressed, 7 (28.0%) developed Richter transformation (RT) and 11 (44.0%) died. Primary cause of death was available for 8 (72.7%) patients and, of these, 5 (62.5%) died due to disease progression, 2 (25.0%) died due to a secondary malignancy, and 1 (12.5%) died from unspecified causes. Among doubly refractory patients, median (95% CI) rwPFS was 1.6 (0.7, 2.4) years and median OS was 3.8 (2.3, not reached) years from the initiation of the latter of BTKi and BCL2i treatment. Among doubly refractory patients, 18 (72.0%) received an additional LOT after the latter of BTKi and BCL2i. The therapies received in the first line after BTKi and BCL2i were allogeneic HSCT (4 patients), duvelisib (3 patients), oral CDK9i (2 patients), and 1 patient each with CAR-T, anti-CD20 bispecific antibody, alemtuzumab, vecabrutinib, zanubrutinib; and for patients with RT: venetoclax plus rituximab with anthracycline chemotherapy (2 patients), PI3Ki/PD-1 (1 patient), duvelisib (1 patient) ( Figure 1). Response to the additional LOT was known for 17 patients and unknown for 1 patient. Clinician-assessed CR or PR to treatment immediately after BCL2i and BTKi was achieved for 4 (23.5%) of these patients at first assessment. Conclusions: Patients with CLL/SLL who were failed by BTKi and BCL2i treatment have poor prognosis. Overall response rates to treatment immediately after BTKi and BCL2i treatment are low among doubly refractory patients. More effective treatments are needed to address the unmet therapeutic needs of CLL/SLL patients who are refractory to both BTKi and BCL2i.
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Mohamed-Hadley, Alisha A., Dan A. Liebermann, and Barbara Hoffman. "Stress Response Gadd45a Gene as Tumor Suppressor in MYC Expressing Myeloid Cells Is Cytokine Specific." Blood 114, no. 22 (November 20, 2009): 1481. http://dx.doi.org/10.1182/blood.v114.22.1481.1481.
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Abstract Abstract 1481 Poster Board I-504 MYC, which regulates proliferation, apoptosis/survival and differentiation, is implicated in the etiology of a wide variety of hematologic malignancies. Multiple cooperating molecular pathways of cell survival and apoptosis determine if a cell lives or dies, and understanding how c-MYC interfaces with these pathways to influence the survival of cells is important to understand tumor initiation and progression, and response of tumors to different treatment regimens. Previously, this laboratory has shown that deregulated c-MYC blocks terminal myeloid differentiation and prematurely recruits both the Type I and Type II CD95/Fas apoptotic pathways, promoting an incompletely penetrant apoptotic response (Amanullah et al., Oncogene 19:2967-77, 2000; Amanullah et al., Oncogene 21;1600-10, 2002). Here we provide data to show that the response of myeloid cells to deregulated MYC expression depends on the status of the Gadd45 family of stress response genes. The gadd45 gene family plays pivotal roles as stress sensors that modulate signaling in response to physiological and environmental stressors, also modulating susceptibility of cells for transformation in vitro and tumor development in vivo. Gadd45 behaves as either tumor suppressor or oncogene depending upon the transforming oncogene and the cell type (Tront et al., Cancer Research 66:8448-54, 2006; Tront et al., manuscript in press). To elucidate the role Gadd45a plays in response to the proto-oncogene c-MYC in myeloid cells, bone marrow (BM) cells from wild type (WT) and Gadd45a null mice were retrovirally infected to constitutively express c-MYC. We showed that Gadd45a null BM expressing constitutive c-MYC exhibited less apoptosis than its WT counterpart in expansion media (IL-3, IL-6, SCF), demonstrating that Gadd45a is required for optimal MYC mediated apoptosis. In addition, enhancement of cell cycle progression was observed. Therefore, loss of gadd45a in conjunction with constitutive MYC expression results in enhanced proliferation. Furthermore, in GM-CSF treated cells the MYC–mediated block/delay in differentiation was more extensive in the Gadd45a null cells compared to similarly treated WT cells. Interestingly, the percent of apoptosis was higher in the Gadd54a null cells expressing constitutive MYC as compared to the WT counterpart. This observation was in contrast to the results seen in expansion media, suggesting that the role Gadd45a plays in the presence of deregulated MYC may be cytokine specific. Data will be presented to explain how gadd45 regulates both the apoptotic response, depending upon the specific cytokine, and differentiation of MYC-expressing myeloid cells. Furthermore, experiments to determine how loss of gadd45a influences MYC-mediated leukemia, including assessing the effect of manipulating the cytokine milieu, are currently underway. Disclosures: No relevant conflicts of interest to declare.
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McKay, John, Matthew Gayhart, Taha Al-Juhaishi, Victor Yazbeck, and Edward B. Perkins. "Venetoclax and Cytarabine in AML Transformed from Myelofibrosis." Blood 134, Supplement_1 (November 13, 2019): 5140. http://dx.doi.org/10.1182/blood-2019-129429.
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Background Acute myeloid leukemia (AML) accounts for 1% of all newly diagnosed cancers with a mean age at diagnosis of 68. Although the majority present de novo, AML can be secondary to conditions such as myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF). The subset of patients with AML transformed from MPN continues to remain a therapeutic challenge with little data to support clinical efficacy. A large retrospective review of 273 patients revealed no significant improvement in overall survival in this patient population for those diagnosed between 1989 and 2016. Prognosis remains dismal with an overall survival of 5-7 months. Treatment options are limited and often with little proven clinical utility. Even the addition of hypomethylating agents to treatment options has failed to show any improvement in survival necessitating the investigation of new treatment options (Chihara et al, ASH 2016). In this case series, we present two AML cases that have transformed from myelofibrosis and were successfully treated with the combination of cytarabine and venetoclax. Objective Our primary objective was to determine the clinical efficacy of the combination of cytarabine and venetoclax in patients with myelofibrosis with leukemic transformation. Methods This is an observational, retrospective case series of two patients that were treated with cytarabine and venetoclax at Virginia Commonwealth University from 2018 to 2019. Both patients had previously been confirmed as meeting WHO criteria for myelofibrosis on bone marrow examination. Upon transformation to acute myeloid leukemia, again confirmed on bone marrow biopsy, both patients were transitioned to the following regimen: cytarabine 20 mg/m2 on days 1-10 of 28-day cycle in combination with venetoclax with rapid dose escalation to goal of 600mg daily with dose adjustments for medication interactions. The patient's response to therapy and side effect monitoring were performed at regular intervals in the outpatient clinic. Results Our study consisted of two females, age 65 (patient 1) and 71 (patient 2) with a median age of 68 and bone marrow biopsy confirmed diagnosis of myelofibrosis. Both females had grade 3+ fibrosis on marrow examination and both harbored JAK2 mutations on initial diagnosis of myelofibrosis. Patient 2 also demonstrated a 20q deletion. Neither female was deemed a suitable candidate for transplantation due to their age and considerable comorbidities. On transformation to leukemia, blast count burden was 27% and 23%, respectively. Patient 1 had received decitabine prior to the cytarabine/venetoclax regiment while the other had no previous therapy for her myelofibrosis or leukemia. Patient 1 was maintained on the regiment with for 10 months and nearly completed 9 cycles before patient decompensated and was transitioned to comfort care and eventually died. Complications during her treatment course included an elevated uric acid requiring a dose of rasburicase, neutropenic fever and subdural hematoma that resolved without any intervention. Patient 2 has completed 6 cycles of therapy and is now 8 months post initiation of therapy. Her most recent bone marrow biopsy showed a hypocellular bone marrow (20-30% cellularity) and severe myelofibrosis (reticulin 3/3+) with less than 1% blasts. She remains independent of transfusions. Conclusions Our case series demonstrates that the combination of cytarabine and venetoclax can be effectively used in patients with AML transformed from myelofibrosis. In a disease historically with an overall survival of 6 months, one patient survived 10 months and the other is 8 months out and currently in remission from her AML on her most recent bone marrow biopsy, and independent of transfusions. Overall, therapy has been well tolerated with manageable adverse events. Although future prospective studies are needed, the combination of cytarabine and venetoclax offers a reasonable treatment option for secondary AML transformed from myelofibrosis. Disclosures Yazbeck: Gilead Sciences: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.
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Ozpolat, Bulent, Ugur Akar, Nancy H. Colburn, and Gabriel Lopez-Berestein. "Novel Tumor Suppressor Protein Programmed Cell Death 4 (PDCD4) Suppresses Activity of PI3K/Akt Pathway and Regulates Expression of p27 (Kip1) and c-myc, DAP5 and Willm’s Tumor (WT1) in Acute Myeloid Leukemia." Blood 110, no. 11 (November 16, 2007): 2656. http://dx.doi.org/10.1182/blood.v110.11.2656.2656.
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Abstract Programmed cell death 4 (PDCD4) is a recently identied novel tumor suppressor protein that inhibits cap-dependent mRNA translation. PDCD4 inhibits tumor promoter incuced carcinogenesis and transformation by suppressing the helicase activity of eIF4A, leading to translational inhibition. Recently we found that PDCD4 is required for all-trans-retinoic acid (ATRA)-induced granulocytic differentiation of acute promyelocytic leukemia (APL) cells (Ozpolat&Akar et al, Mol Cancer Res, in press), type of acute myeloid leukemia characterized by a t(15;17) and a differentiation block. Here we investigated the downstream mediators or targets of PDCD4 in leukemia cell differentiation. ATRA is currently used as a first line standard treatment in APL. Recently, we reported that ATRA induces translational suppression through multiple posttranscriptional mechanisms that involve suppression of translation initiation, a rate limiting step of protein synthesis (Harris&Ozpolat et al, Blood, 104 (5) 2004). We found that ATRA treatment induced PDCD4 expression in NB4 APL, HL60 AML, primary APL patient leukemia cells and normal human CD34+ bone marrow progenitors cells during granulocytic differentiation. However, ATRA/maturation resistant NB4.R1 and HL60R cells failed to express and translocate PDCD4 into nucleus after ATRA treatment. To identify downstream targets of PDCD4 we knock downed PDCD4 expression by siRNA and examined changes in the expression of target proteins that are known to be regulated by ATRA by Western blot analysis in NB4 cells. We found that PDCD4 represses c-myc, and WT1 expression however, it is required for the expression of DAP5 (death associated protein 5), and cyclin dependent kinase inhibitor p27KIP1, and but not c-jun, p21Cip1, and tissue transglutaminase (TG2). Inhibition of PDCD4 by siRNA resulted in upregulation of phospho-P70S6K, suggesting that PDCD4 inhibits activity of PI3K/Akt pathway. RT-PCR analysis revealed that mRNA of these proteins did not change suggesting that PDCD4 tumor suppressor protein regulates expression of these important cellular proteins at translational level and suppresses PI3K/Akt pathway. Furthermore we rapamycin, a specific mTOR inhibitor currently in clinical trials in AML, induced a marked expression of PDCD4, which regulates c-myc and p27 Kip1, revealing a novel mechanism of action of rapamycin, providing new rationale for targeting translational pathways as a therapeutic intervention in the treatment of AML. Overall, data suggest that PDCD4 regulates expression of critical cellular proteins involved in differentiation of leukemia cells and PDCD4 mediated translational control may be an important regulatory mechanism for regulation of gene expression.
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Ozpolat, Bulent, Maribel Tirado-Gomez, Nancy H. Colburn, and Gabriel Lopez-Berestein. "All-trans-Retinoic acid (ATRA) and Arsenic Trioxide-Induced Expression and Regulation of Programmed Cell Death 4 (PDCD4) in Acute Promyelocytic Leukemia." Blood 104, no. 11 (November 16, 2004): 886. http://dx.doi.org/10.1182/blood.v104.11.886.886.
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Abstract All-trans-retinoic acid (ATRA) induces growth inhibition, differentiation and apoptosis in acute promyelocytic leukemia (APL) characterized by t(15;17), which leads to expression of PML-RARa and differentiation arrest. ATRA treatment alone results in complete remission (CR) about 90% of APL patients. However these remissions are transient and APL patients commonly become resistant to ATRA therapy. Recently, arsenic trioxide, As(2)O(3), was proven to be highly effective in inducing CRs not only in relapsed after ATRA and primary APL patients. Despite the well documented clinical efficacy ATRA and As(2)O(3) in APL, precise downstream molecular mechanisms of action of these agents and the molecular mechanisms responsible for the resistance largely remain unknown. Recently, employing comprehensive proteomics methods we studied molecular mechanisms of ATRA-induced growth inhibition in APL cells. We reported that ATRA induces translational suppression through multiple posttranscriptional mechanisms involved in translation initiation and elongation phases (Harris &Ozpolat et al, Blood, 104 (5) 2004). We also demonstrated that ATRA inhibits expression translation initiation factors including IF2, eIF4AI, eIF4G, eIF5, eIF6 but upregulates expression of translation inhibitor DAP5/p97/NAT1 in APL cells. Translational control of gene expression has been identified as an important regulatory mechanism for gene products involved in regulation of cell proliferation, differentiation and apoptosis. Programmed cell death 4(PDCD4) inhibits cap-dependent translation and exerts transformation-suppressing activity by inhibiting the helicase activity of eIF4A. . Here we investigated whether PDCD4 plays a role in ATRA-induced growth inhibition and terminal differentiation by mediating translational suppression. We found for the first time that ATRA (1 mM) and As(2)O(3) ( 0.4 mM and 2 mM) induced PDCD4 expression at mRNA and protein level detected by RT-PCR and western blotting analyses, respectively, after 24 h of treatment in NB4 cells. As(2)O(3) induced maximum PDCD4 protein expression at 72 h of treatment in NB4 cells ATRA induced PDCD4 mRNA expression in ATRA responsive human acute myeloid leukemia cells (HL-60) but not in ATRA-resistant HL60 cells (HL-60R), which express a point mutation in ATRA binding domain of RARa, suggesting PDCD4 expression is mediated through retinoid receptor alpha in HL-60 leukemia cells. Overall data suggest that translational control may play a role in ATRA-induced differentiation and As(2)O(3)-induced effects. We are currently determining whether other retinoid receptors are involved in ATRA-induced expression of PDCD4 and testing the hypothesis that whether PDCD4-mediated translational suppression is critical to ATRA-induced APL cell differentiation. Activation of these pathways that lead to translational suppression reveals a novel mechanism of ATRA action and provide novel insights into ATRA-induced differentiation program in APL cells.Better understanding of posttranscriptional control of gene expression may offer targets for the differentiation therapy and chemo preventive strategies.
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Chiu, Vi Kien, Rama Gallupalli, Diaa Osman, Zhaoshi Zeng, Jinru Shia, Philip Paty, and Anne-France Le Rolle. "Effect of tumor progression on colon cancer stem cell plasticity." Journal of Clinical Oncology 36, no. 4_suppl (February 1, 2018): 688. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.688.
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688 Background: Stage I colon cancer initiation is optimized through the activation of the embryonic stem cell (SC)-like program in colon adenoma cells (Le Rolle AF, et al., 2016). This malignant transformation requires cellular dedifferentiation since the embryonic SC-like program does not exist a priori in colon cells. High initial tumor plasticity provides a competitive advantage as the tumor has more intrinsic phenotypic flexibility to survive environmental challenges. Inhibition of the embryonic SC-like program represents a novel therapeutic strategy. Herein, we examine the evolution this high tumor plasticity in stage I-IV colon cancer. Methods: Human colon cancer tissues were collected prospectively under an MSKCC IRB protocol (Jan 1990-Dec 2000). RNA in situ hybridization of LGR5, a colon SC marker, was carried out on human colon tumors before and after therapeutic interventions. We performed Gene Set Enrichment Analysis (GSEA 2.0 Broad Institute software) using Affymetrix U133A expression profiles from normal colon mucosa (n = 33) and colon cancer epithelia from stage I (n = 17), II (n = 35), III (n= 39) and IV (n= 46) tumors. Statistical analyses were conducted with GraphPad Prism 5 and Microsoft Excel. Results: Putative colon SC markers and differentiation markers are increased and decreased, respectively, in stage I-IV colon cancer in comparison to normal colon. Although colon adenoma originates from LGR5+ colon SC, LGR5+ overexpression per se correlates with good prognosis stage IV colon cancer and is not a colon cancer stem cell biomarker. Maximal embryonic SC-like program enrichment occurs in stage I colon cancer. GSEA comparisons of moderately differentiated stages II-IV versus stage I colon cancer reveal progressive tumor differentiation from the stage I embryonic SC-like program toward the intestinal SC program at more advanced tumor stages. Notably, poorly differentiated stage IV colon cancer retains an embryonic SC-like program. Conclusions: We conclude that except for poorly differentiated tumors, colon cancer progression from stage I to IV involves a heterogeneous tumor differentiation process from an embryonic SC-like program towards the intestinal SC or more differentiated intestinal cell programs.
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Wang, Peng, James C. McWilliams, and Claire Ménesguen. "Ageostrophic instability in rotating, stratified interior vertical shear flows." Journal of Fluid Mechanics 755 (August 19, 2014): 397–428. http://dx.doi.org/10.1017/jfm.2014.426.
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AbstractThe linear instability of several rotating, stably stratified, interior vertical shear flows $\def \xmlpi #1{}\def \mathsfbi #1{\boldsymbol {\mathsf {#1}}}\let \le =\leqslant \let \leq =\leqslant \let \ge =\geqslant \let \geq =\geqslant \def \Pr {\mathit {Pr}}\def \Fr {\mathit {Fr}}\def \Rey {\mathit {Re}}\overline{U}(z)$ is calculated in Boussinesq equations. Two types of baroclinic, ageostrophic instability, AI1 and AI2, are found in odd-symmetric $\overline{U}(z)$ for intermediate Rossby number ($\mathit{Ro}$). AI1 has zero frequency; it appears in a continuous transformation of the unstable mode properties between classic baroclinic instability (BCI) and centrifugal instability (CI). It begins to occur at intermediate $\mathit{Ro}$ values and horizontal wavenumbers ($k,l$) that are far from $l= 0$ or $k = 0$, where the growth rate of BCI or CI is the strongest. AI1 grows by drawing kinetic energy from the mean flow, and the perturbation converts kinetic energy to potential energy. The instability AI2 has inertia critical layers (ICL); hence it is associated with inertia-gravity waves. For an unstable AI2 mode, the coupling is either between an interior balanced shear wave and an inertia-gravity wave (BG), or between two inertia-gravity waves (GG). The main energy source for an unstable BG mode is the mean kinetic energy, while the main energy source for an unstable GG mode is the mean available potential energy. AI1 and BG type AI2 occur in the neighbourhood of $A-S= 0$ (a sign change in the difference between absolute vertical vorticity and horizontal strain rate in isentropic coordinates; see McWilliams et al., Phys. Fluids, vol. 10, 1998, pp. 3178–3184), while GG type AI2 arises beyond this condition. Both AI1 and AI2 are unbalanced instabilities; they serve as an initiation of a possible local route for the loss of balance in 3D interior flows, leading to an efficient energy transfer to small scales.
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Batlevi, Connie, Anna Alperovich, Katy Smith, Zhitao Ying, Jacob D. Soumerai, Amanda R. Copeland, Erel Joffe, et al. "Outcomes of Follicular Lymphoma Patients By Dynamic FLIPI at Diagnosis and Initial Treatment in the Post-Rituximab Era." Blood 128, no. 22 (December 2, 2016): 4119. http://dx.doi.org/10.1182/blood.v128.22.4119.4119.
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Abstract Background: Prognosis of follicular lymphoma (FL) has long been defined by the FLIPI score (Solal-Céligny et al., 2004) which is a 5 factor risk model consisting of age, stage, lactate dehydrogenase, hemoglobin and number of nodal areas. The FLIPI model has been validated at diagnosis in both the pre- and post-Rituximab eras. However, many patients are initially observed and have prolonged lead time from diagnosis to first treatment. In this study, we investigated whether FLIPI risk group at diagnosis changed by the time of initial treatment, and whether change of FLIPI risk group impacted treated outcome. Patients and Methods: All adult (≥18 yo) patients with de novo follicular lymphoma (FL) treated at our center between 1998 and 2007 were evaluated. Study excluded patients with ≤2 follow up visits, known divergent of composite histology at diagnosis, and active concurrent malignancies. FLIPI was scored at diagnosis and at initiation of first treatment. For patients with missing FLIPI data, FLIPI category was scored if the omission did not alter the FLIPI category. Stable FLIPI risk group was defined as FLIPI score being low or intermediate at diagnosis and at initiation of first treatment (Low-Low, Int-Int). Progressed FLIPI risk group was defined by the population which changed categories from low or intermediate at diagnosis to a higher category at initiation of treatment (Low-Int, Low-High, Int-High). FLIPI scores were available for 570 patients at both diagnosis and initial treatment. Overall survival (OS) and progression free survival (PFS) were evaluated by Kaplan-Meier method and compared by log-rank tests. Time of diagnosis was used as time origin for OS analyses. When OS analyses involved FLIPI score at the first treatment, time of the first treatment was used as the entry time to adjust the risk sets to account for the fact that FLIPI at first treatment is unknown before the onset of the first treatment. Chi-squared tests and Fisher's exact tests were used to compare categorical variables by FLIPI score change status. Progression free survival before and after 24 months (PFS24) of initial therapy were calculated. Results: For 898 FL patients, median follow up was 9.2 years (range 0.23 - 16.84), median OS not reached. Based on FLIPI at diagnosis, the 5 year OS is 97.2% for low risk, 93.0% for int risk, and 80.2% for high risk, 10 yr OS is 90.9% for low risk, 77.7% for int risk, and 67.6% for high risk. Of 570 patients with FLIPI at diagnosis and first treatment, median time to first treatment was 0.18 years (range 0-12.5) for patients with stable FLIPI (N=280) and 2.70 years (range 0.01-13.33) for patients with progressed FLIPI (N=83). For patients observed ≥ 6 and 12 months, the median time to first treatment was 1.21 years (N=47, range 0.51-12.5) and 2.49 years (N=29, range 1.0-12.5) for patients with stable FLIPI and 3.77 years (N=62, range 0.54-13.3) and 3.92 years (N=57, range 1.13-13.3) for patients with progressed FLIPI, respectively. Progressed FLIPI was observed in 14.6% (83/570) of patients. The incidence of progressed FLIPI was 51.4% (57/111) in patients observed ≥1 year before initiating therapy. Parameters contributing to progressed FLIPI compared to stable FLIPI were decreased hemoglobin (29% versus 6%), increased nodal areas affected (43% versus 2%) and higher LDH (37% versus 5%). Patients with stable FLIPI had longer PFS at 12 and 24 months, 88.6% versus 73.8% (P=0.006) and 79.3% versus 66.1% (P= 0.031) (Figure 1). Analysis of patients initially observed ≥ 6 or 12 months demonstrated that progressed FLIPI negatively affected OS and PFS (Figure 2, observed ≥ 12 month data not shown). Median PFS for patients observed ≥ 6 months was 8.36 years for stable FLIPI, 3.14 years for progressed FLIPI. At observation of ≥ 12 months, median PFS was 6.25 and 3.22 years for stable and progressed FLIPI, respectively. Increased FLIPI was associated with increased risk of transformation throughout the disease course (25% vs 16%, P=0.039). Conclusion: Progressed FLIPI between diagnosis and first line treatment is associated with a reduced PFS, and increased incidence of histologic transformation. In patients who are initially observed, a progressed FLIPI reduces OS and PFS. The effect on PFS may be related to treatment bias and ongoing analysis is underway. Progressed FLIPI potentially identifies a population with heightened risk of transformation. Disclosures Hamlin: Seattle Genetics: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Portola: Research Funding; Novartis: Research Funding; Molecular Templates: Research Funding; Xencor: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Horwitz:Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy; Huya: Consultancy; Infinity: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Spectrum: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Kumar:Celgene: Honoraria, Other: Scientific Advisory Board; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Adaptive Biotechnologies: Research Funding; Celgene: Research Funding. Moskowitz:Bristol Myers Squibb: Honoraria; Merck: Honoraria; Seattle Genetics: Honoraria, Research Funding. Moskowitz:Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Palomba:Pharmacyclics: Consultancy. Zelenetz:Gilead Sciences: Research Funding.
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Brown, Jennifer R., Matthew S. Davids, Julie E. Chang, Shuo Ma, Juliana M. L. Biondo, Yong Mun, Madlaina Breuleux, and William G. Wierda. "Outcomes of Ibrutinib (Ibr) Therapy in Ibr-Naïve Patients (pts) with Chronic Lymphocytic Leukemia (CLL) Progressing after Venetoclax (Ven)." Blood 134, Supplement_1 (November 13, 2019): 4320. http://dx.doi.org/10.1182/blood-2019-123665.
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Introduction: The approval of several new, targeted agents has been transformative in the treatment of CLL. Prospective clinical trial data support the use of Ven after Ibr in CLL (Jones JA et al. Lancet Oncol 2018); however, limited data are available on the inverse sequencing of these agents (Mato AR et al. Br J Haematol 2018; Anderson M et al. Blood 2017). Given the recent FDA approval of Ven + obinutuzumab in first-line (1L) CLL, an upsurge in Ibr-naïve pts needing therapy post-Ven is likely; characterizing this sequencing is of the upmost importance. Here we present a US multicentre, retrospective, chart-review analysis to explore outcomes of Ibr post-Ven, in Ibr-naïve pts with CLL. Methods: Efficacy and safety outcomes were investigated for pts with Ibr-naïve CLL, treated with Ven +/- CD20 monoclonal antibody (mAb), who developed progressive disease ([PD] or discontinued Ven) and received Ibr salvage therapy (+/- CD20 mAb). Analyses included pts in 1L or relapsed/refractory setting. Pts were treated between Feb 14, 2012 and Jun 6, 2019, across four institutions (US); data cutoff was Jul 18, 2019. Results: Data were available for 27 pts with CLL who received Ibr post-Ven - the largest cohort to date. Median age was 64 (41-79) years, median time from diagnosis to first therapy was 9.0 (0-117.7) months (mo), and the median number of therapies prior to Ven was 2 (0-9). Prior therapies were varied and included: 1 Bruton's tyrosine kinase inhibitor (BTKi; not Ibr), 3 lenalidomide, 1 pt received 9 lines of therapy (including: idelalisib, lenalidomide, anti-CD22 and temsirolimus), others received chemo- or chemoimmunotherapy, or CD20 mAb only. Median time from diagnosis to initiation of Ven was 56.3 (0-157.7) mo. At baseline, the median lymphocyte count was 2.2 (0.2-220.0) K/µL; 8/24 (33.3%) pts had a lymph node ≥ 5cm. All evaluable pts (26/26) had ≥1 unfavourable prognostic risk factor; 12/20 (60.0%) pts had del17p, 10/16 (62.5%) had del11q, 12/24 (50.0%) had complex karyotype (CK) and 13/15 (86.7%) pts had unmutated IGHV. A complete or partial response (CR or PR) to Ven was achieved in 4/26 (15.4%) and 18/26 (69.2%) evaluable pts, respectively. The median time to PD on Ven was 29.0 (1.0-118.0) mo, with a median treatment duration of 18.0 (0.1-64.3) mo. Pts discontinued Ven due to PD (n=18), consent withdrawal (n=2), non-compliance (n=1), and other (n=6; allogeneic stem cell transplantation n=2, physician decision n=3, not evaluable n=1). Prior to initiation of Ibr, the median lymphocyte count was 1.9 (0.01-179.0) K/µL; 15/26 (57.7%) pts had adenopathy, and 5/13 (38.5%) had a lymph node ≥ 5cm. Risk factors included: del17p (4/10; 40.0%), del11q (4/9; 44.4%), CK (8/17; 47.1%) and unmutated IGHV (11/14; 78.6%). Median time from Ven initiation to Ibr initiation was 31.9 (1.8-60.3) mo; median time to Ibr initiation post-Ven was 0.7 (0-39.7) mo. The overall response rate to Ibr was 56.0% (CR: 1/25, PR: 13/25). The time to progression on Ibr, post-Ven, varied from 3.0 to 53.0 mo (n=10). The median duration of Ibr therapy was 18.3 (3.7-53.2) mo and 20.0 (4.9-44.3) mo for those remaining on Ibr (8/27); the median follow-up time matched the median therapy duration. Nineteen pts discontinued Ibr due to: PD (n=9), physician decision (n=4), adverse events (AEs; n=2), transplant (n=2), symptomatic deterioration and unknown reason (n=1 each). The median number of therapies prior to Ven for the 9 pts who discontinued Ibr due to PD was 2 (1-9); 4/9 pts received novel targeted therapies. Richter's transformation occurred in 1 pt (1/9). The 2 pts who discontinued Ibr due to AEs experienced either atrial fibrillation (AF)/brain abscess or pneumonia after 11.6 and 18.2 mo of Ibr, respectively. Other notable AEs were: major bleeding (n=1), AF (n=2), infection (n=1), neutropenia (n=1), myalgia/arthralgia (n=2), and other cardiac event (n=1). Ibr dose reductions due to fatigue and general malaise occurred in 1 pt. Conclusions: With the limitations of a retrospective series using real-world data, these data suggest that Ibr had substantial clinical activity post-Ven in heavily pre-treated, high-risk CLL pts; no new safety signals arose. Larger, prospective studies are required to fully characterize the efficacy of Ibr after Ven. Meanwhile, salvage therapy with Ibr remains a good option for pts with CLL who relapse after Ven. Disclosures Brown: Sunesis: Consultancy; Pharmacyclics: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Invectys: Other: Data safety monitoring board; Octapharma: Consultancy; Morphosys: Other: Data safety monitoring board; Janssen: Honoraria; Dynamo Therapeutics: Consultancy; Teva: Honoraria; Sun Pharmaceuticals: Research Funding; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; BeiGene: Consultancy; Catapult Therapeutics: Consultancy; AstraZeneca: Consultancy; Acerta Pharma: Consultancy; AbbVie: Consultancy; Juno/Celgene: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding. Davids:Research to Practice: Honoraria; AbbVie, Acerta Pharma, Adaptive, Biotechnologies, Astra-Zeneca, Genentech, Gilead Sciences, Janssen, Pharmacyclics, TG therapeutics: Membership on an entity's Board of Directors or advisory committees; AbbVie, Astra-Zeneca, Genentech, Janssen, MEI, Pharmacyclics, Syros Pharmaceuticals, Verastem: Consultancy; Acerta Pharma, Ascentage Pharma, Genentech, MEI pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem: Research Funding. Chang:Genentech: Research Funding; Celgene: Research Funding; Adaptive Biotechnologies: Research Funding. Ma:Kite: Consultancy; Xeme: Research Funding; Abbvie: Research Funding; Beigene: Research Funding; Bioverativ: Consultancy; Incyte: Research Funding; Genentech: Consultancy; Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Gilead: Research Funding; Janssen: Consultancy, Speakers Bureau; Novartis: Research Funding; Juno: Research Funding; Acerta: Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau. Biondo:Genentech, Inc.: Employment; F. Hoffmann-La Roche Ltd: Equity Ownership. Mun:Genentech: Employment, Equity Ownership. Breuleux:F. Hoffmann - La Roche Ltd: Employment, Equity Ownership; Gilead: Equity Ownership; Basilea Ltd: Equity Ownership. Wierda:Janssen: Research Funding; Xencor: Research Funding; Gilead Sciences: Research Funding; Pharmacyclics LLC: Research Funding; Cyclcel: Research Funding; Sunesis: Research Funding; AbbVie: Research Funding; KITE pharma: Research Funding; Miragen: Research Funding; Juno Therapeutics: Research Funding; GSK/Novartis: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Loxo Oncology Inc.: Research Funding; Genentech: Research Funding; Acerta Pharma Inc: Research Funding.
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Mendoza-Castrejon, Jonny, Emily B. Casey, Riddhi M. Patel, and Jeffrey A. Magee. "SKIDA1 Sustains MLL-ENL-Expressing Hematopoietic Stem and Progenitor Cells." Blood 138, Supplement 1 (November 5, 2021): 3294. http://dx.doi.org/10.1182/blood-2021-148604.
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Abstract Chromosomal translocations involving the MLL1 gene often drive infant acute myeloid leukemia (AML). MLL fusion proteins (e.g., MLL-ENL, MLL-AF9, MLL-AF10) activate self-renewal programs in hematopoietic stem and progenitor cells, ultimately leading to transformation. The high frequency of MLL1 rearrangements in infant leukemias suggests that neonatal progenitors are uniquely poised to transform in response to these mutations. Indeed, we have recently shown that MLL-ENL initiates AML more efficiently in neonatal progenitors than in adult progenitors (Okeyo-Owuor et. al. Blood Advances, 2019). This raises the question of whether MLL-ENL induces key effectors of transformation more efficiently in neonatal progenitors than in adult progenitors. We identified Ski/Dach Domain Containing 1 (Skida1) as a gene that is highly induced by MLL-ENL in neonatal, but not adult hematopoietic progenitors. SKIDA1 is also highly expressed in human pediatric AML, and this expression is largely restricted to leukemias with MLL1 rearrangements. These observations suggest that Skida1 may be a critical, neonate-specific effector of MLL-ENL driven leukemogenesis. To test whether SKIDA1 plays a role in hematopoiesis and leukemogenesis, we generated a germline loss-of-function mouse allele. First, we tested whether loss of SKIDA1 perturbed hematopoiesis by flow cytometry. SKIDA1 deletion caused modest expansion of hematopoietic stem cells (HSCs) in neonates at post-natal day 0 (P0) and a modest decrease of hematopoietic committed progenitor cells (HPCs) at P14, but no changes in fetal or adult HSC/HPC numbers were observed. We then assessed HSC function by transplanting HSCs into lethally irradiated mice to assess their multi-lineage repopulating potential. Loss of SKIDA1 did not perturb HSC function at any stage of development, indicating a minor role in normal hematopoiesis. Next, we tested whether SKIDA1 modulates HSC or HPC numbers in the context of MLL-ENL expression. We crossed Skida1-/- mice to mice with a tetracycline inducible MLL-ENL transgene. The resulting mice (TetO-MLL-ENL; Vav1-Cre) express MLL-ENL specifically in hematopoietic cells beginning at embryonic day 10.5 (E10.5) in the absence of doxycycline, concordant with the onset of Vav1-Cre expression. When we induced MLL-ENL expression in Skida1 -/- mice, we observed near complete loss of HSCs and a severe reduction of HPCs. The reduction in HSC and HPC numbers in TetO-MLL-ENL; Vav1-Cre; Skida1 -/- neonates was far more severe than we observed in TetO-MLL-ENL; Vav1-Cre mice alone. Furthermore, this phenotype emerged between P0 and P14, indicating that it requires a neonatal context to manifest. This coincides with the developmental stage at which MLL-ENL most efficiently induces AML (Okeyo-Owuor et. al. Blood Advances, 2019). This data suggest that SKIDA1 helps sustain pre-leukemic MLL-ENL-expressing HSCs and HPCs shortly after birth. Ongoing studies will address the mechanism by which SKIDA1 regulates AML. Our current work raises two important points. First, SKIDA1 appears to have a far more important role in sustaining MLL-ENL-expressing progenitors than normal progenitors, raising the prospect for an excellent therapeutic window. Secondly, our findings show that age-specific MLL-ENL targets can shape pre-leukemic hematopoiesis and potentially AML initiation. This may help explain why MLL1 rearrangements account for a higher percentage of infant and childhood leukemias than adult leukemias. Disclosures No relevant conflicts of interest to declare.
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Ysebaert, Loic, Anne-Sophie Michallet, Fontanet Bijou, Aline Clavert, Anne Quinquenel, Anne Calleja, Romain Guieze, Emmanuelle Ferrant, Annie Brion, and Kamel Laribi. "Real-World Ibrutinib Validation of the Ball Score to Predict Overall Survival: A Filo Group Study in RR CLL Patients." Blood 134, Supplement_1 (November 13, 2019): 1741. http://dx.doi.org/10.1182/blood-2019-122318.
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Abstract Ibrutinib has revolutionized the management of RR CLL in the past 5 years, improving overall survival (OS) over standard chemo-immunotherapies (CIT) in the registration trials HELIOS and RESONATE. Recently, based on these two studies, a score has been validated able to predict 3 groups with different OS (acronym BALL, further validated in cohorts of patients treated with CIT or other targeted agents) (1). The BALL model consists of four factors with 1 point each (serum ß2-microglobulin>5mg/dL, lactate dehydrogenase >upper limit of normal, hemoglobin <110g/L for women or <120g/L for men, and time from initiation of last therapy <24 months). It separates patients into low (score 0-1), intermediate (score 2-3), and high risk (score 4) groups. Yet, BALL score has never been validated in large cohorts of ibrutinib patients. Methods We collected survival data and causes of death across 10 FiLO centers, in patients treated with ibrutinib monotherapy as per label for RR disease. We included patients across performans statuses, irrespective of previous line of therapies (LOT) or age, with 3 (n=329) or 4 (n=250) available BALL criteria at the time of initiation. Results Median FU was 29.3 months. Stratification of BALL scores in 250 patients (with 4 parameters known) was as follows: low risk (n=88, 35.2%), intermediate risk (n=122, 48.8%), and high risk (n=40, 16%), with estimated 2-years OS rates of 87.3%, 82.3% and 58.8%, respectively (Figure 1A, C-statistics index 0.64). These results are very similar (all 3 groups) to what Soumerai J et al.reported in their ibrutinib/CIT training dataset of 581 patients (1). Causes of 60/250 deaths were as follows: CLL 28.3%, Richter transformation 15%, infectious (33.3%) or cardiovascular (18.3%) toxicity, second cancer (5%). High risk score was significantly associated to deletion 17p/TP53 mutational status (69.4% vs47%, p<0.001), LOT3+ (65.8% vs33.8%, p=0.02), but not age or gender. We also calculated a "worse BALL score" by adding 1 point to 79 more patients with 3 known parameters (n=329 in total). Stratification was as follows: low risk (6.7%, 2y-OS 100%), intermediate risk (45.6%, 2y-OS 82.9%), and high risk (47.7%, 2y-OS 74.6%) (Figure 1B). The latter results were very comparable to the internal validation dataset of ibrutinib/CIT in 242 patients. Causes of 79/329 deaths were as follows: CLL 27.8%, Richter transformation 17.7%, infectious (35.4%) or cardiovascular (15.2%) toxicity, second cancer (3.8%). Altogether, the BALL score was useful to delineate 3 risk-groups with statistically different survivals in real-world ibrutinib patients, despite 50% of deaths were due to toxicity. By Cox univariate analysis for OS (n=227, events=57), variables with significant impact on prognosis were: age>79y (HR 2.09, p=0.003), male gender (HR 1.5, p=0.046), del17p/TP53 mutation (HR 1.45, p=0.049), previous lines of therapy (LOT1-2 vs 3+, HR 2.17, p<0.0001), and BALL score (2-3 vs0-1 HR 1.8, and 4 vs0-1 HR 5.69, p<0.0001). By multivariate analysis, only LOT3+ (HR 2.6, p=0.003) and BALL score (2-3 vs0-1 HR 2.16, p=0.05, and 4 vs0-1 HR 5.2, p<0.001) were shown as independent factors significantly associated with shorter OS. These results further advocated for the use of BALL score in our practice, because we validated its use even in elderly RR patients. In the clinical trials used for model building, median age was <65y, and we included 23.1% of patients >79y. On the other hand, LOT was excluded from the model, and so its impact left unanswered by the first publication. Our data suggested that OS of multi-relapsing patients (3 or more previous lines of therapy) was not adequately predicted by the BALL score. On the other hand, we confirmed that deletion 17p/TP53mutational status was not an independent factor for OS, because predicted by the BALL score parameters (1). Conclusions In our series, the BALL score also identified a well-defined cohort of real-world RR CLL patients with an unmet clinical need despite the use of ibrutinib (median OS 27 months). We suggest that patients in the high-risk group should be thoroughly monitored, or even proposed clinical trials with drug combinations, or even cellular therapies approaches (CAR-T cells, bispecific antibodies) due their shorter OS. (1) Soumerai J, et al. Risk Model for Overall Survival in Relapsed or Refractory Chronic Lymphocytic Leukaemia in the Era of Targeted Therapies. Lancet Haematol 2019. Disclosures No relevant conflicts of interest to declare.
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Perez, Ruben Hernandez, Ang Li, Sarvari Venkata Yellapragada, Matthew Zheng, Maria Otazo, Martha Mims, and Gustavo A. Rivero. "Intrinsic Biological Variability In High-Risk-Myelodysplastic Syndrome Impacts Overall Survival (OS) In Patients Experiencing Cytogenetic Evolution Treated With Azanucleosides." Blood 122, no. 21 (November 15, 2013): 1537. http://dx.doi.org/10.1182/blood.v122.21.1537.1537.
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Abstract Background Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal myeloid disorders characterized by marrow failure and variable risk for acute leukemia transformation. The revised International prognostic scoring system (R-IPSS) biologically defines 5 risk disease categories and assists in logistic outcome prediction and treatment algorithm. For those patients (pts) with high risk MDS, treatment with hypomethylating agents (HMAs) such as azacitidine (AZA) and decitabine (DAC) is associated with prolonged survival. However primary and secondary treatment failures are common phenomenon and treatment outcomes after failure are dismal (Prebet T et al. JCO. 2011; Prebet T. Haematologica.2013). Mechanisms of loss of response to azanucleosides are largely unknown. Cytogenetic evolution (CE) defined as the acquisition of additional clones or karyotypic abnormalities in pts with preexisting normal or aberrant karyotype, during disease course or after treatment, is observed in about 30% of MDS patients, and is linked to genomic instability resulting in adverse outcomes. We investigated risk factors for CE in MDS pts treated with HMAs and its impact of OS. Method From 2000-2012, 13/124 pts (16%) (Median age 59 years; range 54-80) with confirmed diagnosis of MDS treated with HMAs were identified from the Michael E. Medical Center Cancer Registry. Patients were included if at least 2 G-banding metaphases studies were available and corresponded to: (1) karyotyping at disease diagnosis; and (2) at the time of azanucleoside failure. Overall Survival (OS) was analyzed for pts who have received HMAs with and without evidence of CE. Multivariate Cox regression analysis was performed to assess the impact of multiple independent variables on clinical outcome. Results The incidence of CE in patients treated with HMAs was 38%. Median R-IPSS scores at diagnosis for pts with and without CE were 7.5 (5-very high; WHO subgroups: RCMD [2] and RAEB-2 [3]) vs. 4.75 (4-high and 4-Int; WHO subgroups: RCMD [3], RCUD [1] CMML [2]; MDS/MPN [2]) P=0.003. OS for pts with and without CE treated with HMAs was 419 days (d) vs 743 d, respectively P=0.001;CI= 0.23-0.89. In patients with CE, univariate analysis identified platelets and blast count at disease initiation (P=0.03, each) as prognostic variables impacting clinical outcome; however, by multivariate analysis a non-statistically significant trend was observed only for R-IPSS, P=0.21. (Table 1). Conclusion In our retrospective analysis, acquisition of CE at the time of azanucleoside failure was associated with unfavorable outcome. Exploratory logistic regression analysis suggests that high-risk disease biology at disease initiation modulates incidence of CE in MDS pts treated with azanucleosides. Larger coalesced cohort of MDS pts experiencing CE could facilitate understanding of mechanisms associated with acquisition of genomic instability during azanucleoside failure and assist in identification of novel MDS targeted therapies that could ensure sustained response. Disclosures: No relevant conflicts of interest to declare.
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Knox, Jennifer J., Mairead Geraldine McNamara, Lipika Goyal, Mark Doherty, Christoph Springfeld, Joon Oh Park, Aimery De Gramont, et al. "NUC-1031 in combination with cisplatin for first-line treatment of patients with advanced biliary tract cancer (NuTide:121)." Journal of Clinical Oncology 38, no. 4_suppl (February 1, 2020): TPS602. http://dx.doi.org/10.1200/jco.2020.38.4_suppl.tps602.
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TPS602 Background: Biliary tract cancer (BTC) carries a poor prognosis and has no approved treatments. Although gemcitabine + cisplatin (GemCis) is accepted as the global standard of care (SoC) for 1st-line treatment, the reported unconfirmed ORR and OS from randomized studies of this combination are low at 18.5-26.1% and 11.2-11.7 months, respectively. NUC-1031, a phosphoramidate transformation of gemcitabine, is designed to overcome key cancer resistance mechanisms associated with gemcitabine. Promising signs of efficacy have been observed with single-agent NUC-1031 in a Phase I study in advanced solid tumors (Blagden et al 2018) and in the Phase Ib ABC-08 study of NUC-1031 + cisplatin 25 mg/m2 on days 1 and 8 of a 21-day cycle for the 1st-line treatment of advanced BTC. Of 14 patients (pts) enrolled in 2 cohorts (NUC-1031: 625 mg/m2 and 725 mg/m2), 1 pt achieved a CR and 6 pts achieved PR, giving an unconfirmed ORR of 50% and representing an approximate doubling of ORR over SoC. The combination was well-tolerated with no unexpected adverse events or dose-limiting toxicities. The RP2D of NUC-1031 in combination with cisplatin is 725 mg/m2. The tolerability profile together with robust efficacy signals suggested NUC-1031 + cisplatin may represent a more effective therapy than GemCis for BTC and led to initiation of a global Phase III study. Methods: A Phase III, open-label, randomized head-to-head study of NUC-1031 + cisplatin versus GemCis for 1st-line treatment of advanced BTC will include pts ≥18 years with histologically- or cytologically-proven BTC (including cholangiocarcinoma, gallbladder, or ampullary cancer), who have had no prior systemic chemotherapy for locally advanced/metastatic disease. A total of 828 pts will be randomized (1:1) to either 725 mg/m2 NUC-1031 + 25 mg/m2 cisplatin or 1000 mg/m2 gemcitabine + 25 mg/m2 cisplatin, administered on days 1 and 8 of a 21-day cycle. Primary objectives are OS and ORR. Secondary objectives include further measurements of efficacy, safety, pharmacokinetics, and patient-reported quality of life. The study will be conducted at approximately 120 sites across North America, Europe and Asia Pacific countries. Clinical trial information: NCT04163900.
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Knox, Jennifer J., Mairead Geraldine McNamara, Daniel H. Palmer, T. R. Jeffry Evans, David Goldstein, John A. Bridgewater, and Juan W. Valle. "NUC-1031 in combination with cisplatin for first-line treatment of advanced biliary tract cancer." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): TPS4156. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.tps4156.
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TPS4156 Background: Cisplatin and gemcitabine (CisGem) is the global standard of care for 1st-line treatment of patients (pts) with advanced biliary tract cancer (BTC). No agents have regulatory approval for this disease. CisGem achieves an objective response rate (ORR) of 26% and median overall survival (OS) of 11.7 months (ABC-02). Key cancer resistance mechanisms limit gemcitabine efficacy. NUC-1031, a phosphoramidate transformation of gemcitabine, is designed to overcome resistance mechanisms associated with poor gemcitabine response. Promising signs of efficacy have been observed with single agent in a phase I study in solid tumors (Blagden et al 2018) and in the phase Ib ABC-08 study of NUC-1031 + cisplatin 25 mg /m2 d1, d8 q 21 days for the 1st-line treatment of advanced BTC. 14 pts have been enrolled across 2 cohorts (NUC-1031: 625 mg/m2 and 725 mg/m2). In 11 pts evaluable for response ORR was 64% (1 CR, 6 PRs) and DCR was 73%. PFS/OS data is maturing. The combination was very well-tolerated with no unexpected adverse events or dose-limiting toxicities. The RP2D in combination with cisplatin is 725 mg/ m2. Safety, coupled with encouraging efficacy signal has led to initiation of a global Phase III development program. Methods: A Phase III, open-label, randomized head-to-head study of NUC-1031 + cisplatin versus CisGem for the 1st-line treatment of advanced BTC will include pts ≥18 years with histologically- or cytologically-proven BTC (including cholangiocarcinoma, gallbladder, or ampullary cancer), that is not resectable and who have had no prior systemic chemotherapy for locally advanced/metastatic disease. A total of 828 pts will be randomized (1:1) to either 725 mg/m2 NUC-1031 + 25 mg/m2 cisplatin or 1000 mg/m2 gemcitabine + 25 mg/m2 cisplatin, administered on Days 1 and 8 of a 21-day cycle, respectively. Primary objectives are OS and ORR. Secondary objectives include further measurements of efficacy, safety, pharmacokinetics, and patient-reported quality of life. The study will be conducted at approximately 120 sites across North America, Europe and Asia Pacific countries. Clinical trial information: NCT02351765.
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Chan, Lai N., Christian Hurtz, Huimin Geng, Erica Ballabio, Gang Xiao, Gauri Deb, Haytham Khoury, et al. "Rationale for Targeting BCL6 in MLL-Rearranged B-ALL." Blood 134, Supplement_1 (November 13, 2019): 1239. http://dx.doi.org/10.1182/blood-2019-131565.
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Background and significance: MLL-gene rearrangements occur in ~10% of B-cell acute lymphoblastic leukemia (B-ALL) and 70% of infant B-ALL and define a group of patients with dismal outcomes. MLL belongs to the family of histone methyltransferases and plays a critical role in maintaining hematopoietic stem cells (Jude et al. 2007). Analyzing gene expression data from 207 children with high-risk ALL, we found that BCL6 is a predictor of poor clinical outcome in B-ALL, particularly in cases with MLL rearrangements. Thus, while the mechanisms of drug-resistance in MLL-rearranged B-ALL are largely unknown, we studied here a potential role of BCL6 in promoting the aggressive and refractory phenotype in this subtype of B-ALL. Results: Immunohistochemical staining of bone marrow biopsies from 10 of 11 MLL-rearranged B-ALL samples studied revealed aberrant expression of BCL6, a transcription factor that promotes oncogenic B-cell transformation and drug-resistance in B-ALL (Duy et al. Nature 2011). Our genetic and ChIP-seq analyses showed that MLL-AF4 and MLL-ENL fusions directly bound to the BCL6 promoter and upregulated BCL6 expression. While oncogenic MLL-fusions strongly induced aberrant BCL6 expression in B-ALL cells, germline MLL was required to upregulate Bcl6 in response to physiological stimuli during normal B-cell development. Inducible expression of Bcl6 increased MLL mRNA levels, which was reversed by genetic deletion and pharmacological inhibition of Bcl6, suggesting a positive feedback loop between MLL and BCL6. Highlighting the central role of BCL6 in MLL-rearranged B-ALL, conditional deletion and pharmacological inhibition of BCL6 compromised leukemogenesis in transplant recipient mice and restored sensitivity to vincristine chemotherapy in MLL-rearranged B-ALL patient samples. Oncogenic MLL-fusions strongly induced transcriptional activation of the pro-apoptotic BH3-only molecule BIM, while BCL6 was required to curb MLL-induced expression of BIM. Notably, peptide (RI-BPI) and small-molecule (FX1) BCL6-inhibitors derepressed BIM and synergized with the BH3-mimetic ABT-199 in eradicating MLL-rearranged B-ALL cells. These findings uncover MLL-dependent transcriptional activation of BCL6 as a previously unrecognized requirement of malignant transformation by oncogenic MLL-fusions and identified BCL6 as a novel target for the treatment of MLL-rearranged B-ALL. Discussion: Pharmacological inhibition of BCL6 using a retro-inverso peptide inhibitor (RI-BPI) compromised MLL-rearranged B-ALL leukemia-initiation and subverted vincristine-resistance. A central mechanistic aspect of BCL6-function in MLL-rearranged B-ALL involves transcriptional repression of the pro-apoptotic BH3-only molecule Bim (BCL2L11). Profiling for BH3-only proteins in various B-ALL subtypes revealed that MLL-rearranged B-ALL is associated with increased expression of the pro-apoptotic protein BIM (Benito et al. 2015). ABT-199 (venetoclax) is a BH3-mimetic that disrupts the interaction between BCL2 and BIM, leading to BIM release and induction of apoptosis. Previous studies have found that MLL-rearranged leukemia cells are sensitive to the BCL2 inhibitor ABT-199. Besides BCL2, we here identified BCL6 as a central antagonist of pro-apoptotic BIM function in MLL-rearranged B-ALL cells. In genetic experiments, we showed that oncogenic MLL-fusions strongly activated BCL2L11 transcription reinforcing the notion that constitutively high Bim expression levels represents an important and selective vulnerability in MLL-rearranged B-ALL. Both BCL2 and BCL6 represent crucial antagonists of BIM in MLL-rearranged B-ALL, BCL2 mediating BIM-sequestration and BCL6 being required for transcriptional repression of BIM. In support of this scenario, peptide (RI-BPI) and small molecule (FX1) inhibitors of BCL6 strongly synergized with blockade of BCL2-mediated BIM sequestration (ABT-199) in killing MLL-rearranged B-ALL cells. Figure 1 Disclosures Armstrong: AstraZeneca: Research Funding; Epizyme, Inc.: Consultancy, Equity Ownership; Imago Biosciences, Inc.: Consultancy, Equity Ownership; Cyteir Therapeutics: Consultancy, Equity Ownership; Janssen: Research Funding; Novartis: Research Funding; Accent Therapeutics: Consultancy, Equity Ownership; Mana Therapeutics: Consultancy, Equity Ownership; C4 Therapeutics: Consultancy, Equity Ownership; Syros Pharmaceuticals: Consultancy, Equity Ownership; OxStem Oncology: Consultancy, Equity Ownership. Melnick:Janssen: Research Funding; Constellation: Consultancy; Epizyme: Consultancy. Milne:OxStem Ltd.: Equity Ownership.