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Literatura académica sobre el tema "Leukemia initiation and transformation"

Autor: Grafiati

Publicado: 25 de mayo de 2024

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Artículos de revistas sobre el tema "Leukemia initiation and transformation"

He, Jin, Anh Tram Nguyen y Yi Zhang. "KDM2b/JHDM1b, an H3K36me2-specific demethylase, is required for initiation and maintenance of acute myeloid leukemia". Blood 117, n.º 14 (7 de abril de 2011): 3869–80. http://dx.doi.org/10.1182/blood-2010-10-312736.

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Abstract The histone H3 lysine 36 dimethyl–specific demethylase KDM2b/JHDM1b, which is highly expressed in various human leukemias, was previously found to be important in regulating cell proliferation and cellular senescence. However, its functions in leukemia development and maintenance are unclear. Here, we demonstrate that ectopic expression of Kdm2b/Jhdm1b is sufficient to transform hematopoietic progenitors. Conversely, depletion of Kdm2b/Jhdm1b in hematopoietic progenitors significantly impairs Hoxa9/Meis1-induced leukemic transformation. In leukemic stem cells, knockdown of Kdm2b/Jhdm1b impairs their self-renewing capability in vitro and in vivo. The functions of Kdm2b/Jhdm1b are mediated by its silencing of p15Ink4b expression through active demethylation of histone H3 lysine 36 dimethyl. Thus, our study suggests that Kdm2b/Jhdm1b functions as an oncogene and plays a critical role in leukemia development and maintenance.

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Hurtz, Christian, Katerina Hatzi, Leandro Cerchietti, Melanie Braig, Eugene Park, Yong-mi Kim, Sebastian Herzog et al. "BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia". Journal of Experimental Medicine 208, n.º 11 (12 de septiembre de 2011): 2163–74. http://dx.doi.org/10.1084/jem.20110304.

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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 (TKIs). However, unless CML patients receive life-long TKI treatment, leukemia will eventually recur; this is attributed to the failure of TKI treatment to eradicate leukemia-initiating cells (LICs). Recent work demonstrated that FoxO factors are critical for maintenance of CML-initiating cells; however, the mechanism of FoxO-dependent leukemia initiation remained elusive. Here, we identified the BCL6 protooncogene as a critical effector downstream of FoxO in self-renewal signaling of CML-initiating cells. BCL6 represses Arf and p53 in CML cells and is required for colony formation and initiation of leukemia. Importantly, peptide inhibition of BCL6 in human CML cells compromises colony formation and leukemia initiation in transplant recipients and selectively eradicates CD34+ CD38− LICs in patient-derived CML samples. These findings suggest that pharmacological inhibition of BCL6 may represent a novel strategy to eradicate LICs 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.

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Mendoza-Castrejon, Jonny, Emily B. Casey, Riddhi M. Patel, Elisabeth Denby y Jeffrey Magee. "Fetal MLL-ENL Initiation Induces Developmental Stage-Specific Programs That Restrict Transformation and Depend on MLL3". Blood 142, Supplement 1 (28 de noviembre de 2023): 950. http://dx.doi.org/10.1182/blood-2023-178865.

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Infant leukemias present as either acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) and are commonly driven by KMT2A/ MLL rearrangements (MLLr). MLLr account for ~70% of infant ALL and ~50% of infant AML. Most of the MLLr that drive infant leukemias occur before birth and require very few cooperating mutations. These observations suggest that MLLr transform fetal/neonatal progenitors with great efficiency. However, this model introduces important paradoxes. First, the incidence of MLLr infant leukemia is ~20-fold lower than the incidence of adult MLLr leukemias. Second, fetal leukemias are exceedingly rare despite the fact that MLLr can arise before birth and require a low secondary mutation threshold for transformation. Third, even in mouse models that demonstrate efficient leukemogenesis, the fraction of MLLr progenitors that actually give rise to AML is quite small. Fourth, in our prior studies, we developed a doxycycline (DOX) inducible MLL-ENL mouse model (Tet-ME) to activate MLL-ENL and found that transformation efficiency is higher when MLL-ENL is induced shortly after birth rather than before birth (PMID: 31405949). These observations raise the question of whether fetal/neonatal progenitors carry intrinsic protection against transformation. To test whether fetal identity conveys protection against MLLr leukemia initiation, we activated MLL-ENL at embryonic day 10.5 (E10.5) or postnatal day 14 (P14), by removing DOX. We then assessed the leukemogenic potential of postnatal progenitors in transplantation assays. Strikingly, progenitors that expressed MLL-ENL from E10.5 onward could engraft efficiently but did not give rise to AML in recipient mice. In contrast, progenitors that expressed MLL-ENL induced from P14 onward gave rise to rapid, fully penetrant AML in recipient mice (Figure 1A). Our data show that MLL-ENL induces heritable epigenetic changes in fetal progenitors, that limit transformation potential after transplantation. To assess the unique response of fetal progenitors to MLL-ENL activation, we used our Tet-ME model and induced MLL-ENL before or after birth. We isolated P28 progenitors, repeated transplantation/survival assays and performed Cellular Indexing of Transcriptomes and Epitopes (CITE-seq), in parallel, to test whether MLL-ENL differentially reprograms pre- and post-natal progenitors (i.e., do P28 progenitors have distinct expression programs depending on when MLL-ENL is induced?). Hematopoietic progenitors had similar differentiation trajectories by pseudotime analysis, but distinct gene expression profiles after fetal and postnatal MLL-ENL induction. Some known MLL-ENL targets, including Hoxa9 and Pim1, were maintained at similar levels following fetal and postnatal induction. Other targets, including Meis1, Pbx1 and Sox4, were only expressed in the HSC/MPP cluster following postnatal induction. Metabolic and differentiation states also differed. As in the initial survival assays, MLL-ENL expressing progenitors only gave rise to AML following postnatal induction. We next sought to identify epigenetic regulators that enforce non-malignant cell fates following fetal MLL-ENL induction. We focused our screen on epigenetic factors with known tumor suppressor roles and identified the SET methyltransferase MLL3 as a candidate effector of fetal protection. Specifically, heterozygous Kmt2c deletions greatly accelerated AML initiation after fetal MLL-ENL induction, but not postnatal induction (Figure 1B). Notably, the MLL3/4 COMPASS-like complex was recently shown to antagonize the KMT2A-MENIN interaction and promote differentiation in AML cells. Our data reinforce the notion that there are ontological windows that permit or repress leukemic transformation. Quite surprisingly, fetal progenitors appear to be more resistant to transformation than neonatal progenitors, potentially accounting for the paucity of fetal MLLr leukemias. Infant leukemias that do occur must bypass heritable protective mechanisms, either via mutations or epigenetic reprogramming.

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Ugale, Amol Sanjay, Gudmundur Logi Norddahl, Martin Wahlestedt, Petter Säwén, Pekka Jaako, Cornelis J. H. Pronk, Shamit Soneji, Jorg Cammenga y David Bryder. "Hematopoietic Stem Cells Are Intrinsically Protected Against MLL-ENL Mediated Transformation". Blood 124, n.º 21 (6 de diciembre de 2014): 839. http://dx.doi.org/10.1182/blood.v124.21.839.839.

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Abstract Studies on the developmental pathways of hematopoietic stem cells (HSCs) have led to roadmaps of differentiation and resulted in key information concerning lineage relationships and restriction points in the blood system. This knowledge is also central to understand the etiology of acute myeloid leukemia (AML), where recent work has proposed that the heterogeneity and aggressiveness of AML can associate with the developmental stage of transformation. Balanced chromosomal translocations that result in fusion proteins with aberrant transcriptional regulatory activities are frequent initiating events in acute myeloid leukemia, and a prototype family of such chimeric transcription factors is represented by fusions involving the mixed lineage leukemia-1 (MLL1) gene. Previous work using mouse models have suggested that at some stage of normal differentiation there is a loss of competence to induce AML. However discrepancies exists between these mouse models concerning the target cells of MLL fusion genes. While it is clear that cells can lose competence for leukemic transformation as part of their normal differentiation, the question remains whether the most primitive HSCs are always imbued with leukemogenic competency as part of their normal biology. To address this, we developed a Doxycycline inducible transgenic mouse model of the human chimeric transcription factor Mixed Lineage Leukemia-Eleven Nineteen Leukemia (MLL-ENL). Prospective isolations of candidate leukemia-initiating cells followed by adoptive transfers allowed us to detail leukemia-initiation and competence throughout the hematopoietic hierarchy. We show that AML can origin from multiple HPC subsets with intrinsic granulocytic/monocytic potential. Closely related myeloid progenitors displayed distinct leukemic- and functional capacity in response to physiological levels of MLL-ENL, highlighting the importance of a careful prospective isolation of progenitor populations. AML could also develop efficiently from common lymphoid progenitors, supporting a latent myeloid potential of these cells. By contrast, early commitment to the megakaryocytic/erythroid lineages was incompatible with leukemic development. By contrast, disease failed to arise from the most primitive progenitor subsets, including HSCs. Investigations of the immediate transcriptional responses to MLL-ENL showed evidence for a block in differentiation in both myeloid progenitors and HSCs, while MLL-ENL restricted cell cycle progression uniquely in HSCs. Our study highlights how an oncogene can exert unique functions depending on the developmental position of its cellular targets and demonstrate the existence of a mechanism, operational at the level of immature HSCs/progenitors, which act to prevent leukemic development. Figure 1 Graphical abstract Figure 1. Graphical abstract Disclosures No relevant conflicts of interest to declare.

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Okeyo-Owuor, Theresa, Yanan Li, Riddhi M. Patel, Wei Yang, Emily B. Casey, Andrew S. Cluster, Shaina N. Porter, David Bryder y Jeffrey A. Magee. "The efficiency of murine MLL-ENL–driven leukemia initiation changes with age and peaks during neonatal development". Blood Advances 3, n.º 15 (12 de agosto de 2019): 2388–99. http://dx.doi.org/10.1182/bloodadvances.2019000554.

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Abstract MLL rearrangements are translocation mutations that cause both acute lymphoblastic leukemia and acute myeloid leukemia (AML). These translocations can occur as sole clonal driver mutations in infant leukemias, suggesting that fetal or neonatal hematopoietic progenitors may be exquisitely sensitive to transformation by MLL fusion proteins. To test this possibility, we used transgenic mice to induce one translocation product, MLL-ENL, during fetal, neonatal, juvenile and adult stages of life. When MLL-ENL was induced in fetal or neonatal mice, almost all died of AML. In contrast, when MLL-ENL was induced in adult mice, most survived for >1 year despite sustained transgene expression. AML initiation was most efficient when MLL-ENL was induced in neonates, and even transient suppression of MLL-ENL in neonates could prevent AML in most mice. MLL-ENL target genes were induced more efficiently in neonatal progenitors than in adult progenitors, consistent with the distinct AML initiation efficiencies. Interestingly, transplantation stress mitigated the developmental barrier to leukemogenesis. Since fetal/neonatal progenitors were highly competent to initiate MLL-ENL–driven AML, we tested whether Lin28b, a fetal master regulator, could accelerate leukemogenesis. Surprisingly, Lin28b suppressed AML initiation rather than accelerating it. This may explain why MLL rearrangements often occur before birth in human infant leukemia patients, but transformation usually does not occur until after birth, when Lin28b levels decline. Our findings show that the efficiency of MLL-ENL–driven AML initiation changes through the course of pre- and postnatal development, and developmental programs can be manipulated to impede transformation.

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Bunworasate, Udomsak, Hilal Arnouk, Hans Minderman, Kieran L. O'Loughlin, Sheila N. J. Sait, Maurice Barcos, Carleton C. Stewart y Maria R. Baer. "Erythropoietin-dependent transformation of myelodysplastic syndrome to acute monoblastic leukemia". Blood 98, n.º 12 (1 de diciembre de 2001): 3492–94. http://dx.doi.org/10.1182/blood.v98.12.3492.

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Abstract Acute monoblastic leukemia (acute myeloid leukemia [AML], French-American-British type M5a) with leukemia cutis developed in a patient 6 weeks after the initiation of erythropoietin (EPO) therapy for refractory anemia with ringed sideroblasts. AML disappeared from both marrow and skin after the discontinuation of EPO. Multiparameter flow cytometric analysis of bone marrow cells demonstrated coexpression of the EPO receptor with CD45 and CD13 on the surface of blasts. The incubation of marrow cells with EPO, compared to without, resulted in 1.3- and 1.6-fold increases, respectively, in tritiated thymidine incorporation and bromodeoxyuridine incorporation into CD13+ cells. Clinical and laboratory findings were consistent with the EPO-dependent transformation of myelodysplastic syndrome (MDS) to AML. It is concluded that leukemic transformation in patients with MDS treated with EPO may be EPO-dependent and that management should consist of the discontinuation of EPO followed by observation, if clinically feasible.

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Tsuruta-Kishino, Takako, Keisuke Kataoka, Hiroshi Kobayashi, Junji Koya, Kensuke Narukawa, Tomohiko Sato y Mineo Kurokawa. "Loss Of p53 Induces Leukemic Transformation In a Murine Model Of JAK2V617F-Induced Polycythemia Vera". Blood 122, n.º 21 (15 de noviembre de 2013): 269. http://dx.doi.org/10.1182/blood.v122.21.269.269.

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Abstract Myeloproliferative neoplasms (MPN) have an inherent tendency toward leukemic transformation, but its mechanisms remain largely unknown. Recently, TP53 mutation is reported to be frequently found in cases with post-MPN leukemia. Here, to address the contribution of p53 loss to leukemic transformation from MPN in vivo, we retrovirally transduced c-kit+ bone marrow (BM) cells from p53 knockout (p53-/-) and littermate mice (p53+/+) with either wild-type Jak2 (Jak2WT) or Jak2V617F respectively, and transplanted them into lethally irradiated mice. At 3 weeks after transplantation, both recipients of Jak2V617F/p53-/- and Jak2V617F/p53+/+ cells developed a polycythemia vera-like disease characterized by high WBC count and elevated hemoglobin (Hb) level. Jak2V617F/p53+/+ mice survived and continued to have elevated Hb level, whereas 5 weeks after transplantation, Jak2V617F/p53-/- recipients developed cachexia, and their Hb level declined. Eventually, these mice developed fatal leukemia with a median survival of 46.5 days after transplantation, suggesting loss of p53 cooperates with Jak2V617F mutation to promote leukemic transformation from MPN. To characterize these leukemias, we analyzed leukemic tissues from moribund Jak2V617F/p53-/- mice. Peripheral blood smears and BM specimen from Jak2V617F/p53-/- recipients showed a marked increase of erythroid precursors with dysplastic features, leading to suppression of normal hematopoiesis. Notably, Jak2V617F/p53-/- mice displayed marked hepatosplenomegaly and extensive pulmonary hemorrhage. Consistent with the histopathologic findings, Jak2V617F/p53-/- animals exhibited a remarkable accumulation of erythroid precursors (CD71+), and especially more immature progenitors (Ter119-/CD71+) in the BM and spleen, compared with Jak2V617F/p53+/+ animals. These data suggest Jak2V617F/p53-/- recipients developed infiltrative disease with accumulation of immature erythroid cells, fulfilling the Bethesda Criteria of erythroleukemia in mice. To assess the transplantability of Jak2V617F/p53-/- leukemia, we injected unfractionated BM cells from Jak2V617F/p53-/- mice into lethally irradiated mice. In all cases, lethal leukemia developed earlier than in primary recipients. Moreover, there was a significant increase in erythroid progenitors in secondary recipients, suggesting the erythroid component is the predominant lineage involved in this leukemia model. As Jak2V617F/p53-/- leukemic tissues contained three major populations: CD71+ erythroid progenitors, Mac1+ mature myeloid cells, and lineage-negative (CD71-/Mac1-) primitive leukemic cells, we purified and transplanted these subfractions into secondary recipients to evaluate their leukemia-initiating potential. As a result, both lineage-negative (CD71-/Mac1-) cells and CD71+ erythroid progenitors possessed leukemia- initiating capacity, but Mac1+ myeloid cells could not reconstitute the disease. In addition, these two fractions had different capacities to induce leukemias; recipients of CD71+ cells rapidly developed erythroleukemia, whereas lineage-negative cells caused lethal leukemia after the polycythemic state. Moreover, hematopoietic tissues in recipients transplanted with CD71+ cells mainly consisted of erythroid lineages, whereas lineage-negative cells produced both erythroid and myeloid lineages, suggesting lineage-negative cells are more immature than CD71+ erythroid precursors. Furthermore, subsequent fractionation of lineage-negative cells revealed leukemia-initiating cells were enriched in Lin-/Sca-1+/c-kit+ (LSK) cells. To further characterize two types of leukemia-initiating cells in Jak2V617F/p53-/- leukemia, we assessed their sensitivity to a JAK2 inhibitor, INCB18424, in vitro. Interestingly, INCB18424 treatment significantly reduced CD71+ cell proliferation, whereas LSK cells were able to expand in the presence of INCB18424, indicating different leukemia-initiating cells existing in post-MPN leukemia have different responsiveness to JAK2 inhibiton. In summary, these results demonstrate p53 loss is sufficient for inducing leukemic transformation in JAK2V617F-postive MPN and offers an in vivo model to assess novel therapeutic approaches for post-MPN leukemia. In addition, we revealed leukemia-initiating cells at different differentiation stages could exist in post-MPN leukemia. Disclosures: Kurokawa: Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Research Funding.

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Wagenblast, Elvin, Joana Araújo, Olga I. Gan, Sarah K. Cutting, Alex Murison, Jessica L. McLeod, Gabriela Krivdova et al. "A Human Model of Down Syndrome Associated Leukemia Reveals Different Cell of Origins for Initiation and Progression". Blood 136, Supplement 1 (5 de noviembre de 2020): 11–12. http://dx.doi.org/10.1182/blood-2020-135867.

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Introduction: Leukemia is the most common cancer in children and sequencing data suggest that the first genetic alterations often occur in utero. Children with Down syndrome (Trisomy 21, T21) have a 150-fold increased risk of childhood leukemia. In 30% of newborns with Down syndrome, a transient myeloproliferative disorder (pre-leukemia) occurs, which is characterized by a clonal proliferation of immature megakaryoblasts carrying somatic mutations in the GATA1 transcription factor (GATA1s) and resolves spontaneously in most cases. In 20% of the cases, acute megakaryoblastic leukemia (AMKL) evolves from the pre-leukemic clone by acquisition of additional mutations, such as in the cohesin subunit STAG2. It is hypothesized that this represents a multi-step process of leukemogenesis with three distinct genetic events: T21, GATA1s and STAG2. Yet, it remains unclear how an extra copy of chromosome 21 predisposes towards leukemia, the interplay between each genetic event and the cellular origin of transformation. Methods: Human long-term hematopoietic stem cells (LT-HSCs) were sorted from normal karyotype and T21 fetal livers (N-FL and T21-FL) and subsequently CRISPR/Cas9 edited to try to establish a humanized model of Down Syndrome associated pre-leukemia and AMKL. To model the initiation of the pre-leukemic state, GATA1s mutations were introduced, while additional STAG2- mutations were overlaid to model the progression to fully transformed AMKL. CRISPR/Cas9-edited control, GATA1s, STAG2- and GATA1s/STAG2- LT-HSCs were functionally interrogated in near-clonal xenograft assays, along with transcriptional and epigenetic profiling. Results: T21 status in combination with GATA1s had a profound synergistic effect on megakaryocytic lineage output in vivo compared to normal karyotype with GATA1s. Moreover, a high percentage of blasts were found in xenografts of GATA1s edited T21-FL LT-HSCs (>30%) but not in xenografts of GATA1s edited N-FL LT-HSCs. Conversely, GATA1s/STAG2- edited LT-HSCs generated grafts with >50% of blasts, regardless of T21 status. The immunophenotype of these blasts recapitulated those observed in patients diagnosed with Down Syndrome pre-leukemia and AMKL (CD117+CD34+CD41+CD71+CD33+CD4+CD7+). Thus, T21 is required for pre-leukemia development, but seems dispensable for AMKL as both N- and T21-FL LT-HSCs underwent leukemic transformation upon GATA1s/STAG2-. Serial xenotransplantation assays from primary engrafted mice were carried out to assess self-renewal properties of GATA1s-induced pre-leukemia and GATA1s/STAG2- induced AMKL. Only GATA1s/STAG2- edited N- and T21-FL grafts were able to propagate the leukemic phenotype with a high stem cell frequency, which was endowed by the additional STAG2- knock-out. ATACseq and RNAseq profiling of blast populations revealed an enrichment of GATA-binding sites with concomitant up-regulation of genes implicated in translation. To assess the role of progenitor cells in pre-leukemic initiation and leukemic progression, we CRISPR/Cas9 edited short-term HSCs, common myeloid progenitors and myelo-erythroid progenitors with GATA1s and/or STAG2- and subjected them to xenotransplantation. Strikingly, all progenitor subsets with combined GATA1s/STAG2- editing were able to drive leukemic transformation, while single GATA1s editing in the same subsets did not initiate pre-leukemia. This data strongly suggests that the initial GATA1s mutation must occur in T21 LT-HSCs, but subsequent STAG2 mutations can occur further downstream in progenitors. Lastly, to gain insight into how chromosome 21 predisposes towards pre-leukemia, three chromosome 21 miRNAs (miR-99a, -125b-2 and -155) were identified to be up-regulated in T21-FL LT-HSCs compared to N-FL LT-HSCs. Over-expression of these miRNAs in N-FL LT-HSCs induced a T21-like state with increased myeloid and megakaryocytic skewing. Dramatically, CRISPR/Cas9-edited knock-out of these miRNAs in GATA1s edited T21-FL LT-HSCs resulted in a block of pre-leukemia initiation. Conclusion: Our findings demonstrate that T21 is required for pre-leukemia initiation, which is mediated by over-expression of chromosome 21 miRNAs in LT-HSCs. Further, this data demonstrates different cell of origins between pre-leukemia initiation and AMKL progression. Ongoing studies focus on preventing the progression of pre-leukemia to AMKL by pharmacological targeting. Figure Disclosures Dick: Bristol-Myers Squibb/Celgene: Research Funding.

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Wang, Pin-Yi, Fay Young, Chun-Yu Chen, Brett M. Stevens, Sarah J. Neering, Randall M. Rossi, Timothy Bushnell et al. "The biologic properties of leukemias arising from BCR/ABL-mediated transformation vary as a function of developmental origin and activity of the p19ARF gene". Blood 112, n.º 10 (15 de noviembre de 2008): 4184–92. http://dx.doi.org/10.1182/blood-2008-02-142190.

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Abstract Recent reports have shown that upon expression of appropriate oncogenes, both stem cells and more differentiated progenitor populations can serve as leukemia-initiating cells. These studies suggest that oncogenic mutations subvert normal development and induce reacquisition of stem-like features. However, no study has described how specific mutations influence the ability of differentiating cell subsets to serve as leukemia-initiating cells and if varying such cellular origins confers a functional difference. We have examined the role of the tumor suppressor gene p19ARF in a murine model of acute lymphoblastic leukemia and found that loss of p19ARF changes the spectrum of cells capable of tumor initiation. With intact p19ARF, only hematopoietic stem cells (HSCs) can be directly transformed by BCR/ABL expression. In a p19ARF-null genetic background expression of the BCR/ABL fusion protein renders functionally defined HSCs, common lymphoid progenitors (CLP), and precursor B-lymphocytes competent to generate leukemia stem cells. Furthermore, we show that leukemias arising from p19ARF-null HSC versus pro-B cells differ biologically, including relative response to drug insult. Our observations elucidate a unique mechanism by which heterogeneity arises in tumor populations harboring identical genetic lesions and show that activity of p19ARF profoundly influences the nature of tumor-initiating cells during BCR/ABL-mediated leukemogenesis.

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Sharma, Ritul, Chunfen Zhang y Aru Narendran. "The Small-Molecule E26-Transformation-Specific Inhibitor TK216 Attenuates the Oncogenic Properties of Pediatric Leukemia". Genes 14, n.º 10 (8 de octubre de 2023): 1916. http://dx.doi.org/10.3390/genes14101916.

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The E26-transformation-specific (ETS) transcription factors regulate multiple aspects of the normal hematopoietic system. There is an increasing body of evidence suggesting aberrant ETS activity and its contribution to leukemia initiation and progression. In this study, we evaluated the small-molecule ETS inhibitor TK216 and demonstrated its anti-tumor activity in pediatric leukemia. We found TK216 induced growth inhibition, cell cycle arrest and apoptosis and inhibited the migratory capability of leukemic cells, without significantly inhibiting the cell viability of normal blood mononuclear cells. Priming the leukemic cells with 5-Azacitidine enhanced the cytotoxic effects of TK216 on pediatric leukemia cells. Importantly, we found purine-rich box1 (PU.1) to be a potential target of TK216 in myeloid and B-lymphoid leukemic cells. In addition, TK216 sharply decreased Mcl-1 protein levels in a dose-dependent manner. Consistent with this, TK216 also potentiated the cytotoxic effects of Bcl-2 inhibition in venetoclax-resistant cells. The sustained survival benefit provided to leukemic cells in the presence of bone-marrow-derived conditioned media is also found to be modulated by TK216. Taken together, our data indicates that TK216 could be a promising targeted therapeutic agent for the treatment of acute myeloid and B-lymphoid leukemia.

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Tesis sobre el tema "Leukemia initiation and transformation"

Bayet, Manon. "Modélisation de la leucémie aiguë lymphoblastique B induite par la mutation PAX5 P80R". Electronic Thesis or Diss., Université de Toulouse (2023-....), 2024. http://www.theses.fr/2024TLSES005.

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L'équipe s'intéresse aux altérations de facteurs de transcription impliquées dans les leucémies aiguës, dont PAX5 qui est essentiel pour le développement des cellules B. C'est pourquoi le modèle murin transgénique PAX5-ELN a été généré, qui exprime la protéine de fusion oncogénique durant le développement des lymphocytes B, et récapitule le processus multi-étapes des LAL-B (Jamrog L et al., PNAS, 2018). J'ai participé à l'identification des cellules à l'origine de la LAL-B et à la caractérisation de leur propriétés fonctionnelles et moléculaires. Nos travaux indiquent qu'au stade pré-leucémique, PAX5-ELN induit l'émergence d'une population aberrante de progéniteurs B avec une propriété anormale d'auto-renouvellement. Cette population est enrichie en cellules quiescentes résistantes aux agents de chimiothérapie, activent un programme moléculaire de cellule souche, et sont le support de l'initiation leucémique à long terme. Ce travail fait l'objet d'une publication récente que je signe en deuxième auteure (Fregona V, Bayet M et al., J Exp Med, in press). En parallèle, ma thèse s'est tournée vers la modélisation de l'initiation et de la transformation leucémique induite par la mutation PAX5P80R, une altération initiatrice fréquente chez les patients. J'ai donc utilisé des cellules de foie fœtal issus d'embryon de souris Pax5-/- pour sélectionner les progéniteurs lymphoïdes non engagés dans le lignage B. Après transduction avec des rétrovirus CTL, PAX5 Wt ou PAX5P80R, j'ai montré que PAX5P80R ne restaure pas efficacement l'engagement définitif des cellules vers le lignage B. Les études de transplantation ont permis de montrer que PAX5P80R induit un potentiel de prise de greffe aberrant suivi du développement de la LAL-B. Cette transformation leucémique est associée à la sélection de clones porteurs de mutations additionnelles affectant la voie JAK/STAT. Nos analyses ont permis d'identifier Hif2 comme un candidat potentiel dans la leucémogenèse. Enfin, un criblage pharmacologique d'inhibiteurs de Hif révèle l'Acriflavine comme un composé intéressant ciblant les cellules leucémiques. Ainsi, la modélisation de la LAL-B par la mutation PAX5P80R fournit à l'équipe un nouvel outil mimant le processus multi-étapes de la LAL-B, et permet de déchiffrer les mécanismes biologiques par lesquels la mutation mène à la transformation tumorale. Ce travail fait l'objet d'un manuscrit en préparation que je signe en première auteure (Bayet M, Fregona V, et al., in preparation). Les modèles PAX5-ELN et PAX5P80R permettent non seulement d'étudier les différentes étapes de la leucémogenèse B, mais servent aussi de support pour le développement de criblage de petites molécules sur cellules primaires. J'ai donc mis en place un protocole miniaturisé et robuste par FACS pour cribler des composés chimiques ciblant les cellules pré-leucémiques. Notre approche multiparamétrique permet d'évaluer simultanément l'effet des composés sur les cellules pré-leucémiques et les sous-populations B normales. J'ai donc criblé une banque de 1040 composés synthétiques et naturels (chimiothèque essentielle) reflétant la diversité chimique de la chimiothèque nationale française. Ce criblage, associé à des contre-criblages en dose-réponse, m'a permis d'identifier 5 molécules d'intérêt. Dans l'ensemble, mon travail montre la faisabilité d'un criblage de petites molécules sur une population enrichie en cellules initiatrice de la leucémie et prenant en compte la complexité intrinsèque des cellules primaires du lignage B. Enfin, j'ai procédé à la rédaction et la publication d'une revue dans le journal Cancers qui expose les concepts d'hétérogénéité tumorales des cellules leucémiques des patients, l'utilité des modèles de souris transgéniques pour explorer le compartiment des cellules initiatrices de la leucémie, et les efforts actuels visant à découvrir de nouvelles thérapies ciblées (Fregona V*, Bayet M* et al, Cancers (Basel), 2021), que je signe en co-première auteure
The team is interested in alterations in transcription factors involved in acute leukemia, including PAX5, which is essential for B-cell development. This is why the PAX5-ELN transgenic mouse model was generated, which expresses the oncogenic fusion protein during B-cell development, and recapitulates the multi-step process of B-ALL (Jamrog L et al., PNAS, 2018). I was involved in identifying the cells at the origin of-B-ALL and characterizing their functional and molecular properties. Our work indicates that at pre-leukemic stage, PAX5-ELN induces the emergence of an aberrant population of B-progenitors with an abnormal self-renewal property. This population is enriched in quiescent cells resistant to chemotherapeutic agents, activating a molecular stem cell program and supporting long-term leukemic initiation. This work is the subject of a recent publication signed by myself as second author (Fregona V, Bayet M et al., J Exp Med, in press). In parallel, my thesis focused on modeling the initiation and leukemic transformation induced by the PAX5P80R mutation, a frequent initiating alteration in patients. I used fetal liver cells derived from Pax5-/- mouse embryos to select lymphoid progenitors not committed to the B lineage. After transduction with CTL, PAX5 Wt or PAX5P80R retroviruses, I showed that PAX5P80R does not restore efficiently definitive commitment of cells to the B lineage. Transplantation experiments have shown that PAX5P80R induces aberrant engraftment potential followed by the development of B-ALL. This leukemic transformation is associated with the selection of clones carrying additional mutations affecting the JAK/STAT signaling pathway. Our analyses identified Hif2 as a potential candidate for leukemogenesis. Finally, pharmalogical screening of Hif inhibitors revealed Acriflavine as an interesting compound targeting leukemic cells. Thus, the modeling of B-ALL by the PAX5P80R mutation provides the team with a new tool to mimic the multi-step process of B-ALL, and to decipher the biological mechanisms by which the mutation leads to tumor transformation. This work is the subject of a manuscript in preparation which I have signed as first author (Bayet M, Fregona V, et al., in preparation). The PAX5-ELN and PAX5P80R models not only make it possible to study the various stages of B leukemogeneis, but also serve as a basis for the development of small molecule screening on primary cells. I therefore set up a miniaturized and robust protocol by FACS to screen chemical compounds targeting pre-leukemic cells. Our multiparametric approach enables us to simultaneously assess the effect of compounds on pre-leukeic cells and normal B subpopulations. I screened a bank of 1040 synthetic and natural compounds (essential chemical library) reflecting the chemical diversity of the French national chemical library. This screening, combined with dose-response counter-screening, enabled me to identify 5 molecules of interest. Overall, my work demonstrates the feasibility of small-molecule screening on a population enriched in leukemia-initiating cells, taking into account the intrinsic complexity of primary B-cells. Finally, I edited and published a review in the journal Cancers outlining the concepts of tumor heterogeneity in patients' leukemic cells, the utility of transgenic mouse models to explore the leukemia initiating cell compartment, and current efforts to discover new targeted therapies (Fregona V*, Bayet M* et al, Cancers (Basel), 2021), wich I co-authored

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Kline, Dana L. "Contextualizing Transformation| Initiation Dreams of Depth Psychotherapists-in-Training". Thesis, Pacifica Graduate Institute, 2015. http://pqdtopen.proquest.com/#viewpdf?dispub=1692045.

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This thesis explores how the depth psychotherapist can experience a sacred passage of initiation in the context of archetypal dreams. It examines the intersections of meaning making in alchemical and mythological dream imagery and the numinous experience of initiation. It explores C. G. Jung’s individuation process and whether identifying dream images as archetypal wounds can deepen the psychotherapist–client therapeutic relationship. Using hermeneutic and heuristic methodology, this research uses a comparative analytical lens and the author’s personal process of tracking two archetypal dreams that coincide with the author’s answer to the soul’s calling to depth psychology and the first phase of seeing psychotherapy clients in graduate training. Honoring the unconscious as a map for psychological complexes, emotional states, unexpressed narratives, and symbols of both the personal and collective, the author expands upon an ancient way of honoring the death and rebirth of an individual in a transformative state of growth.

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Mishra, Shrikant. "Mechanism of TNF-α cytotoxicity in a leukemia virus transformation model". Diss., Virginia Tech, 1991. http://hdl.handle.net/10919/39214.

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Mishra, Shrikant. "Mechanism of TNF-[alpha] cytotoxicity in a leukemia virus transformation model /". This resource online, 1991. http://scholar.lib.vt.edu/theses/available/etd-08232007-112933/.

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Voronin, Yegor A. "Investigation of initiation of reverse transcription in retroviruses using vectors with two primer-binding sites". Morgantown, W. Va. : [West Virginia University Libraries], 2003. http://etd.wvu.edu/templates/showETD.cfm?recnum=3136.

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Jenkins, Catherine Elfi Sarah. "Mechanisms of acute leukemia disease initiation and maintenance through manipulation of IGF1R and RUNX family members". Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/61331.

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Characterization of new pathways in Acute Myeloid Leukemia and T-cell Acute Lymphoblastic Leukemia which contribute to oncogenesis is necessary to relieve dependence on conventional chemotherapy for treatment of these diseases. In this dissertation, I characterized the role of signaling molecules (IGF1R) and transcription factors (RUNX1, RUNX3, NOTCH1) in regulating mechanisms of leukemia initiation and maintenance. I discovered that committed myeloid progenitor cells with genetically reduced levels of IGF1R were less susceptible to myelogenous leukemogenic transformation due, at least in part, to a cell-autonomous defect in clonogenic activity. Genetic deletion of IGF1R by inducible Cre recombinase however had no effect on growth/survival of established leukemia cells. I raise the possibility that IGF1R inhibitors in clinical development may be acting through alternate/related pathways. Second, in a retroviral insertional mutagenesis study, I cloned retroviral integration sites from hNOTCH1ΔE mouse leukemias to find genes which collaborate with Notch signaling in T-ALL initiation. Common integration sites include the previously identified Ikzf1, and a novel potentially Notch-collaborating gene, Runx3. Using a multicistronic lentiviral system, I show that RUNX1A, RUNX1B and RUNX3 were able to collaborate with the ΔEΔL allele of NOTCH1 to initiate leukemia. Finally, I sought to understand how RUNX1 and RUNX3 contribute to the biology of established T-cell leukemias. I found that both RUNX1 and RUNX3 contribute to T-ALL cell proliferation and survival. Although RUNX3 can induce cell proliferation, RUNX1 expression is finely tuned with overexpression and knockdown resulting in negative growth phenotypes. This may be in part to regulation of MYC, IL7R, IGF1R, and CDKN1B as well as affecting genome-wide H3K27Ac. I found that RUNX1 expression was targeted by the CDK7 inhibitor, THZ1. RUNX1 and RUNX3 are mediators of Notch-directed regulation of PKCθ, and as such are indirect regulators of LIC-activity. Finally, I showed that RUNX1 and Notch signaling provide complimentary, additive signals for growth of T-ALL cells. These experiments provide insight into the role of RUNX1 mutations in T-cell leukemia and point to a complementary role in supporting the Notch pathway.
Medicine, Faculty of
Graduate

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Chakraborty, Pritam. "WAVELET TRANSFORMATION BASED MULTI-TIME SCALE METHOD FOR FATIGUE CRACK INITIATION IN POLYCRYSTALLINE ALLOYS". The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1325091714.

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Seok, Daniel y Grant Skrepnek. "Inpatient Charges and Mortality of Richter’s Transformation of Chronic Lymphocytic Leukemia in the United States". The University of Arizona, 2012. http://hdl.handle.net/10150/614535.

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Class of 2012 Abstract
Specific Aims: The objectives of this study were to determine the financial impact and mortality of CLL and Richter’s transformation in CLL in the inpatient setting in the payer’s perspective, the common diagnoses at discharge for patients with CLL, and to compare demographics, hospital characteristics, and co-morbidities for CLL cases versus Richter’s only cases. Methods: This study was a retrospective cohort of inpatient hospital charges and mortality of CLL patients and CLL patients with Richter’s transformation in the United States in the perspective of the payer. Using weighted statistical methods, results of this investigation yielded nationally-representative findings. The hospital charges were analyzed with a gamma regression with log link, and mortality was analyzed with a generalized linear regression. Main Results: There were total of 391,287 cases and 7% (27,259) were Richter’s cases. The overall hospital charges for CLL and CLL patients with Richter’s transformation from 2005 to 2009 were $38,735 (±58859) per case and $53,118 (±77993) per case, respectively. The mortality was 6.3% (24,520 deaths) overall and 9.1% mortality (2,485 deaths) for Richter’s transformation patients. The significant predictors (p < 0.05) that were associated with an increase the hospital charges for Richter’s patients was sepsis while sepsis and weight loss were associated with an increase in mortality. Conclusions This study adds to the few studies published to show the impact of CLL and Richter’s. However, due to the limitation on pharmacotherapies, it was not possible to determine therapeutic cost drivers for these cases. Future studies are warranted to determine the cost of therapies associated to the different stages of CLL.

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Apichella, Michael. "Interstate '69 : the separation, initiation, and transformation of the fatherless hero in myth and literature". Thesis, Aberystwyth University, 2008. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.742419.

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Kennah, Erin. "Identification of differentially expressed genes in AHI-1-mediated leukemic transformation in cutaneous t-cell lymphoma". Thesis, University of British Columbia, 2008. http://hdl.handle.net/2429/962.

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The oncogene Ahi-1 was recently identified through provirus insertional mutagenesis in murine leukemias and lymphomas. Its involvement in human leukemogenesis is demonstrated by gross perturbations in its expression in several leukemic cells lines, particularly in cutaneous T-cell lymphoma (CTCL) cell lines (Hut 78 and Hut 102). Hut 78 is derived from a patient with Sezary syndrome, a common leukemic variant of the human CTCL mycosis fungoides. Aberrant expression of AHI-1 mRNA and protein has been found in CD4⁺CD7⁻ leukemic Sezary cells from patients with Sezary syndrome. Moreover, stable suppression of AHI-1 using retroviral-mediated RNA interference in Hut 78 cells inhibits their transforming activity in vitro and in vivo. In an effort to identify genes involved in AHI-1-mediated leukemic transformation in CTCL, microarray analysis was performed to compare six RNA samples from AHI-1 suppressed Hut 78/sh4 cells to five samples from Hut 78 control cells. Limma and dChip analyses identified 218 and 95 differentially expressed genes, respectively, using a fold change criteria of > or < 2 and a p-value threshold of ≤ 0.01. After evaluation of both analyses, 21 genes were selected based upon interesting structural and functional information, specificity to hematopoietic cells or T-cells, and previous connections to cancer. Expression patterns of these 21 genes were validated by qRT-PCR with p-values < 0.05 ranging from 1.97 x 10⁻¹⁰ to 6.55 x 10⁻³, with the exception of BRDG1 at 5.88 x 10⁻². The observed up-regulation of both BIN1 and HCK in AHI-1 suppressed Hut 78/sh4 cells as compared to control cells further confirmed at the protein level. The tumor suppressor BIN1 is known to physically interact with c-MYC, which also exhibits differential protein expression in these cells. Characterization of BIN1 identified 4 isoforms all of which contain exon 10 and demonstrate alternative splicing of exons 12A and 13. Additionally, qRT-PCR results from primary Sezary samples indicate there is clinical significance in the expression changes detected for BIN1, HCK, REPS2, BRDG1, NKG7 and SPIB. These findings identify several new differentially expressed genes that may play critical roles in AHI-1-mediated leukemic transformation of human CTCL cells.

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Libros sobre el tema "Leukemia initiation and transformation"

Kate, Burns. Paths to transformation: From initiation to liberation. Asheville, North Carolina: Chiron Publications, 2014.

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1927-, Freireich Emil J. y Kantarjian Hagop 1952-, eds. Leukemia: Advances in research and treatment. Boston: Kluwer Academic Publishers, 1993.

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Steward, R. J. The Underworld Initiation: A journey towrds psychic transformation. Wellingborough: Aquarian, 1985.

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The underworld initiation: A journey towards psychic transformation. Wellingborough: Aquarian, 1985.

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Stewart, R. J. The underworld initiation: A journey towards psychic transformation. Lake Toxaway, NC: Mercury Pub., 1998.

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Beyerl, Paul. A Wiccan bardo, revisited: Initiation and self-transformation. 2^a ed. Kirkland, WA: Hermit's Grove, 1999.

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The underworld initiation: A journey towards psychic transformation. Lake Toxaway, NC: Mercury Pub., 1999.

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The chromosomes in human cancer and leukemia. 2^a ed. New York: Elsevier, 1990.

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L, Moore Robert. The archetype of initiation: Sacred space, ritual process, and personal transformation : lectures and essays. [Philadelphia]: Xlibris Corp., 2001.

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Nougier, Paul. Déformation des roches et transformation de leurs minéraux: Initiation à la tectonique. Paris: Ellipses-Marketing, 2000.

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Capítulos de libros sobre el tema "Leukemia initiation and transformation"

Zeisig, Bernd B. y Chi Wai Eric So. "Retroviral/Lentiviral Transduction and Transformation Assay". En Leukemia, 207–29. Totowa, NJ: Humana Press, 2009. http://dx.doi.org/10.1007/978-1-59745-418-6_10.

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So, Chi Wai Eric. "An Overview: From Discovery of Candidate Mutations to Disease Modeling and Transformation Mechanisms of Acute Leukemia". En Leukemia, 1–5. Totowa, NJ: Humana Press, 2009. http://dx.doi.org/10.1007/978-1-59745-418-6_1.

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Sarin, Prem S. "HTLV in Adult T Cell Leukemia and Acquired Immune Deficiency Syndrome". En Cell Transformation, 185–208. Boston, MA: Springer US, 1985. http://dx.doi.org/10.1007/978-1-4684-5009-5_12.

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Schetelig, Johannes y Peter Dreger. "Chronic Lymphocytic Leukemia". En The EBMT Handbook, 771–75. Cham: Springer International Publishing, 2024. http://dx.doi.org/10.1007/978-3-031-44080-9_85.

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AbstractCLL is a rare indication for HCT/Cellular Therapy since it usually follows an indolent course. Allogeneic HCT is considered as standard of care in eligible high-risk patients who have failed at least two classes of modern pathway inhibitor-based therapy, and in select patients with CLL transformed in to an aggressive B-cell lymphoma (Richter transformation). Except for Richter transformation, there is no role for autologous HCT in CLL. In the absence of a labeled indication, CAR T-cells should not be used outside of clinical trials.

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Dhekney, Sadanand A., Zhijian T. Li, Manjul Dutt y Dennis J. Gray. "Initiation and Transformation of Grapevine Embryogenic Cultures". En Methods in Molecular Biology, 215–25. Totowa, NJ: Humana Press, 2012. http://dx.doi.org/10.1007/978-1-61779-558-9_18.

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Pawelski, S., L. Konopka, K. Szczepanik y H. Zdziechowska. "Therapy of Blastic Transformation of Chronic Myeloid Leukemia". En Leukemias, 249–55. Berlin, Heidelberg: Springer Berlin Heidelberg, 1993. http://dx.doi.org/10.1007/978-3-642-77083-8_45.

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Yasunaga, Junichiro y Kuan-Teh Jeang. "Human T-Cell Leukemia Virus Type 1, Cellular Transformation, and Adult T-Cell Leukemia". En National Institute of Allergy and Infectious Diseases, NIH, 41–49. Totowa, NJ: Humana Press, 2010. http://dx.doi.org/10.1007/978-1-60761-512-5_5.

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Taylor, C., A. Jalava y S. Mai. "c-Myc Dependent Initiation of Genomic Instability During Neoplastic Transformation". En Current Topics in Microbiology and Immunology, 201–7. Berlin, Heidelberg: Springer Berlin Heidelberg, 1997. http://dx.doi.org/10.1007/978-3-642-60801-8_20.

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Kolch, W., R. H. Bassin y U. R. Rapp. "Raf Function Is Required for Proliferation of NIH|3T3 Cells and Transformation by Nonnuclear Oncogenes". En Modern Trends in Human Leukemia IX, 208–12. Berlin, Heidelberg: Springer Berlin Heidelberg, 1992. http://dx.doi.org/10.1007/978-3-642-76829-3_33.

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Chi, Ya-Hui y Kuan-Teh Jeang. "Chromosomal Instability and Human T Cell Leukemia Virus 1 Transformation". En Translational Research in Biomedicine, 228–38. Basel: KARGER, 2008. http://dx.doi.org/10.1159/000141523.

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Actas de conferencias sobre el tema "Leukemia initiation and transformation"

Minami, Yosuke, Nobuaki Fukushima, Anil Sadarangani, Hironobu Minami, Catriona Jamieson y Tomoki Naoe. "Abstract 1884: Treatment with Hedgehog inhibitor PF-913 attenuates leukemia-initiation potential in acute myeloid leukemia cells". En Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-1884.

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Bhattacharjee, Romel y Lalit Mohan Saini. "Detection of Acute Lymphoblastic Leukemia using watershed transformation technique". En 2015 International Conference on Signal Processing, Computing and Control (ISPCC). IEEE, 2015. http://dx.doi.org/10.1109/ispcc.2015.7375060.

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Aifantis, Iannis. "Abstract IA24: Regulation of acute leukemia initiation and progression by long noncoding RNAs." En Abstracts: AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; September 20-23, 2014; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1557-3265.hemmal14-ia24.

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Wan, Minjie, Guohua Gu, Qian Chen, Weixian Qian y Pengcheng Wang. "Fast randomized Hough transformation track initiation algorithm based on multi-scale clustering". En Applied Optics and Photonics China (AOPC2015), editado por Chunhua Shen, Weiping Yang y Honghai Liu. SPIE, 2015. http://dx.doi.org/10.1117/12.2197916.

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Chen, Rong, Mingzhao Zhu, Rajan R. Chaudhari, Omar Robles, Yuling Chen, Wesley Skillern, Qun Qin et al. "Abstract 1854: Novel pateamine analogs to target the translation initiation factor eIF4A in chronic lymphocytic leukemia". En Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-1854.

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Shakir, A., S. Nusrat y A. Keruakous. "Ruxolitinib Discontinuation Syndrome in a Patient with Myelofibrosis to Acute Myeloid Leukemia Transformation". En American Thoracic Society 2019 International Conference, May 17-22, 2019 - Dallas, TX. American Thoracic Society, 2019. http://dx.doi.org/10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a1479.

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Frolov, Nikita, Elena Pitsik y Nikolaj Schukovskii. "Transformation of the Theta-band Functional Connectivity During Motor Initiation Under Healthy Aging". En 2020 4th Scientific School on Dynamics of Complex Networks and their Application in Intellectual Robotics (DCNAIR). IEEE, 2020. http://dx.doi.org/10.1109/dcnair50402.2020.9216901.

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Oka, Takashi, Lamia Abd Al-Kader, Hiaki Sato, Kana Washio, Yoko Shinnou, Katsuyoshi Takata, Ichiro Murakami, Atae Utsunomiya y Tadashi Yoshino. "Abstract 3132: Dynamic changes of epigenetic abnormalities during initiation and progression of adult T-cell leukemia/lymphoma (ATLL)". En Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-3132.

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Ichim, Christine V., Alden Chesney, Marciano Reis, Norman N. Iscove y Richard A. Wells. "Abstract 1588: NR2F6, a novel regulator of stem cell maintenance, is necessary and sufficient for initiation of acute leukemia". En Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-1588.

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Informes sobre el tema "Leukemia initiation and transformation"

Halene, Stephanie. Assessing the Mechanisms of MDS and its Transformation to Leukemia in a Novel Humanized Mouse. Fort Belvoir, VA: Defense Technical Information Center, septiembre de 2014. http://dx.doi.org/10.21236/ada610689.

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Jiang, Zhiping, Ao Zhang, Shuxing Wang, Quanlei Ren y Yizhu Wang. Prognostic value of ASXL1 mutations in patients with myelodysplastic syndromes and acute myeloid leukemia: A meta-analysis. INPLASY - International Platform of Registered Systematic Review and Meta-analysis Protocols, abril de 2022. http://dx.doi.org/10.37766/inplasy2022.4.0013.

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Review question / Objective: A meta-analysis was performed to investigate prognostic value of ASXL1 mutations in patients with myelodysplastic syndromes and acute myeloid leukemia. Condition being studied: Some MDS or AML patients have ASXL1 mutations while others haven’t. Main outcome(s): We used OS as the primary endpoint and AML transformation as the secondary endpoint. OS was defined as either death (failure) or survival at the last follow-up. AML transformation was defined as starting when the patient entered the trial and proceeding to the time of AML diagnosis.Combined HRs and 95% CIs for OS and AML transformation were used to evaluate the prognostic effect of ASXL1 mutations using the generic inverse variance method.

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Elroy-Stein, Orna y Dmitry Belostotsky. Mechanism of Internal Initiation of Translation in Plants. United States Department of Agriculture, diciembre de 2010. http://dx.doi.org/10.32747/2010.7696518.bard.

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Original objectives Elucidation of PABP's role in crTMV148 IRES function in-vitro using wheat germ extract and krebs-2 cells extract. Fully achieved. Elucidation of PABP's role in crTMV148 IRES function in-vivo in Arabidopsis. Characterization of the physical interactions of PABP and other potential ITAFs with crTMV148 IRES. Partly achieved. To conduct search for additional ITAFs using different approaches and evaluate the candidates. Partly achieved. Background of the topic The power of internal translation via the activity of internal ribosomal entry site (IRES) elements allow coordinated synthesis of multiple gene products from a single transcription unit, and thereby enables to bypass the need for sequential transformation with multiple independent transgenes. The key goal of this project was to identify and analyze the IRES-trans-acting factors (ITAFs) that mediate the activity of a crucifer-infecting tobamovirus (crTMV148) IRES. The remarkable conservation of the IRES activity across the phylogenetic spectrum (yeast, plants and animals) strongly suggests that key ITAFs that mediate its activity are themselves highly conserved. Thus, crTMV148 IRES offers opportunity for elucidation of the fundamental mechanisms underlying internal translation in higher plants in order to enable its rational manipulation for the purpose of agricultural biotechnology. Major conclusions and achievements. - CrTMV IRES requires PABP for maximal activity. This conclusion was achieved by PABP depletion and reconstitution of wheat germ- and Krebs2-derived in-vitro translation assays using Arabidopsis-derived PABP2, 3, 5, 8 and yeast Pab1p. - Mutations in the internal polypurine tract of the IRES decrease the high-affinity binding of all phylogenetically divergent PABPs derived from Arabidopsis and yeast in electro mobility gel shift assays. - Mutations in the internal polypurine tract decrease IRES activity in-vivo. - The 3'-poly(A) tail enhances crTMV148 IRES activity more efficiently in the absence of 5'-methylated cap. - In-vivo assembled RNPs containing proteins specifically associated with the IRES were purified from HEK293 cells using the RNA Affinity in Tandem (RAT) approach followed by their identification by mass spectroscopy. - This study yielded a list of potential protein candidates that may serve as ITAFs of crTMV148 IRES activity, among them are a/b tubulin, a/g actin, GAPDH, enolase 1, ribonuclease/angiogenin inhibitor 1, 26S proteasome subunit p45, rpSA, eEF1Bδ, and proteasome b5 subunit. Implications, both scientific and agriculture. The fact that the 3'-poly(A) tail enhances crTMV148 IRES activity more efficiently in the absence of 5'-methylated cap suggests a potential joint interaction between PABP, the IRES sequence and the 3'-poly(A). This has an important scientific implication related to IRES function in general.

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Meir, Shimon, Michael S. Reid, Cai-Zhong Jiang, Amnon Lers y Sonia Philosoph-Hadas. Molecular Studies of Postharvest Leaf and Flower Senescence. United States Department of Agriculture, enero de 2011. http://dx.doi.org/10.32747/2011.7592657.bard.

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Original objectives: To understand the regulation of abscission by exploring the nature of changes of auxin-related gene expression in tomato (Lycopersicon esculatumMill) abscission zones (AZs) following organ removal, and by analyzing the function of these genes. Our specific goals were: 1) To complete the microarray analyses in tomato flower and leaf AZs, for identifying genes whose expression changes early in response to auxin depletion; 2) To examine, using virus-induced gene silencing (VIGS), the effect of silencing target genes on ethylene sensitivity and abscission competence of the leaf and flower AZs; 3) To isolate and characterize promoters from AZ-specific genes to be used in functional analysis; 4) To generate stable transgenic tomato plants with selected genes silenced with RNAi, under the control of an AZ-specific promoter, for further characterization of their abscission phenotypes. Background: Abscission, the separation of organs from the parent plant, results in postharvest quality loss in many ornamentals and other fresh produce. The process is initiated by changes in the auxin gradient across the AZ, and is triggered by ethylene. Although changes in gene expression have been correlated with the ethylene-mediated execution of abscission, there is almost no information on the initiation of the abscission process, as the AZ becomes sensitized to ethylene. The present project was focused on elucidating these early molecular regulatory events, in order to gain a better control of the abscission process for agricultural manipulations. Major conclusions, solutions, achievements: Microarray analyses, using the Affymetrix Tomato GeneChip®, revealed changes in expression, occurring early in abscission, of many genes with possible regulatory functions. These included a range of auxin- and ethylene-related transcription factors (TFs), other TFs that are transiently induced just after flower removal, and a set of novel AZ-specific genes. We also identified four different defense-related genes, including: Cysteine-type endopeptidase, α- DOX1, WIN2, and SDF2, that are newly-associated with the late stage of the abscission process. This supports the activation of different defense responses and strategies at the late abscission stages, which may enable efficient protection of the exposed tissue toward different environmental stresses. To facilitate functional studies we implemented an efficient VIGS system in tomato, and isolated two abscission-specific promoters (pTAPG1 and pTAPG4) for gene silencing in stable transformation. Using the VIGS system we could demonstrate the importance of TAPGs in abscission of tomato leaf petioles, and evaluated the importance of more than 45 genes in abscission. Among them we identified few critical genes involved in leaf and flower abscission. These included: PTRP-F1, PRP, TKN4, KNOTTED-like homeobox TF, KD1, and KNOX-like homeodomain protein genes, the silencing of which caused a striking retardation of pedicel abscission, and ERF1, ERF4, Clavata-like3 protein, Sucrose transporter protein, and IAA10 genes, the silencing of which delayed petiole abscission. The importance of PRPand KD1 genes in abscission was confirmed also by antisense–silencing using pTAPG4. Experiments testing the effects of RNAi silencing of few other genes are still in progress, The analysis of the microarray results of flower and leaf AZs allowed us to establish a clear sequence of events occurring during acquisition of tissue sensitivity to ethylene, and to confirm our hypothesis that acquisition of ethylene sensitivity in the AZ is associated with altered expression of auxin-regulated genes in both AZs. Implication, both scientific and agricultural: Our studies had provided new insights into the regulation of the abscission process, and shaded light on the molecular mechanisms that drive the acquisition of abscission competence in the AZ. We pointed out some critical genes involved in regulation of abscission, and further expanded our knowledge of auxin-ethylene cross talk during the abscission process. This permits the development of novel techniques for manipulating abscission, and thereby improving the postharvest performance of ornamentals and other crops.

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