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1
Liang, Kai Ling, Loveena Rishi, and Karen Keeshan. "Tribbles in acute leukemia." Blood 121, no. 21 (May 23, 2013): 4265–70. http://dx.doi.org/10.1182/blood-2012-12-471300.
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Abstract There is growing research interest in the mammalian Tribbles (Trib) family of serine/threonine pseudokinases and their oncogenic association with acute leukemias. This review is to understand the role of Trib genes in hematopoietic malignancies and their potential as targets for novel therapeutic strategies in acute myeloid leukemia and acute lymphoblastic leukemia. We discuss the role of Tribs as central signaling mediators in different subtypes of acute leukemia and propose that inhibition of dysregulated Trib signaling may be therapeutically beneficial.
2
Roti, Giovanni, Claudia Sorrentino, and Antonio Cuneo. "THERAPEUTIC TARGETING OF NOTCH SIGNALING PATHWAY IN HEMATOLOGICAL MALIGNANCIES." Mediterranean Journal of Hematology and Infectious Diseases 11, no. 1 (June 25, 2019): e2019037. http://dx.doi.org/10.4084/mjhid.2019.037.
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The Notch pathway plays a key role in several processes including stem-cell self-renewal, proliferation, and cell differentiation. Several studies identified recurrent mutations in hematological malignancies making Notch one of the most desirable target in leukemia and lymphoma. The Notch signaling mediates resistance to therapy and controls cancer stem cells supporting the development of on-target therapeutic strategies to improve patients’ outcome. In this brief review, we outline the therapeutic potential of targeting Notch pathway in T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia and mantle cell lymphoma.
3
Liedtke, Michaela, and Michael L. Cleary. "Therapeutic targeting of MLL." Blood 113, no. 24 (June 11, 2009): 6061–68. http://dx.doi.org/10.1182/blood-2008-12-197061.
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AbstractTreatment of hematologic malignancies is evolving from a uniform approach to targeted therapies directed at the underlying molecular abnormalities of disease. The mixed lineage leukemia (MLL) proto-oncogene is a recurrent site of genetic rearrangements in acute leukemias; and since its discovery in 1992, many advances have been made in understanding its role in leukemogenesis. A variety of MLL translocation partners have been described, and detailed structure/function studies have identified functional domains that are required for transformation. Proteins associated with the MLL core complex or its fusion partners have been isolated and characterized for their critical roles in leukemia pathogenesis. Downstream mediators of MLL transcriptional regulation and multiple collaborating signaling pathways have been described and characterized. These advances in our understanding of MLL-related leukemogenesis provide a foundation for ongoing and future efforts to develop novel therapeutic strategies that will hopefully result in better treatment outcomes.
4
Reikvam, Håkon. "Inhibition of NF-κB Signaling Alters Acute Myelogenous Leukemia Cell Transcriptomics." Cells 9, no. 7 (July 12, 2020): 1677. http://dx.doi.org/10.3390/cells9071677.
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Acute myelogenous leukemia (AML) is an aggressive hematological malignancy. The pathophysiology of the disease depends on cytogenetic abnormalities, gene mutations, aberrant gene expressions, and altered epigenetic regulation. Although new pharmacological agents have emerged during the last years, the prognosis is still dismal and new therapeutic strategies are needed. The transcription factor nuclear factor-κB (NF-κB) is regarded a possible therapeutic target. In this study, we investigated the alterations in the global gene expression profile (GEP) in primary AML cells derived from 16 consecutive patients after exposure to the NF-κB inhibitor BMS-345541. We identified a profound and highly discriminative transcriptomic profile associated with NF-κB inhibition. Bioinformatical analyses identified cytokine/interleukin signaling, metabolic regulation, and nucleic acid binding/transcription among the major biological functions influenced by NF-κB inhibition. Furthermore, several key genes involved in leukemogenesis, among them RUNX1 and CEBPA, in addition to NFKB1 itself, were influenced by NF-κB inhibition. Finally, we identified a significant impact of NF-κB inhibition on the expression of genes included in a leukemic stem cell (LSC) signature, indicating possible targeting of LSCs. We conclude that NF-κB inhibition significantly altered the expression of genes central to the leukemic process.
5
Tyner, Jeffrey W., Stephen Spurgeon, Luke B. Fletcher, Wayne Yang, Tibor Kovacsovics, Brian J. Druker, and Marc M. Loriaux. "A Small-Molecule Inhibitor Screen Rapidly Identifies Therapeutic Targets and Individualized Therapeutic Strategies In Patients with Acute and Chronic Leukemias." Blood 116, no. 21 (November 19, 2010): 2754. http://dx.doi.org/10.1182/blood.v116.21.2754.2754.
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Abstract Abstract 2754 The development of more effective and less toxic therapies for acute and chronic leukemias will require the identification of the molecular abnormalities contributing to leukemogenesis and the identification of drugs that specifically block the activity of these lesions. We hypothesize that aberrantly activated tyrosine kinase signaling pathways play a critical role in the pathogenesis of a substantial proportion of leukemia cases, and our preliminary data suggest that the molecular abnormalities causing aberrant kinase activation are unique in a significant number of patients. Thus, effective therapies for leukemia will need to be determined on an individual patient basis. To address this need, we have developed a function-first, small-molecule kinase inhibitor assay that can identify therapeutic targets in tyrosine kinase signaling pathways in primary leukemia samples and provide individualized therapeutic options in a clinically relevant time frame. Methods: To rapidly identify drug sensitivity profiles and activated kinase pathways in individual, primary leukemia samples, we have developed a small-molecule inhibitor array which includes 90 small-molecule, cell-permeable inhibitor compounds including a core of 36 tyrosine kinase inhibitors that collectively target the majority of the tyrosine kinome. Many of the inhibitors are available for clinical use or are in clinical development. Inhibitors were placed in 96-well plates at four serial dilutions to allow IC50 calculations. Three days after adding primary leukemia cells to each well, we performed a tetrazolium based cell viability assay to evaluate the effect of each inhibitor. Because most inhibitors affect multiple kinases, we utilized automated scripts to compare target specificities of compounds that uniquely decreased primary leukemia cell viability to identify potential targets. Results: In preliminary proof-of-principal experiments, we tested leukemia cell lines and primary leukemia samples with known activating tyrosine kinase mutations and Ba/F3 cell lines expressing activated tyrosine kinases. As expected, all cells showed hypersensitivity to compounds with activity against the primary, mutated target. In addition, downstream targets were frequently identified. For example, MKPL-1 cells, which depend on an activating CSF1R translocation for viability, also showed sensitivity to phosphoinositol 3-kinase and NFKB inhibitors. To date, we have fully analyzed approximately 150 primary myeloid and lymphoid leukemia samples. Hierarchical clustering of IC50 data for individual patients identifies activated pathways characteristic to specific leukemia subtypes. Pathways include PI3K activation in acute lymphoblastic leukemia, SRC kinase and BTK activation in chronic lymphocytic leukemia, FLT3 and KIT activation in AML patients, and MEK kinase activation in chronic myelomonocytic leukemia. Importantly, the results show heterogeneous inhibitor sensitivity profiles and potential kinase targets for individual samples even within diagnosis groups supporting a need for individualized targeted therapies. We are currently utilizing inhibitor assay results for clinical trial development. Approximately 40% of samples show sensitivity to at least one FDA approved drug in the inhibitor panel, and we are developing phase II proof-of-concept trials to test the ability of the inhibitor assay to predict effective targeted therapies for individual patients. Conclusions: Our data demonstrate that the small-molecule inhibitor functional assay can rapidly identify genes contributing to leukemogenesis, provide insights into their mechanism of action, and suggest therapeutic options. The unique patterns of inhibitor sensitivity in many samples support the hypothesis that tyrosine kinases and related pathways contributing to leukemogenesis in each patient may be different. These findings, in turn, support the concept that targeted therapy will be most effective when administered on an individualized basis. By utilizing our pre-clinical assay to select individualized leukemia therapies, we hope to create a platform upon which we can rapidly test the effectiveness of individualized kinase therapy and apply this information to enhance development of new drugs and new drug combinations in leukemia patients. Disclosures: Kovacsovics: Celator Pharmaceuticals: Research Funding. Druker:Molecular MD: Consultancy, Equity Ownership. Loriaux:Celator Pharmaceuticals: Research Funding.
6
Hallek, Michael. "Signaling the end of chronic lymphocytic leukemia: new frontline treatment strategies." Blood 122, no. 23 (November 28, 2013): 3723–34. http://dx.doi.org/10.1182/blood-2013-05-498287.
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AbstractThe management of chronic lymphocytic leukemia (CLL) is undergoing profound changes. Several new drugs have been approved for CLL treatment (fludarabine, bendamustine, and the monoclonal antibodies alemtuzumab, rituximab, and ofatumumab) and many more drugs are in advanced clinical development to be approved for this disease. In addition, the extreme heterogeneity of the clinical course and our improved ability to foresee the prognosis of this leukemia by the use of clinical, biological, and genetic parameters now allow us to characterize patients with a very mild onset and course, an intermediate prognosis, or a very aggressive course with high-risk leukemia. Therefore, it becomes increasingly challenging to select the right treatment strategy for each condition. This article summarizes the currently available diagnostic and therapeutic tools and gives an integrated recommendation of how to manage CLL in 2013. Moreover, I propose a strategy how we might integrate the novel agents for CLL therapy into sequential treatment approaches in the near future.
7
Thanendrarajan, S., Y. Kim, and I. G. H. Schmidt-Wolf. "Understanding and Targeting the Wnt/β-Catenin Signaling Pathway in Chronic Leukemia." Leukemia Research and Treatment 2011 (December 4, 2011): 1–7. http://dx.doi.org/10.4061/2011/329572.
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It has been revealed that the Wnt/β-catenin signaling pathway plays an important role in the development of solid tumors and hematological malignancies, particularly in B-cell neoplasia and leukemia. In the last decade there have been made experimental approaches targeting the Wnt pathway in chronic leukemia. In this paper we provide an overview about the current state of knowledge regarding the Wnt/β-catenin signaling pathway in chronic leukemia with special focus on therapeutic options and strategies.
8
Stevenson, Freda K., Sergey Krysov, Andrew J. Davies, Andrew J. Steele, and Graham Packham. "B-cell receptor signaling in chronic lymphocytic leukemia." Blood 118, no. 16 (October 20, 2011): 4313–20. http://dx.doi.org/10.1182/blood-2011-06-338855.
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Abstract The B-cell receptor (BCR) is a key survival molecule for normal B cells and for most B-cell malignancies. Recombinatorial and mutational patterns in the clonal immunoglobulin (Ig) of chronic lymphocytic leukemia (CLL) have revealed 2 major IgMD-expressing subsets and an isotype-switched variant, each developing from distinct B-cell populations. Tracking of conserved stereotypic features of Ig variable regions characteristic of U-CLL indicate circulating naive B cells as the likely cells of origin. In CLL, engagement of the BCR by antigen occurs in vivo, leading to down-regulated expression and to an unanticipated modulation of glycosylation of surface IgM, visible in blood cells, especially in U-CLL. Modulated glycoforms of sIgM are signal competent and could bind to environmental lectins. U-CLL cases express more sIgM and have increased signal competence, linking differential signaling responses to clinical behavior. Mapping of BCR signaling pathways identifies targets for blockade, aimed to deprive CLL cells of survival and proliferative signals. New inhibitors of BCR signaling appear to have clinical activity. In this Perspective, we discuss the functional significance of the BCR in CLL, and we describe strategies to target BCR signaling as an emerging therapeutic approach.
9
Bremer, Edwin, Bram ten Cate, Douwe F. Samplonius, Lou F. M. H. de Leij, and Wijnand Helfrich. "CD7-restricted activation of Fas-mediated apoptosis: a novel therapeutic approach for acute T-cell leukemia." Blood 107, no. 7 (April 1, 2006): 2863–70. http://dx.doi.org/10.1182/blood-2005-07-2929.
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AbstractAgonistic anti-Fas antibodies and multimeric recombinant Fas ligand (FasL) preparations show high tumoricidal activity against leukemic cells, but are unsuitable for clinical application due to unacceptable systemic toxicity. Consequently, new antileukemia strategies based on Fas activation have to meet the criterion of strictly localized action at the tumor-cell surface. Recent insight into the FasL/Fas system has revealed that soluble homotrimeric FasL (sFasL) is in fact nontoxic to normal cells, but also lacks tumoricidal activity. We report on a novel fusion protein, designated scFvCD7:sFasL, that is designed to have leukemia-restricted activity. ScFvCD7:sFasL consists of sFasL genetically linked to a high-affinity single-chain fragment of variable regions (scFv) antibody fragment specific for the T-cell leukemia-associated antigen CD7. Soluble homotrimeric scFvCD7:sFasL is inactive and acquires tumoricidal activity only after specific binding to tumor cell-surface-expressed CD7. Treatment of T-cell acute lymphoblastic leukemia (T-ALL) cell lines and patient-derived T-ALL, peripheral T-cell lymphoma (PTCL), and CD7-positive acute myeloid leukemia (AML) cells with homotrimeric scFvCD7:sFasL revealed potent CD7-restricted induction of apoptosis that was augmented by conventional drugs, farnesyl transferase inhibitor L-744832, and the proteasome inhibitor bortezomib (Velcade; Millenium, Cambridge, MA). Importantly, identical treatment did not affect normal human peripheral-blood lymphocytes (PBLs) and endothelial cells, with only moderate apoptosis in interleukin-2 (IL-2)/CD3-activated T cells. CD7-restricted activation of Fas in T-cell leukemic cells by scFvCD7:sFasL revitalizes interest in the applicability of Fas signaling in leukemia therapy.
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Rodriguez-Rodriguez, Sonia, Lin Wang, Huajia Zhang, Amy Zollman, Angelo A. Cardoso, and Nadia Carlesso. "SKP2 Is Dispensable for Normal T-Cell Development but Required for T-Cell Leukemogenesis." Blood 124, no. 21 (December 6, 2014): 2214. http://dx.doi.org/10.1182/blood.v124.21.2214.2214.
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Abstract Acute Lymphoblastic Leukemia (ALL) is the most common pediatric cancer. Despite the significant clinical successes in the treatment of pediatric T-ALL, leukemia relapse, refractory disease and induction failure (around 30% of patients) remain significant clinical problems, which are often life-threatening. ALL remains the second leading cause of childhood death. Thus, more effective, curative therapeutic strategies are much needed, particularly for refractory and relapse T- ALL. Recent advances in understanding the biology and the molecular alterations of acute lymphoblastic leukemias have led to identification of new molecular targets, such as the Notch signaling pathway. Constitutive activation of Notch signaling is involved in more than 50% of human T-ALL, and overexpression of activated Notch induces T-cell leukemia and lymphoma in murine tumor models. However, disruption of Notch signaling by gamma-secretase inhibitors (GSI) failed to fulfill its clinical promise and, overall, the significant advances attained in dissecting the molecular effectors in T-ALL has yet to translate into effective, curative molecular therapies for relapse patients. Furthermore, despite multiple studies on Notch signaling, little is known on the role of its downstream mediators in T-cell ALL. Previous studies in our laboratory demonstrated that Notch1 activation induces transcriptional activation of SKP2, the F-box protein of the SCF E3-ubiquitin ligase complex. SKP2 is the main F-box protein regulating cell cycle, promoting downregulation of the CKIs (p21Cip1, p27Kip1, p57Kip2 and p130) and its overexpression accelerate cell cycle progression in hematopoietic cells. SKP2 overexpression is frequently associated with cancers, in particular lymphomas and leukemias, and correlates with poor prognosis. We found that Skp2 expression is dynamically regulated during T-cell development coinciding with the Notch expression pattern. Moreover, primary thymocytes cultured in vitro, responded to Notch stimulation by the Delta1 ligand increasing their Skp2 expression and their cell cycle status, whereas the loss of SKP2 impaired their ability to mount a proliferative response to IL-7 stimulation. Importantly, we observed that SKP2 expression is increased in T-ALL patient samples and that mice with Notch-induced T-cell leukemia showed 5 fold upregulation of Skp2 expression. Our hypotheses are that Notch activation promotes T-cell leukemogenesis by altering the cell cycle control through upregulation of Skp2, and that selective targeting of SKP2 is a novel, effective therapeutic strategy for childhood T-ALL. To test whether SKP2 is a key downstream mediator of Notch in T-ALL, we transduced oncogenic Notch (ICN; the constitutive intracellular form) in hematopoietic cells lacking SKP2 from Skp2-/- null mice, and in controls and we determine their ability to induce leukemia in irradiated recipients. Loss of SKP2 significantly delayed the development of T-cell leukemia and increased animal survival by 40%. Taken together, these results demonstrate a previously unrecognized role for SKP2 in the initiation and progression of T-ALL and its potential role as a therapeutic target. Disclosures No relevant conflicts of interest to declare.
11
Hamad, Ahmad, Zeyad Sahli, Maya El Sabban, Maha Mouteirik, and Rihab Nasr. "Emerging Therapeutic Strategies for Targeting Chronic Myeloid Leukemia Stem Cells." Stem Cells International 2013 (2013): 1–12. http://dx.doi.org/10.1155/2013/724360.
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Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder. Current targeted therapies designed to inhibit the tyrosine kinase activity of the BCR-ABL oncoprotein have made a significant breakthrough in the treatment of CML patients. However, CML remains a chronic disease that a patient must manage for life. Although tyrosine kinase inhibitors (TKI) therapy has completely transformed the prognosis of CML, it has made the therapeutic management more complex. The interruption of TKI treatment results in early disease progression because it does not eliminate quiescent CML stem cells which remain a potential reservoir for disease relapse. This highlights the need to develop new therapeutic strategies for CML to achieve a permanent cure, and to allow TKI interruption. This review summarizes recent research done on alternative targeted therapies with a particular focus on some important signaling pathways (such as Alox5, Hedgehog, Wnt/b-catenin, autophagy, and PML) that have the potential to target CML stem cells and potentially provide cure for CML.
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Brown, Patrick, Rob Pieters, and Andrea Biondi. "How I treat infant leukemia." Blood 133, no. 3 (January 17, 2019): 205–14. http://dx.doi.org/10.1182/blood-2018-04-785980.
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Abstract Leukemia in infants is rare but generates tremendous interest due to its aggressive clinical presentation in a uniquely vulnerable host, its poor response to current therapies, and its fascinating biology. Increasingly, these biological insights are pointing the way toward novel therapeutic approaches. Using representative clinical case presentations, we review the key clinical, pathologic, and epidemiologic features of infant leukemia, including the high frequency of KMT2A gene rearrangements. We describe the current approach to risk-stratified treatment of infant leukemia in the major international cooperative groups. We highlight recent discoveries that elucidate the molecular biology of infant leukemia and suggest novel targeted therapeutic strategies, including modulation of aberrant epigenetic programs, inhibition of signaling pathways, and immunotherapeutics. Finally, we underscore the need for increased global collaboration to translate these discoveries into improved outcomes.
13
Martelli, Alberto M., Francesca Paganelli, Serena Truocchio, Carla Palumbo, Francesca Chiarini, and James A. McCubrey. "Understanding the Roles of the Hedgehog Signaling Pathway during T-Cell Lymphopoiesis and in T-Cell Acute Lymphoblastic Leukemia (T-ALL)." International Journal of Molecular Sciences 24, no. 3 (February 3, 2023): 2962. http://dx.doi.org/10.3390/ijms24032962.
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The Hedgehog (HH) signaling network is one of the main regulators of invertebrate and vertebrate embryonic development. Along with other networks, such as NOTCH and WNT, HH signaling specifies both the early patterning and the polarity events as well as the subsequent organ formation via the temporal and spatial regulation of cell proliferation and differentiation. However, aberrant activation of HH signaling has been identified in a broad range of malignant disorders, where it positively influences proliferation, survival, and therapeutic resistance of neoplastic cells. Inhibitors targeting the HH pathway have been tested in preclinical cancer models. The HH pathway is also overactive in other blood malignancies, including T-cell acute lymphoblastic leukemia (T-ALL). This review is intended to summarize our knowledge of the biological roles and pathophysiology of the HH pathway during normal T-cell lymphopoiesis and in T-ALL. In addition, we will discuss potential therapeutic strategies that might expand the clinical usefulness of drugs targeting the HH pathway in T-ALL.
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Petersen, Marianne Agerlund, Carina Agerbo Rosenberg, Marie Bill, Marie Beck Enemark, Ole Rahbek, Anne Stidsholt Roug, Henrik Hasle, Bent Honoré, and Maja Ludvigsen. "Proteomic Profiling Identifies Specific Leukemic Stem Cell-Associated Protein Expression Patterns in Pediatric AML Patients." Cancers 14, no. 15 (July 22, 2022): 3567. http://dx.doi.org/10.3390/cancers14153567.
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Novel therapeutic tools are warranted to improve outcomes for children with acute myeloid leukemia (AML). Differences in the proteome of leukemic blasts and stem cells (AML-SCs) in AML compared with normal hematopoietic stem cells (HSCs) may facilitate the identification of potential targets for future treatment strategies. In this explorative study, we used mass spectrometry to compare the proteome of AML-SCs and CLEC12A+ blasts from five pediatric AML patients with HSCs and hematopoietic progenitor cells from hematologically healthy, age-matched controls. A total of 456 shared proteins were identified in both leukemic and control samples. Varying protein expression profiles were observed in AML-SCs and leukemic blasts, none having any overall resemblance to healthy counterpart cell populations. Thirty-four proteins were differentially expressed between AML-SCs and HSCs, including the upregulation of HSPE1, SRSF1, and NUP210, and the enrichment of proteins suggestive of protein synthesis perturbations through the downregulation of EIF2 signaling was found. Among others, NUP210 and calreticulin were upregulated in CLEC12A+ blasts compared with HSCs. In conclusion, the observed differences in protein expression between pediatric patients with AML and pediatric controls, in particular when comparing stem cell subsets, encourages the extended exploration of leukemia and AML-SC-specific biomarkers of potential relevance in the development of future therapeutic options in pediatric AML.
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Al-Shahrour, Fatima, Kimberly A. Hartwell, Lisa P. Chu, Jaras Marcus, Rishi V. Puram, Alexandre Puissant, Kevin Callahan, et al. "In Vivo RNA Interference Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling." Blood 118, no. 21 (November 18, 2011): 758. http://dx.doi.org/10.1182/blood.v118.21.758.758.
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Abstract Abstract 758 Primary leukemia stem cells (LSCs) reside in an in vivo microenvironment that supports the growth and survival of malignant cells. Despite the increasing understanding of the importance of niche interactions and primary cell biology in leukemia, many studies continue to focus on cell autonomous processes in artificial model systems. The majority of strategies to-date that attempt to define therapeutic targets in leukemia have relied on screening cell lines in culture; new strategies should incorporate the use of primary disease within a physiologic niche. Using a primary murine MLL-AF9 acute myeloid leukemia (AML) model highly enriched for LSCs, we performed an in vivo short hairpin RNA (shRNA) screen to identify novel genes that are essential for leukemia growth and survival. LSCs infected with pools of shRNA lentivirus were transplanted and grown in recipient mice for 2 weeks, after which bone marrow and spleen cells were isolated. Massively parallel sequencing of infected LSCs isolated before and after transplant was used to quantify the changes in shRNA representation over time. Our in vivo screens were highly sensitive, robust, and reproducible and identified a number of positive controls including genes required for MLL-AF9 transformation (Ctnnb1, Mef2c, Ccna1), genes universally required for cell survival (Ube2j2, Utp18), and genes required in other AML models (Myb, Pbx1, Hmgb3). In our primary and validation screens, multiple shRNAs targeting Integrin Beta 3 (Itgb3) were consistently depleted by more than 20-fold over two weeks in vivo. Follow up studies using RNA interference (RNAi) and Itgb3−/− mice identified Itgb3 as essential for murine leukemia cells growth and transformation in vivo, and loss of Itgb3 conferred a statistically significant survival advantage to recipient mice. Importantly, neither Itgb3 knockdown or genetic loss impaired normal hematopoietic stem and progenitor cell (HSPC) function in 16 week multilineage reconstitution assays. We further identified Itgav as the heterodimeric partner of Itgb3 in our model, and found that knockdown of Itgav inhibited leukemia cell growth in vivo. Consistent the therapeutic aims or our study, flow cytometry on primary human AML samples revealed ITGAV/ITGB3 heterodimer expression. To functionally assess the importance of gene expression in a human system, we performed another RNAi screen on M9 leukemia cells, primary human cord blood CD34+ cells transduced with MLL-ENL that are capable of growing in vitro or in a xenotransplant model in vivo. We found that ITGB3 loss inhibited M9 cell growth in vivo, but not in vitro, consistent with the importance of ITGB3 in a physiologic microenvironment. We explored the signaling pathways downstream of Itgb3 using an additional in vivo, unbiased shRNA screen and identified Syk as a critical mediator of Itgb3 activity in leukemia. Syk knockdown by RNAi inhibited leukemia cell growth in vivo; downregulation of Itgb3 expression resulted in decreased levels of Syk phosphorylation; and expression of an activated form of Syk, TEL-SYK, rescued the effects of Itgb3 knockdown on leukemia cell growth in vivo. To understand cellular processes controlled by Itgb3, we performed gene expression studies and found that, in leukemia cells, Itgb3 knockdown induced differentiation and inhibited multiple previously published LSC transcriptional programs. We confirmed these results using primary leukemia cell histology and a model system of leukemia differentiation. Finally, addition of a small molecule Syk inhibitor, R406, to primary cells co-cultured with bone marrow stroma caused a dose-dependent decrease in leukemia cell growth. Our results establish the significance of the Itgb3 signaling pathway, including Syk, as a potential therapeutic target in AML, and demonstrate the utility of in vivo RNA interference screens. Disclosures: Armstrong: Epizyme: Consultancy.
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Lanasa, Mark C. "Novel Insights into the Biology of CLL." Hematology 2010, no. 1 (December 4, 2010): 70–76. http://dx.doi.org/10.1182/asheducation-2010.1.70.
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Abstract Significant advancements in the care of patients with chronic lymphocytic leukemia (CLL) have occurred over the past decade. Nonetheless, CLL remains incurable outside of allogeneic transplantation. CLL is the most common leukemia in the United States and Europe, and new treatments and therapeutic strategies are clearly needed. To address this need, the pathogenesis of CLL has been an area of intense ongoing investigation. These international efforts illuminate a complex biology that is reliant on the interplay of inherited, environmental, and host factors. This broad review will discuss the recent advances in our understanding of CLL biology including the elucidation of inherited and acquired genetic changes; the role of the B-cell receptor and B-cell receptor signaling; CLL cell kinetics; and the interactions in the microenvironment between CLL cells, other immune cells, and stromal elements. This improved understanding of disease pathogenesis is facilitating the development of novel therapeutic treatment strategies.
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Guarente, Valerio, and Paolo Sportoletti. "Lessons, Challenges and Future Therapeutic Opportunities for PI3K Inhibition in CLL." Cancers 13, no. 6 (March 13, 2021): 1280. http://dx.doi.org/10.3390/cancers13061280.
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Chronic lymphocytic leukemia (CLL) shows constitutive phosphatidylinositol 3-kinase (PI3K) activation resulting from aberrant regulation of the B-cell receptor (BCR) signaling. PI3K inhibitors have been evaluated in CLL therapy, bringing a new treatment opportunity for patients with this disease. Despite the proven therapeutic efficacy, the use of approved PI3K inhibitors is limited by severe immune-mediated toxicities and given the availability of other more tolerable agents. This article reviews the relevance of PI3K signaling and pharmacologic inhibition in CLL. Data on efficacy and toxicity of PI3K inhibitors are also presented, as well as strategies for overcoming barriers for their clinical use in CLL treatment.
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Podar, Klaus, Yu-Tzu Tai, Faith E. Davies, Suzanne Lentzsch, Martin Sattler, Teru Hideshima, Boris K. Lin, et al. "Vascular endothelial growth factor triggers signaling cascades mediating multiple myeloma cell growth and migration." Blood 98, no. 2 (July 15, 2001): 428–35. http://dx.doi.org/10.1182/blood.v98.2.428.
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Multiple myeloma (MM) remains incurable, with a median survival of 3 to 4 years. This study shows direct effects of vascular endothelial growth factor (VEGF) upon MM and plasma cell leukemia (PCL) cells. The results indicate that VEGF triggers tumor cell proliferation via a protein kinase C (PKC)–independent Raf-1–MEK–extracellular signal-regulated protein kinase pathway, and migration via a PKC-dependent pathway. These observations provide the framework for novel therapeutic strategies targeting VEGF signaling cascades in MM.
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DiNardo, Courtney D., and Jorge E. Cortes. "Mutations in AML: prognostic and therapeutic implications." Hematology 2016, no. 1 (December 2, 2016): 348–55. http://dx.doi.org/10.1182/asheducation-2016.1.348.
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Abstract Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the proliferation and aberrant differentiation of immature clonal myeloid cells. The prognosis of AML is variable, based on clinical features such as patient age, performance status, and comorbidities, as well as leukemia-specific genetic features including cytogenetics and molecular classification. The modern application of next-generation sequencing technology has uncovered marked heterogeneity and genomic complexity within AML, based on the presence or absence of cooperating mutations within functional categories such as epigenetic regulators, cell signaling and proliferation pathways, and master hematopoietic transcription factors. Although the treatment of AML has hitherto changed little in the past 40 years, the enhanced scientific understanding of AML pathophysiology and leukemogenesis has led to the recent development of multiple targeted and selective treatment approaches, and our increasing awareness of functional AML subsets will be evermore used to inform rational and personalized treatment strategies.
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Twizere, Jean-Claude, Jean-Yves Springael, Mathieu Boxus, Arsène Burny, Franck Dequiedt, Jean-François Dewulf, Julie Duchateau, et al. "Human T-cell leukemia virus type-1 Tax oncoprotein regulates G-protein signaling." Blood 109, no. 3 (September 21, 2006): 1051–60. http://dx.doi.org/10.1182/blood-2006-06-026781.
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AbstractHuman T-cell leukemia virus type-1 (HTLV-1) is associated with adult T-cell leukemia (ATL) and neurological syndromes. HTLV-1 encodes the oncoprotein Tax-1, which modulates viral and cellular gene expression leading to T-cell transformation. Guanine nucleotide–binding proteins (G proteins) and G protein–coupled receptors (GPCRs) constitute the largest family of membrane proteins known and are involved in the regulation of most biological functions. Here, we report an interaction between HTLV-1 Tax oncoprotein and the G-protein β subunit. Interestingly, though the G-protein β subunit inhibits Tax-mediated viral transcription, Tax-1 perturbs G-protein β subcellular localization. Functional evidence for these observations was obtained using conditional Tax-1–expressing transformed T-lymphocytes, where Tax expression correlated with activation of the SDF-1/CXCR4 axis. Our data indicated that HTLV-1 developed a strategy based on the activation of the SDF-1/CXCR4 axis in the infected cell; this could have tremendous implications for new therapeutic strategies.
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Santos, Juliana Carvalho, Núria Profitós-Pelejà, Salvador Sánchez-Vinces, and Gaël Roué. "RHOA Therapeutic Targeting in Hematological Cancers." Cells 12, no. 3 (January 28, 2023): 433. http://dx.doi.org/10.3390/cells12030433.
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Primarily identified as an important regulator of cytoskeletal dynamics, the small GTPase Ras homolog gene family member A (RHOA) has been implicated in the transduction of signals regulating a broad range of cellular functions such as cell survival, migration, adhesion and proliferation. Deregulated activity of RHOA has been linked to the growth, progression and metastasis of various cancer types. Recent cancer genome-wide sequencing studies have unveiled both RHOA gain and loss-of-function mutations in primary leukemia/lymphoma, suggesting that this GTPase may exert tumor-promoting or tumor-suppressive functions depending on the cellular context. Based on these observations, RHOA signaling represents an attractive therapeutic target for the development of selective anticancer strategies. In this review, we will summarize the molecular mechanisms underlying RHOA GTPase functions in immune regulation and in the development of hematological neoplasms and will discuss the current strategies aimed at modulating RHOA functions in these diseases.
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Pillsbury, Claire E., Jairo A. Fonseca, Jodi Dougan, Hasan Abukharma, Linda N. Liu, and Christopher C. Porter. "Siglec-15 Is a Novel Immunomodulatory Protein and Therapeutic Target in Childhood Leukemia." Blood 136, Supplement 1 (November 5, 2020): 6–7. http://dx.doi.org/10.1182/blood-2020-142833.
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Despite advances that have greatly improved the overall survival of pediatric B cell acute lymphoblastic leukemia (B-ALL), it remains one of the leading causes of cancer-related death in children. Immunotherapy has shown efficacy in treatment of refractory disease, highlighting the need for greater understanding of the immune evasion mechanisms underlying this disease so that additional immune modulating therapeutic strategies can be developed. Siglec-15 (Sig15) was recently reported to have immune modulatory functions in the context of solid tumors. We have found that SIGLEC15 is overexpressed at the RNA level in primary B cell acute lymphoblastic leukemia (B-ALL), acute myelogenous leukemia (AML), and diffuse large B cell lymphoma as compared to healthy donor controls. As compared to healthy donor PBMCs, we have confirmed higher expression of Sig15 at the RNA and protein levels through RT-qPCR, immunoblotting, and flow cytometry across a panel of human B-ALL, AML, DLBCL, and T cell acute lymphoblastic leukemia (T-ALL) cell lines. Knockout of Sig15 expression in a BCR-ABL1+ murine model of B-ALL engrafted in immunocompetent and Rag1-/- immunodeficient recipients resulted in leukemia clearance in immunocompetent, but not immunodeficient, recipients and 100% survival (Figure 1). These data suggest a prominent role for Sig15 in the suppression of adaptive immune response to B-ALL as well as other hematological malignancies. Additional studies suggest that SIGLEC15 expression is positively regulated by NFκB signaling, which is known to be constitutively activated in certain B-ALL subsets. Importantly, we have observed release of a soluble form of Sig15 (sSig15) from B-ALL cells, which is regulated by PKC and calcineurin-mediated signaling. To discover translational application, we measured sSig15 in the plasma of both healthy and pediatric leukemia patients and found significantly higher levels of sSig15 as compared to healthy individuals (Figure 2; LLD = 5 pg/ml; **P<0.01). Together, these results suggest Siglec-15 is a novel and potent immunosuppressive molecule active in leukemia that may be targeted therapeutically to activate lymphocytes against leukemia cells. Disclosures Abukharma: NextCure, Inc.: Current Employment. Liu:NextCure, Inc.: Current Employment.
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Aguadé-Gorgorió, Júlia, Scott McComb, Cornelia Eckert, Anna Guinot, Blerim Marovca, Caterina Mezzatesta, Silvia Jenni, et al. "TNFR2 is required for RIP1-dependent cell death in human leukemia." Blood Advances 4, no. 19 (October 7, 2020): 4823–33. http://dx.doi.org/10.1182/bloodadvances.2019000796.
Full textAbstract:
Abstract Despite major advances in the treatment of patients with acute lymphoblastic leukemia in the last decades, refractory and/or relapsed disease remains a clinical challenge, and relapsed leukemia patients have an exceedingly dismal prognosis. Dysregulation of apoptotic cell death pathways is a leading cause of drug resistance; thus, alternative cell death mechanisms, such as necroptosis, represent an appealing target for the treatment of high-risk malignancies. We and other investigators have shown that activation of receptor interacting protein kinase 1 (RIP1)–dependent apoptosis and necroptosis by second mitochondria derived activator of caspase mimetics (SMs) is an attractive antileukemic strategy not currently exploited by standard chemotherapy. However, the underlying molecular mechanisms that determine sensitivity to SMs have remained elusive. We show that tumor necrosis factor receptor 2 (TNFR2) messenger RNA expression correlates with sensitivity to SMs in primary human leukemia. Functional genetic experiments using clustered regularly interspaced short palindromic repeats/Cas9 demonstrate that TNFR2 and TNFR1, but not the ligand TNF-α, are essential for the response to SMs, revealing a ligand-independent interplay between TNFR1 and TNFR2 in the induction of RIP1-dependent cell death. Further potential TNFR ligands, such as lymphotoxins, were not required for SM sensitivity. Instead, TNFR2 promotes the formation of a RIP1/TNFR1-containing death signaling complex that induces RIP1 phosphorylation and RIP1-dependent apoptosis and necroptosis. Our data reveal an alternative paradigm for TNFR2 function in cell death signaling and provide a rationale to develop strategies for the identification of leukemias with vulnerability to RIP1-dependent cell death for tailored therapeutic interventions.
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Smolewski, Piotr, Magdalena Witkowska, and Anna Korycka-Wołowiec. "New Insights into Biology, Prognostic Factors, and Current Therapeutic Strategies in Chronic Lymphocytic Leukemia." ISRN Oncology 2013 (August 22, 2013): 1–7. http://dx.doi.org/10.1155/2013/740615.
Full textAbstract:
Chronic lymphocytic leukemia (CLL) is characterized by the clonal proliferation and accumulation of mature B lymphocytes. CLL cells show an antiapoptotic profile, suggesting the important role of apoptosis inhibition in the disease development. However, there is some population of proliferating CLL cells, which may also play a role in progression of the disease. There are several newer, biological prognostic factors in CLL. Currently, cytogenetic abnormalities with different prognostic values seem to be the most biologically relevant. During the last decades, the treatment of CLL has been significantly changed. Different strategies such as monotherapy with chlorambucil and purine nucleoside analogues (PNA) used alone or in combination with cyclophosphamide have been introduced. Most recently, immunochemotherapy with anti-CD20 monoclonal antibody, rituximab, combined with fludarabine and cyclophosphamide, became a gold standard of first-line treatment in eligible CLL patients. Currently, new treatment strategies including new monoclonal antibodies, bendamustine, lenalidomide, or inhibitors of several cell signaling pathways are under clinical studies in resistant/relapsed CLL patients. Moreover, allogeneic stem cell transplantation has to be considered, especially in younger high risk patients, for example, those who are resistant to PNA or those with 17p deletion. In this paper, we present the most important recent advances in CLL biology and treatment.
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She, Miaorong, Jinggao Li, Xilin Chen, Xingqing Niu, Kunyuan Guo, Xin Du, Maohua Zhou, Yanjie He, and Yi Le. "Increase of Sensitivity to Chemotherapy and NK-Mediated Cytotoxicity of Leukemic Stem Cell by a Farnesyltransferase Inhibitor." Blood 114, no. 22 (November 20, 2009): 4161. http://dx.doi.org/10.1182/blood.v114.22.4161.4161.
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Abstract Abstract 4161 Acute myeloid leukemia (AML) is a serious and often lethal hematopoietic malignant disease arising from stem cells. Leukemic stem cells (LSCs) play the central role in the relapse and refractory of AML and highlight the critical need for the new therapeutic strategies to directly target the LSC population. We previous found that LSC were resistant to chemotherapy and NK-mediated cytotoxicity, which were resulted from the apoptosis defect and NKG2D ligands change. Our previous data also showed that Manumycin induced apoptosis in leukemia cells through mitochondria pathway. Here, we demonstrated that manumycin increased the sensitivity of LSC to chemotherapy and NK cell-mediated cytotoxicity. Manumycin enhanced sensitivity to chemotherapy in LSCs via induced apoptosis. Analysis of signaling pathways revealed that manumycin enhanced mitoxantrone activation of caspase 3 and significantly decreasing Bcl2 protein. These finding indicated that manumycin sensitized mitoxantrone to chemotherapy via down-regulating Bcl2. Importantly, manumycin enhanced the sensitivities of LSCs to NK cells cytotoxicity through up-regulating the expressions of NKG2D ligands MICA/B and ULBP3. Thus, Manumycin present a promising novel therapeutic approach for AML therapy especially when resistant to chemotherapy and NK cell immunotherapy. Disclosures: No relevant conflicts of interest to declare.
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Seyedmehdi, Shojaee, Zhengshan Chen, Maike Buchner, Christian Hurtz, Huimin Geng, Hilde Schjerven, Lai N. Chan, et al. "Erk and Stat5 Feedback Control Enables Pre-B Cell Transformation and Represents a Therapeutic Target in Acute Lymphoblastic Leukemia." Blood 124, no. 21 (December 6, 2014): 787. http://dx.doi.org/10.1182/blood.v124.21.787.787.
Full textAbstract:
Abstract Background and Hypothesis: Targeted therapy of cancer typically focuses on the development of agents that will inactivate a transforming oncogene. In this study, we tested the concept that besides the oncogene itself, factors that enable permissiveness of a normal cell to oncogenic signaling represent a novel class of therapeutic targets. This hypothesis was based on three findings. First, acute activation of oncogenes in normal pre-B cells typically caused immediate cell death, unless pre-B cells were capable of adapting quickly enough to a high level of signaling output. Second, few surviving pre-B cell clones achieved permissiveness to oncogenic signaling by strong activation of negative feedback control of Erk and Stat5. Third, robust feedback control of Erk and Stat5 distinguishes normal pre-B cells from fully transformed pre-B acute lymphoblastic leukemia (ALL) cells. Results: To test the significance of strong feedback control of Erk and Stat5 signaling in pre-B ALL cells, we developed genetic loss-of function models for six central molecules in Erk (DUSP6, SPRY2, ETV5) and Stat5 (Cish, SOCS2, SOCS3) feedback control. Genetic deletion of the sprouty family Ras inhibitor Spry2, the Erk dual specificity phosphatase Dusp6 and their transcriptional activator Etv5, decreased robustness of Erk feedback control and compromised oncogenic transformation in mouse models for pre-B ALL. Likewise, ablation of Stat5 feedback control through deletion of the suppressors of cytokine signaling (SOCS) family molecules Cish, Socs2 and Socs3 reversed permissiveness of pre-B cells. Studying deletion of Spry2 (Erk) and Cish (Stat5) in an in vivo transplant model using inducible, Cre-mediated deletion of Spry2 and Cish in pre-B ALL cells confirmed that Erk and Stat5 feedback control are essential for malignant transformation and development of lethal leukemia. Genetic deletion of Erk (Dusp6, Spry2, Etv5) and Stat5 (Cish, Socs2, Socs3) feedback control impairs leukemic transformation of pre-B cells. Searching for factors that restrict permissiveness to oncogene signaling, we identified the pre-B cell tumor suppressor IKZF1, which is deleted in a large fraction of pre-B ALL cases. IKZF1 directly bound to and transcriptionally repressed multiple promoters of Erk and Stat5 feedback control and IKZF1 deletion raised the limit of maximum allowable oncogene signaling strength in pre-B ALL cells. We propose that the pre-B cell tumor suppressor IKZF1 functions as transcriptional repressor of Erk and Stat5 feedback control and thereby retains pre-B cells in a Non-permissive state. Clinical relevance: To assess potential usefulness of this finding for the development of future treatment strategies, we tested the effect of a specific small molecule inhibitor of DUSP6, E-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI), which was designed as an allosteric inhibitor of the interaction between DUSP6 and phospho-ERK1/2. Interestingly, BCI acutely subverted Erk feedback control and selectively induced cell death in pre-B ALL cells. Small molecule inhibition of DUSP6 was sufficient to overcome conventional mechanisms of drug-resistance in pre-B ALL and selectively killed patient-derived pre-B ALL cells in a leukemia transplant model. BCI treatment, similar to Dusp6-deletion in our leukemia mouse model, led to the accumulation of P53 and ARF in patient-derived pre-B ALL cells. In addition, small molecule inhibition of DUSP6 had strong selective activity on drug-resistant patient-derived pre-B ALL cells that were injected into NOD/SCID transplant recipient mice. These findings identify permissive negative feedback control of oncogenic signaling as a previously unrecognized vulnerability of pre-B ALL cells and a new class of potential therapeutic targets. Conclusion: Targeting negative feedback regulation of both Erk and Stat5 signaling for the treatment of pre-B ALL seems counter-intuitive because it represents effectively the opposite of current efforts of targeted inhibition of oncogenic signaling. Our results, however, demonstrate that a robust negative feedback regulation is required for the leukemic transformation and development of fatal leukemia in pre-B ALL. We demonstrate that feedback control of Erk and Stat5 signaling represents a previously unrecognized vulnerability and, potentially, a novel class of therapeutic targets in human pre-B ALL. Disclosures No relevant conflicts of interest to declare.
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Schinke, Carolina, Orsolya Giricz, Shanisha A. K. Gordon, Laura Barreyro, Tushar D. Bhagat, Andrea Pellagatti, Jacqueline Boultwood, Yiting Yu, Ulrich Steidl, and Amit Verma. "Inhibition Of CXCR2 As a Therapeutic Strategy In AML and MDS." Blood 122, no. 21 (November 15, 2013): 484. http://dx.doi.org/10.1182/blood.v122.21.484.484.
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Abstract Acute Myeloid Leukemia (AML) and Myelodysplastic syndrome (MDS) arise from accumulation of multiple stepwise genetic and epigenetic changes in hematopoietic stem cells (HSC) and/or committed progenitors. A series of transforming events can initially give rise to pre-leukemia stem cells (pre-LSC) as well as fully transformed leukemia stem cells (LSC), both of which need to be targeted in strategies aimed at curing these diseases. We conducted parallel transcriptional analysis of multiple, highly fractionated stem and progenitor populations in individual patients of MDS and AML (N=16) and identified candidate genes that are consistently dysregulated at multiple immature stem and progenitor cell stages. Interleukin 8 (IL8), was one of the most consistently overexpressed genes in MDS/AML Hematolpoetic Stem Cells (HSCs) and progenitors when compared to healthy control HSCs and progenitors. IL8 is a pro-inflammatory chemokine, which is able to activate multiple intracellular signaling pathways after binding to its surface receptor CXCR2. Even though increased IL8-CXCR2 signaling has been shown to promote angiogenesis, metastasis and chemotherapy resistance in many solid tumors, its role in AML and MDS is not well elucidated. We further analyzed gene expression profiles of CD34+ cells from 183 MDS patients and found significant increased expression of CXCR2 in MDS when compared to healthy controls (FDR<0.1). Most importantly, analysis of The Cancer Genome Atlas (TCGA) AML (n=200) dataset showed that CXCR2 expression was predictive of significantly adverse prognosis (log rank P value=0.0182; median survival of 245 days in cxcr2 high vs 607 days in cxcr2 low) in patients, further pointing to a critical role of IL8-CXCR2 signaling in AML/MDS. Next, we studied the functional role of IL8 and CXCR2 in AML. A panel of leukemic cell lines (THP-1, U937, KG-1, MOLM13, HL-60, K532) were screened for CXCR2 expression and revealed significantly higher expression when compared to healthy CD34+ control cells. SB-332235, a specific inhibitor of CXCR2 was used for functional studies. CXCR2 inhibition led to significant, (p<0.05) reduction in proliferation in all 6 cell lines tested and an effect was seen as early as 24 hrs of exposure. CXCR2 inhibition was found to lead to G0/G1 cell cycle arrest and trigged apoptosis in THP-1 and U937 cells (p-value 0.004 and 0.02 respectively). Incubation of primary AML/MDS bone marrow samples with SB-332235 similarly lead to significantly reduced proliferation at 24hrs, when compared to healthy CD34+ cells. Selective, and highly significant inhibition of leukemic cell growth was also seen in colony assays from primary MDS/AML samples (mean leukemic colonies in AML/MDS= 73 vs 313 in controls, P < 0.001). Interestingly, inhibition of CXCR2 in primary AML marrow samples led to induction of apoptosis in immature CD34+/CD38- cells when compared to healthy controls. Lastly, xenografting studies with THP-1 leukemic cells revealed that CXCR2 inhibitor treatment led to decreased leukemic burden and organ infiltration when compared to placebo controls in vivo. In summary we have found significantly increased expression of IL8 and its receptor CXCR2 in sorted HSCs and progenitors from AML and MDS patients. High CXCR2 expression was a marker of adverse prognosis in a large cohort of AML patients. Most importantly, in vitro and in vivo functional studies showed that CXCR2 is a potential therapeutic target in AML/MDS and is able to selectively target immature, LSC-enriched cell fractions in AML. Disclosures: No relevant conflicts of interest to declare.
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Huang, Benjamin, Eugene Hwang, Anica M. Wandler, Ben Powell, Gideon Bollag, and Kevin Shannon. "Response and Resistance to Bromodomain Inhibition in AML Driven By Hyperactive Ras Signaling." Blood 128, no. 22 (December 2, 2016): 1654. http://dx.doi.org/10.1182/blood.v128.22.1654.1654.
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Abstract Background: Acute myeloid leukemia (AML) is an aggressive hematologic cancer characterized by clonal proliferation of hematopoietic stem and progenitor cells that exhibit impaired differentiation. Event free survival for patients with AML remains poor despite intensive myelosuppressive therapies and improvements in supportive care measures. This underscores the need for novel, biologically based therapies. Somatic mutations that deregulate epigenetic programs (e.g. DNMT3A, TET2, IDH1/2, EZH2, ASXL1) and signal transduction pathways (e.g., FLT3, NRAS, KRAS) frequently coexist in AML. While the former class of mutations is hypothesized to promote a chromatin state that is permissive for AML development and essential for leukemia maintenance, experimental data also suggest that signaling mutations play a central role in driving leukemic growth in vivo. Thus, simultaneously targeting the abnormal epigenetic landscape and aberrant signaling pathways in AML is a rational new therapeutic approach. Recent publications identified the bromodomain and extraterminal (BET) proteins, an important class of epigenetic reader proteins, as particularly promising therapeutic targets in AML. While these studies support the therapeutic potential of BET inhibition in AML, they have limitations. These include their dependence on exogenous overexpression of oncogenes, failure to inform potential combination therapeutic strategies, and a reliance on monoclonal in vitro systems that do not recapitulate the inherent genetic heterogeneity of human cancers. Methods: We previously generated a heterogeneous collection of murine AMLs by infecting Nras, Kras, and Nf1 mutant mice with the MOL4070 retrovirus, which exhibit distinct retroviral integrations that are maintained upon transplantation into sublethally irradiated recipient mice. We first established 15 mg/kg/day as the maximally tolerated dose of PLX51107, a selective and potent BET inhibitor, in sublethally irradiated mice in a C57Bl/6 x 129sv/J strain background. We performed pharmacokinetic analysis, which demonstrated excellent drug exposure at doses of 10 and 15 mg/kg/day. We next treated cohorts of recipient mice with PLX51107 (10 mg/kg/day) and in combination with the MEK inhibitor PD0325901 (PD901; 1.5 mg/day). Mice that appeared ill were euthanized and underwent full pathological examination. Despite continuous drug treatment, all recipient mice eventually succumbed to progressive AML. Results: We enrolled eight AMLs, including four with a Nras(G12D) mutation, two with a Kras(G12D) mutation, and two with Nf1 inactivation. Recipient mice received 450 cGy of sublethal irradiation followed by 2x10E6 leukemia cells via tail vein injection. Recipient mice were randomized to receive vehicle (n = 4 for each AML), PLX51107 (n = 5), or PLX51107+PD901 (n = 5). PLX51107 markedly extended the survival of recipients transplanted with Nras(G12D) AMLs 6695, 6606, and 6613 that was further enhanced by PD901 (Fig. 1A). Whereas, PD901 resulted in a 1.5-fold increase in survival over vehicle-treated mice, PLX51107 alone resulted in a 4-fold increase in survival and PLX51107+PD901 in a nearly 6-fold increase in survival in this cohort of Nras(G12D) AMLs. Surprisingly, the response to PLX51107 was blunted in Kras(G12D) and Nf1 inactivated AMLs compared to Nras(G12D) AMLs. The observation of novel MOL4070 integration sites in relapsed AMLs provided definitive evidence of clonal evolution (Fig. 1B). Importantly, we went on to show that drug-treated clones emerging at relapse demonstrate intrinsic drug resistance by re-transplanting these leukemias into secondary recipients and re-treating them in vivo (Fig. 1C). Conclusion: PLX51107 shows impressive efficacy in a panel of primary AMLs treated in vivo that is further enhanced by PD901. The differential response between Nras(G12D) and Kras(G12D)/Nf(-/-) AMLs leads to the intriguing and unexpected hypothesis that the type of hyperactive Ras signaling mutation may influence the response to BET inhibition in AML. We are interrogating relapsed AMLs to identify and functionally validate candidate mechanisms underlying drug response and resistance through the use of established strategies to directly compare untreated and relapsed leukemias. Ongoing studies include assessing retroviral integrations and performing Western blotting, whole exome sequencing, RNA-seq, and ChIP-seq. Disclosures Powell: Plexxikon: Employment. Bollag:Plexxikon Inc.: Employment.
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Chen, Yingyu, Donghui Gan, Qinghua Huang, Xiaofeng Luo, Donghong Lin, and Jianda Hu. "Emodin and Its Combination with Cytarabine Induce Apoptosis in Resistant Acute Myeloid Leukemia Cells in Vitro and in Vivo." Cellular Physiology and Biochemistry 48, no. 5 (2018): 2061–73. http://dx.doi.org/10.1159/000492544.
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Background/Aims: Acute myeloid leukemia (AML) remains a hematologic malignancy with poor survival and a high risk of relapse, which is mainly caused by the emergence of multidrug resistance (MDR). The identification of novel agents to improve therapeutic strategies becomes important priority for AML treatment. It has been shown that emodin has therapeutic effects on many kinds of human malignant tumors. In this study, we investigated the anti-leukemia effects of emodin alone or in combination with cytarabine (Ara-C) on multidrug-resistant AML HL-60/ADR cells and in a mouse xenograft model of human highly tumorigenic AML HL-60/H3 cells. The underlying mechanism was also addressed. Methods: Cell viability after treatment was measured by MTT assay. The DNA fragmentation assay, Annexin V-PE/7-AAD, AO/EB staining, and electron microscopy were introduced to assess the apoptotic induction effects. Changes in protein expression in the Akt and ERK signaling pathways were determined by western blotting. In vivo antileukemia effects on HL-60/H3 xenograft model and overall mouse survival outcomes were further analyzed in this study. Results: Emodin dose-dependently induced growth inhibition and apoptotic effects in resistant HL-60/ADR cells in vitro as well as in the HL-60/H3 xenograft models in vivo. Moreover, emodin significantly enhanced chemosensitivity of AML cells to Ara-C, inhibited leukemic cell growth, and improved survival in the mouse xenograft model of AML. Dual targeting of Akt and ERK signaling pathways might contribute to the anti-leukemia effects on AML cells in vitro and in vivo. Conclusion: Emodin and its combination with Ara-C may be considered a promising therapeutic approach in AML and worthy of further investigation.
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Martins, Leila R., Paulo Lúcio, Milene C. Silva, Kenna L. Anderes, Paula Gameiro, Maria G. Silva, and João T. Barata. "Targeting CK2 overexpression and hyperactivation as a novel therapeutic tool in chronic lymphocytic leukemia." Blood 116, no. 15 (October 14, 2010): 2724–31. http://dx.doi.org/10.1182/blood-2010-04-277947.
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Abstract Expression of protein kinase CK2 is frequently deregulated in cancer and mounting evidence implicates CK2 in tumorigenesis. Here, we show that CK2 is overexpressed and hyperactivated in chronic lymphocytic leukemia (CLL). Inhibition of CK2 induces apoptosis of CLL cells without significantly affecting normal B and T lymphocytes. Importantly, this effect is not reversed by coculture with OP9 stromal cells, which are otherwise capable of rescuing CLL cells from in vitro spontaneous apoptosis. CLL cell death upon CK2 inhibition is mediated by inactivation of PKC, a PI3K downstream target, and correlates with increased PTEN activity, indicating that CK2 promotes CLL cell survival at least in part via PI3K-dependent signaling. Although CK2 antagonists induce significant apoptosis of CLL cells in all patient samples analyzed, sensitivity to CK2 blockade positively correlates with the percentage of CLL cells in the peripheral blood, β2 microglobulin serum levels and clinical stage. These data suggest that subsets of patients with aggressive and advanced stage disease may especially benefit from therapeutic strategies targeting CK2 function. Overall, our study indicates that CK2 plays a critical role in CLL cell survival, laying the groundwork for the inclusion of CK2 inhibitors into future therapeutic strategies.
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Bose, Prithviraj, and Varsha Gandhi. "Recent therapeutic advances in chronic lymphocytic leukemia." F1000Research 6 (October 31, 2017): 1924. http://dx.doi.org/10.12688/f1000research.11618.1.
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The last several years have witnessed a paradigm shift in the management of patients with chronic lymphocytic leukemia (CLL). The course of this very heterogeneous disease, traditionally treated with chemotherapeutic agents usually in combination with rituximab, typically has been characterized by remissions and relapses, and survival times vary greatly, depending on intrinsic biological attributes of the leukemia. The developments of the last few years have been transformative, ushering in an era of novel, molecularly targeted therapies, made possible by extensive efforts to elucidate the biology of the disease that predated the new targeted drugs. Thus, successful therapeutic targeting of the B-cell receptor signaling pathway and of the Bcl-2 anti-apoptotic protein with small molecules has now made chemotherapy-free approaches possible, hopefully mitigating the risk of development of therapy-related myeloid neoplasms and making eventual cure of CLL with the use of optimal drug combinations a realistic goal. Most importantly, these therapies have demonstrated unprecedented efficacy in patients with deletion 17p/TP53 mutation, a subset that historically has been very difficult to treat. However, as we gain more experience with the newer agents, unique safety concerns and resistance mechanisms have emerged, as has the issue of cost, as these expensive drugs are currently administered indefinitely. Accordingly, novel laboratory-based strategies and clinical trial designs are being explored to address these issues. The availability of whole exome/genome sequencing has given us profound insights into the mutational landscape of CLL. In this article, we highlight some of the most impactful advances since this topic was last reviewed in this journal.
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Airiau, Kelly, Pierre Vacher, Olivier Micheau, Valerie Prouzet-Mauleon, Guido Kroemer, Mohammad Amin Moosavi, and Mojgan Djavaheri-Mergny. "TRAIL Triggers CRAC-Dependent Calcium Influx and Apoptosis through the Recruitment of Autophagy Proteins to Death-Inducing Signaling Complex." Cells 11, no. 1 (December 25, 2021): 57. http://dx.doi.org/10.3390/cells11010057.
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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively kills various cancer cell types, but also leads to the activation of signaling pathways that favor resistance to cell death. Here, we investigated the as yet unknown roles of calcium signaling and autophagy regulatory proteins during TRAIL-induced cell death in leukemia cells. Taking advantage of the Gene Expression Profiling Interactive Analysis (GEPIA) project, we first found that leukemia patients present a unique TRAIL receptor gene expression pattern that may reflect their resistance to TRAIL. The exposure of NB4 acute promyelocytic leukemia cells to TRAIL induces intracellular Ca2+ influx through a calcium release-activated channel (CRAC)-dependent mechanism, leading to an anti-apoptotic response. Mechanistically, we showed that upon TRAIL treatment, two autophagy proteins, ATG7 and p62/SQSTM1, are recruited to the death-inducing signaling complex (DISC) and are essential for TRAIL-induced Ca2+ influx and cell death. Importantly, the treatment of NB4 cells with all-trans retinoic acid (ATRA) led to the upregulation of p62/SQSTM1 and caspase-8 and, when added prior to TRAIL stimulation, significantly enhanced DISC formation and the apoptosis induced by TRAIL. In addition to uncovering new pleiotropic roles for autophagy proteins in controlling the calcium response and apoptosis triggered by TRAIL, our results point to novel therapeutic strategies for sensitizing leukemia cells to TRAIL.
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Youn, Minyoung, Jesus Omar Gomez, Kailen Mark, and Kathleen M. Sakamoto. "RSK Isoforms in Acute Myeloid Leukemia." Biomedicines 9, no. 7 (June 24, 2021): 726. http://dx.doi.org/10.3390/biomedicines9070726.
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Ribosomal S6 Kinases (RSKs) are a group of serine/threonine kinases that function downstream of the Ras/Raf/MEK/ERK signaling pathway. Four RSK isoforms are directly activated by ERK1/2 in response to extracellular stimuli including growth factors, hormones, and chemokines. RSKs phosphorylate many cytosolic and nuclear targets resulting in the regulation of diverse cellular processes such as cell proliferation, survival, and motility. In hematological malignancies such as acute myeloid leukemia (AML), RSK isoforms are highly expressed and aberrantly activated resulting in poor outcomes and resistance to chemotherapy. Therefore, understanding RSK function in leukemia could lead to promising therapeutic strategies. This review summarizes the current information on human RSK isoforms and discusses their potential roles in the pathogenesis of AML and mechanism of pharmacological inhibitors.
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De La Puente, Pilar, Ellen Weisberg, Atsushi Nonami, Micah John Luderer, Richard M. Stone, Junia V. Melo, James D. Griffin, and Abdel Kareem Azab. "Integrin-Linked Kinase a Novel Therapeutic Target for Acute and Chronic Myeloid Leukemia." Blood 126, no. 23 (December 3, 2015): 3694. http://dx.doi.org/10.1182/blood.v126.23.3694.3694.
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Abstract Introduction: Current treatment options as well as clinical efficacy are limited for acute myeloid leukemia (AML), Ph+ acute lymphoblastic leukemia (Ph+ ALL), and chronic myelogenous leukemia (CML). In response to the pressing need for more efficacious treatment approaches and strategies to override drug resistance in advanced stage AML, Ph+ ALL, and CML, we investigated the effects of inhibition of integrin-linked kinase (ILK) as a potentially novel and effective approach to treatment of these challenging malignancies. ILK is an intracellular adaptor and kinase that links the integrins, cell-adhesion receptors, and growth factors to a range of signaling pathways. It has been shown that inhibition of ILK expression and activity is anti-tumorigenic, which makes ILK an attractive target for cancer therapeutics. Compound 22 (Cpd22, N-Methyl-3-(1-(4-(piperazin-1-yl)phenyl)-5-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-1H-pyrazol-3-yl)propanamide) is a cell-permeable, tri-substituted pyrazol compound that acts as a potent and targeted ILK inhibitor. In the present study, we investigated ILK as a putative novel target for treatment of AML, Ph+ ALL, and CML, and Cpd22 as a potential novel anti-leukemia agent. Methods: Compound 22 (Cpd22) was purchased from EMD Millipore. The expression of ILK in AML (K052, NOMO-1, THP, MOLM14), CML (K562, Ku812F, LAMA84S and LAMA84R), and Ph+ ALL (SUP-B15) cell lines, primary patient cells, and human Bone Marrow Mononuclear Cells (BM MNCs) was analyzed by flow cytometry. AML, Ph+ ALL, CML cell lines and peripheral blood mononuclear cells (PBMCs) were cultured with ILK inhibitor, Cpd22 (0-1000 nM) for 3 days. Toxicity of Cdp22 (0-500 nM) toward BM MNCs and primary patient cells (CML, ALL, and AML) was also assessed. Cell lines and/or primary patient cells were analyzed for cell proliferation by MTT assay; cell cycle by DNA staining with PI and analyzed by flow cytometry; apoptosis was analyzed by Annexin V/PI staining and analyzed by flow cytometry; and cell signaling associated with proliferation, cell cycle, and apoptosis was analyzed by western blotting. In addition, ILK knockdown of AML and CML cell lines was evaluated. Results: Normal BM MNCs showed ILK expression, but expression was lower than in cell lines and primary samples from AML, CML, and ALL. Cpd22 inhibited the proliferation of AML, ALL, and CML cell lines, while none of normal PBMC and normal BM MNCs controls were affected by the same concentration range after three days of treatment with Cpd22 as a single agent. ILK expression in primary AML patient cells correlated with efficacy of Cpd22: Specifically, the higher the ILK expression, the more sensitivity to Cpd22. ILK expression in primary ALL patient cells also correlated with the efficacy of Cpd22: Specifically, the higher the ILK expression, the more sensitivity to Cpd22. We validated the target specificity of Cpd22 in CML cells by immuno-blotting and investigating inhibitor effects on signaling molecules downstream of ILK. Cpd22 potently suppressed the phosphorylation levels of Ser-473-Akt (pAKT) and another ILK substrate, pGSK-3. We observed cell cycle arrest in Cpd22-treated cells, specifically accumulation of apoptotic cells in subG1 and Annexin/PI staining showed a 3-fold increase in the fraction of apoptotic cells staining positive for Annexin and PI in Cpd22-treated cells. Immuno-blotting confirmed cell cycle arrest by decreased pRb and increased cell cycle inhibitor p27; and drug induction of apoptosis through the caspase intrinsic pathway by demonstrating increased cleavage of caspase-3 and caspase-9. The importance of ILK for the growth of leukemia cells was demonstrated by knockdown of ILK in AML and CML cell lines, which led to decreases in cell proliferation. These results suggest a partial dependency of acute and chronic myeloid leukemia cells on ILK for growth, and are consistent with results obtained with the ILK inhibitor, Cpd22. Conclusions: In conclusion, our results suggest that the ILK inhibition may be an effective treatment for AML, Ph+ ALL, and CML as a single therapy, with ILK expression levels positively correlating with the efficacy of ILK inhibition. The identification of ILK as a novel target for leukemia therapy warrants further investigation as a therapeutic approach that could be of potential clinical benefit in both acute and chronic myeloid leukemias. Disclosures Azab: Verastem: Research Funding; Selexys: Research Funding; Karyopharm: Research Funding; Targeted Therapeutics LLC: Other: Founder and owner; Cell Works: Research Funding.
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Fukuda, Seiji, Mariko Abe, Chie Onishi, Takeshi Taketani, Jamiyan Purevsuren, Seiji Yamaguchi, Edward M. Conway, and Louis M. Pelus. "Survivin Selectively Modulates Genes Deregulated in Human Leukemia Stem Cells." Journal of Oncology 2011 (2011): 1–14. http://dx.doi.org/10.1155/2011/946936.
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ITD-Flt3 mutations are detected in leukemia stem cells (LSCs) in acute myeloid leukemia (AML) patients. While antagonizing Survivin normalizes ITD-Flt3-induced acute leukemia, it also impairs hematopoietic stem cell (HSC) function, indicating that identification of differences in signaling pathways downstream of Survivin between LSC and HSC are crucial to develop selective Survivin-based therapeutic strategies for AML. Using a Survivin-deletion model, we identified 1,096 genes regulated by Survivin in ITD-Flt3-transformed c-kit+, Sca-1+, and lineageneg(KSL) cells, of which 137 are deregulated in human LSC. Of the 137, 124 genes were regulated by Survivin exclusively in ITD-Flt3+KSL cells but not in normal CD34negKSL cells. Survivin-regulated genes in LSC connect through a network associated with the epidermal growth factor receptor signaling pathway and falls into various functional categories independent of effects on apoptosis. Pathways downstream of Survivin in LSC that are distinct from HSC can be potentially targeted for selective anti-LSC therapy.
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Fowler, Nathan, and Yasuhiro Oki. "Developing Novel Strategies to Target B-Cell Malignancies." American Society of Clinical Oncology Educational Book, no. 33 (May 2013): 366–72. http://dx.doi.org/10.14694/edbook_am.2013.33.366.
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In the past several years we have seen the identification and validation of several key pathways that drive malignant B-cell development. In addition, the effect nonmalignant effector cells within the immune microenvironment have on tumor survival, proliferation, and possibly chemotherapy resistance is increasingly understood. Although there is still much to be learned, this improved understanding combined with rapid advances in medicinal chemistry focusing on structure-based drug design have resulted in a shift in the development of new agents away from traditional chemotherapy to more selective agents targeting key cellular pathways. Examples of “hot” new therapeutic targets include the B-cell receptor signaling pathway, PI3K/mTOR/AKT pathway, histone deacetylases (HDAC), regulators of apoptosis such as the BCL-2 family, the proteasome, and cell–cell interactions within the tumor environment. Many drugs that target specific agents in early clinical development have demonstrated activity in various subtypes of lymphoma and leukemia. Monoclonal and conjugated antibodies targeting cell surface proteins such as CD19, CD22, CD37, and different epitopes of CD20 have also shown promise in relapsed B-cell malignancies and are rapidly moving into efficacy studies. This review will focus on a few of the new nonantibody-based targeted agents in development, their respective pathways, and their activity in various B-cell malignancies.
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Kreutmair, Stefanie, Teresa Poggio, Chuanjiang Yu, Sivahari Prasad Gorantla, Khalid Shoumariyeh, Dietmar Pfeifer, Michael Lubbert, et al. "Checkpoint Inhibition in CSF3R Mutated Chronic Neutrophilic Leukemia." Blood 132, Supplement 1 (November 29, 2018): 3056. http://dx.doi.org/10.1182/blood-2018-99-113847.
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Abstract Mutations in the colony-stimulating factor 3 receptor (CSF3R) have been identified in 90% of chronic neutrophilic leukemia (CNL) and lower frequency in atypical chronic myeloid leukemia (aCML). It was shown recently, that signaling of the different types of CSF3R mutations varies, but a central role of the JAK/STAT pathway activation by oncogenic CSF3R membrane proximal point mutations has been anticipated. However, the exact downstream signaling pathways mediated by CSF3R mutations are still not completely understood. Recent studies in JAK mutated myeloproliferative diseases uncovered the vital importance of JAK/STAT signaling in PD-L1 mediated immune escape, thereby suggesting a possible role and mechanistic link for PD-1/PD-L1 immune checkpoint regulation in CNL and aCML. To investigate the dependence of the oncogenic CSF3R signaling cascade on an activated JAK/STAT axis, we performed Ruxolitinib treatment in MTT assays with BaF3 cells retrovirally infected with pMIG-R1 vectors harboring either CSF3R point or truncation mutations. Our data indicate, that both, CSF3R point and truncation mutations induced cell growth could be inhibited by Ruxolitinib treatment. To narrow down the involvement of the different JAK family kinases, we included CSF3R mutation transduced JAK1 deficient U4C, JAK2 deficient y2A and TYK2 deficient U1A cell lines in combination with different JAK inhibitors. Interestingly, here we were able to show that CSF3R point mutations require functional JAK1/TYK2-STAT3 signaling for oncogenic potential, whereas truncation mutations depend on all JAK kinases through STAT3/5 for activation. To further study potential therapeutic strategies, we examined checkpoint inhibition in CSF3R mutated disease. In this regard we demonstrate a significant induction of PD-L1 expression in murine cell lines upon expression of CSF3R point mutations T615A or T618I. To investigate the impact of PD-L1 upregulation in vivo, we used a retroviral murine bone marrow (BM) transplantation model where we infected BM of Balb/c mice with a vector carrying CSF3R T618I point mutation and transplanted it into lethally irradiated recipients. Transplanted mice developed a CSF3R driven leukemia and died by leukocytosis and organ infiltration, whereas mice transplanted with BM harboring CSF3RT618I and additional ADA mutation failed to induce leukemia. To test checkpoint inhibition as a potential therapeutic strategy in vivo, CSF3RT618I transplanted mice were treated regularly with anti-PD-L1-antibody or isotype control. Interestingly, checkpoint inhibition led to reduced EGFP burden and prolonged survival of responder mice suggesting a treatment response of immunooncologic agents in these rare diseases. In immunophenotypic analyses of primary patient material, we were able to show increased PD-L1 expression in primary diseased myeloid cells isolated from peripheral blood of CNL and aCML patients, thereby defining this structure as a possible new therapeutic target. To summarize, our data expand the knowledge of oncogenic CSF3R signaling pathways and implicate an immunotherapeutic strategy by checkpoint inhibition in CSF3R driven CNL and atypical CML. Disclosures Lubbert: Teva: Other: Study drug; Celgene: Other: Travel Grant; Janssen: Honoraria, Research Funding.
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Landmeier, Silke, Bianca Altvater, Sibylle Pscherer, Jutta Meltzer, Josef Vormoor, Juan F. Vera, Martin Pule, Marc Hotfilder, Heribert Juergens, and Claudia Rossig. "CD19-Redirected Cytotoxic T Cells Prevent Engraftment of Primary Human Leukemia Cells In Vivo." Blood 114, no. 22 (November 20, 2009): 3025. http://dx.doi.org/10.1182/blood.v114.22.3025.3025.
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Abstract Abstract 3025 Poster Board II-1001 Due to its restriction to the B-cell lineage and high surface expression in B-cell malignancies, CD19 is an attractive target antigen for immunological strategies in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). While preclinical in vivo studies of CD19-specific cellular immunotherapy have generally used xenografts from human CD19+ leukemia cell lines, primary leukemia cells are likely to more closely mimic the disease in humans and allow to differentiate between standard and high risk situations. Therefore, we investigated the in vivo sensitivity of human leukemic bone marrow to adoptive immunotherapy with gene-modified CD19-specific T cells. Among 15 primary leukemias obtained from the bone marrow of pediatric patients at diagnosis, 10 were successfully engrafted in NOD/scid mice by intrafemoral injection within 6 to 20 weeks. For therapeutic experiments, we focused on one standard risk leukemia, characterized by a rapid and sustained response to multiagent chemotherapy, and on a leukemia bearing the high-risk feature of an MLL rearrangement, which was refractory to standard treatment. Titration experiments demonstrated reliable engraftment of 1×104 leukemic cells per mouse. For CD19-directed T-cell therapy, cytotoxic T cells (CTLs) with native specificity for Epstein-Barr virus antigens were expanded from 4 healthy donors and transduced to express either a codon-optimized CD19-specific chimeric antigen receptor (CAR) containing the intracellular signaling domain of the TCRz chain (CD19-z), or a control CAR directed against the neuroectodermal antigen GD2 (14.G2a-z). Costimulatory domains now commonly used to ensure sustained T-cell activation via CARs were not included, since previous studies have shown that CAR activity in virus-specific CTLs does not benefit from additional signaling elements. CTLs had a uniform CD8+ effector memory T-cell phenotype (CD45RO+, CCR7-), and CAR surface expression was 73±21%, range 32-93% (CD19-z, n=9) and 18±13%, range 6-35% (14.G2a-z, n=5). In vitro cytotoxicity experiments confirmed specific lysis of the CD19+ leukemia cell lines REH (51Cr release 59.7±7.2% at an effector target ratio of 20:1) and SupB15 (66.7±8.6) as well as primary CD19+ leukemic cells from 5 pediatric patients (47.2±13.2%), in the absence of background lysis by 14.G2a-z-transduced control CTLs. 1×104 leukemic cells per mouse from primary engrafted mice were transferred into further cohorts of NOD/scid mice by secondary intrafemoral transplantation, followed by adoptive transfer of 4 doses of 5×106 CTLs via tail vein injection on days 1, 4, 8, and 11. IL-2 (500 IU/mouse) was administered twice-weekly, and sequential murine bone marrow aspirates were analyzed for human leukemia engraftment by flow cytometry using human CD45 and CD19-specific antibodies starting 3 weeks after transplantation. CD19z CTLs prevented engraftment of the standard risk leukemia in 3 of 4 mice, while 3 of 4 control mice developed the leukemia (p = 0.158, Log Rank/Mantel-Cox Test). Moreover, while the MLL-rearranged human leukemia became detectable in the bone marrow of 4 of 5 control mice, followed by overt and fatal leukemia, 5 of 8 mice receiving transfusions of CD19-z transduced CTLs remained disease-free (p = 0.067), and 6 of 8 remained alive, one of them with detectable leukemia cells (p = 0.054) (see Figure). Thus, adoptive transfer of CD19-redirected CTLs efficiently delayed or prevented engraftment of both standard and high risk ALLs in mice and therefore provides a promising treatment option for patients with BCP-ALL refractory to standard treatment. Disclosures No relevant conflicts of interest to declare.
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McQueen, Teresa, Yoko Tabe, Marina Konopleva, and Michael Andreeff. "Inhibition of PI3K or Integrin-Linked Kinase (ILK) Target Primary AML Cells within the Bone Marrow Microenvironment in the In Vitro Co-Culture System." Blood 108, no. 11 (November 16, 2006): 1903. http://dx.doi.org/10.1182/blood.v108.11.1903.1903.
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Abstract In hematological malignancies, there are reciprocal interactions between leukemic cells and cells of the bone marrow microenvironment such as marrow stromal cells (MSC). It is proposed that specific niches within the bone marrow microenvironment provide a sanctuary for subpopulations of leukemic cells to evade chemotherapy-induced death, and we indeed demonstrated that MSC protect primary AML cells from Ara-C induced apoptosis in vitro (Konopleva, Leukemia 2002). Integrin-linked kinase (ILK) has been shown to directly interact with β integrins and phosphorylate AKT in a PI3-kinase(PI3K)-dependent manner to promote cell survival and proliferation. In this study, we tested the hypothesis that selective inhibition of ILK signaling will provide a novel approach for targeting both leukemic cells and cells in their surrounding microenvironment. Direct co-culture of human MSC and leukemic NB4 cells results in activation of PI3K/ILK/AKT signaling as evidenced by enhanced ILK kinase activity, elevated phospho(p)-Akt, p-GSK3β and nuclear translocation of β-catenin. Both, PI3K inhibitor LY294002 (10μM) and specific ILK inhibitor QLT0267 (10μM) inhibited stroma-induced activation of AKT and suppressed GSK phosphorylation. This resulted in massive induction of apoptosis which was not abrogated by stromal co-culture (AnnexinV positivity %, MSC(−) vs MSC(+); 51.4+2.5 vs 55.8+3.5 p=0.26, LY 47.0+8.1 vs 47.9+6.1 p=0.85, 48hrs). In contrast, MSC co-culture effectively blocked apoptosis induced by MEK inhibitor PD98059 despite activation of pERK (62.5+3.2% vs 45.6+2.3%, p=0.02). We next examined anti-leukemia effects of PI3K and ILK inhibitors in the co-culture system of primary AML and human MSC. AML blasts from 7 primary AML samples with high (>54%) blast count were co-cultured with MSC for 24 hours, after which they were exposed to 10μM LY294002 or QLT0267 for 4–8 days. After this period, induction of apoptosis was analyzed in non-adherent AML cells by Annexin V flow cytometry after gating on the CD90-negative (non-MSC) population. To control for differences in spontaneous apoptosis, we calculated % specific apoptosis as (test - control) x 100 / (100 - control). MSCs protected leukemic blasts from spontaneous apoptosis in all 7 samples studied (mean annexin V positivity, 49.5±7.2% vs 25.3±4.8%, p<0.001). In contrast, inhibition of PI3K/ILK signaling induced unopposed apoptosis even in MSC co-cultures (% specific apoptosis, LY294002, 30.3±4.8%; LY+MSC, 28.3±7.7%; QLT0267, 26.9±9.8%; QLT+MSC, 33.1±9.3%, p>0.3 comparing cell death in the presence or absence of MSC). This resulted in corresponding loss of viability (% of control, LY294002, 66.0±11.0%; LY+MSC, 57.6±11.2%; QLT0267, 66.4±7.28%; QLT+MSC, 50.4±11.3%, p>0.1 comparing viability in the presence or absence of MSC). These observations indicate that disruption of leukemia/stroma interactions by specific PI3K/ILK inhibitors represents a novel therapeutic approach to eradicate leukemia in the bone marrow microenvironment. Further studies are aimed at the elucidation of the role of the BM microenvironment and its ability to activate specific signaling pathways in the pathogenesis of leukemias. Focus on this stroma-leukemia crosstalk may result in the development of strategies that alleviate the acquisition of a chemoresistant phenotype and enhance the efficacy of therapies in hematological malignancies.
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Milella, Michele, Maria Rosaria Ricciardi, Paola Bergamo, Maria Cristina Scerpa, Jacopo Gervasoni, Maria Teresa Petrucci, Sabina Chiaretti, et al. "Development of Mek inhibition (MEK-I)-Based Therapeutic Strategies in Acute Myeloid Leukemia (AML)." Blood 112, no. 11 (November 16, 2008): 860. http://dx.doi.org/10.1182/blood.v112.11.860.860.
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Abstract In hematologic malignancies, constitutive activation of the Raf/MEK/ERK pathway is frequently observed, conveys a poor prognosis, and constitutes a promising target for therapeutic intervention. Indeed, we have recently demonstrated that selective MEK-I potently inhibit the growth of AML cell lines and ex vivo-cultured primary AML blasts (Blood2006, 108:254). However, these effects are mostly related to the inhibition of cell cycle progression, while apoptosis induction requires higher concentrations of the inhibitors and longer times of exposure. Thus, we investigated MEK-I-induced changes in phospho-protein expression and gene expression profiles, in order to identify relevant downstream targets and to design rational MEK-I-based combination strategies. Analysis of phosphorylation levels of 18 different target proteins performed in OCI-AML3 cells indicated that MEK blockade induces, among other effects, an over-activation of RAF and MEK, suggesting the interruption of a negative feedback loop. Moreover, gene expression profiling indicated that, in the same cellular model, MEK-I induced upregulation of the Flt-3 receptor. Based on these observations, as well as on recent evidence indicating that the Raf inhibitor sorafenib directly inhibits signaling through Flt-3 (JNCI2008, 100:184), experiments were performed in OCI-AML3 and MOLM-13 (which harbors a Flt3 ITD) cells to test the activity of MEK-I in combination with sorafenib. Simultaneous inhibition of Flt3/Raf and MEK resulted in the synergistic inhibition of cell growth, as measured by isobologram analysis (Chou–Talalay method) in both model systems, with combination indexes (CI) of 0.12 and 0.48 for OCI-AML3 and MOLM-13 cells, respectively. Neither sorafenib nor MEK-I induced apoptosis in either cell line when used alone; however, apoptosis was observed in up to 50% of the cells with the combined treatment. Based on our previous experience, as well as on the ability of MEK-I to modulate the expression, among others, of genes controlling mitochondrial homeostasis (e.g. PPIF, GRPEL1), we next investigated the impact of simultaneous inhibition of the MEK and Bcl-2 pathways in AML cells. Exposure of OCI-AML3 and MOLM-13 cells to a combination of MEK-I and the Bcl-2/Bcl-xL inhibitor, ABT-737 (kindly provided by Abbott Laboratories) synergistically inhibited cell growth, with CI ranging from 0.45 to 0.04 in OCI-AML3 and from 0.75 to 0.14 in MOLM-13, respectively. In both cellular models, ABT-737dose-dependently induced apoptosis, while MEK-I, at the concentrations used in combination experiments, did not appreciably increase apoptotic cell death; however, simultaneous Bcl- 2/Bcl-xL inhibition and MEK blockade resulted in the massive induction of apoptosis (up to 85% and 67% net apoptosis induction in OCI-AML3 and MOLM-13 cells, respectively). Such pro-apoptotic interaction was highly synergistic with CI of 0.18 and 0.16 in OCIAML3 and MOLM-13 cells, respectively. In contrast, combination with MEK-I did not appreciably sensitize the MEK-I-resistant cell line U937 to either sorafenib- or ABT-737- induced growth inhibitory and pro-apoptotic effects. Overall these results support the role of the Raf/MEK/ERK kinase module as a prime target for the molecular therapy of AML and suggest that both “vertical” and “lateral” combination strategies based on MEK inhibition may produce highly synergistic anti-leukemic effects.
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Yoshida, Noriaki, Hiroaki Miyoshi, and Koichi Ohshima. "Clinical Applications of Genomic Alterations in ATLL: Predictive Markers and Therapeutic Targets." Cancers 13, no. 8 (April 9, 2021): 1801. http://dx.doi.org/10.3390/cancers13081801.
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Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell lymphoma (PTCL) caused by human T-cell leukemia virus type 1 (HTLV-1). Recent comprehensive genomic analyses have revealed the genomic landscape. One of the important findings of genomic alterations in ATLL is that almost all alterations are subclonal, suggesting that therapeutic strategies targeting a genomic alteration will result in partial effects. Among the identified alterations, genes involved in T-cell receptor signaling and immune escape mechanisms, such as PLCG1, CARD11, and PD-L1 (also known as CD274), are characteristic of ATLL alterations. From a geographic perspective, ATLL patients in Caribbean islands tend to be younger than those in Japan and the landscape differs between the two areas. Additionally, young Japanese ATLL patients frequently have CD28 fusions, compared with unselected Japanese cases. From a clinical perspective, PD-L1 amplification is an independent prognostic factor among every subtype of ATLL case. Recently, genomic analysis using deep sequencing identified a pre-ATLL clone with ATLL-common mutations in HTLV-1 carriers before development, indicating that genomic analysis can stratify cases based on the risks of development and mortality. In addition to genomic alterations, targetable super-enhancers have been identified in ATLL. These data can be leveraged to improve the prognosis of ATLL.
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Lehal, Rajwinder, Jelena Zaric, Michele Vigolo, Charlotte Urech, Viktoras Frismantas, Nadine Zangger, Linlin Cao, et al. "Pharmacological disruption of the Notch transcription factor complex." Proceedings of the National Academy of Sciences 117, no. 28 (June 29, 2020): 16292–301. http://dx.doi.org/10.1073/pnas.1922606117.
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Notch pathway signaling is implicated in several human cancers. Aberrant activation and mutations of Notch signaling components are linked to tumor initiation, maintenance, and resistance to cancer therapy. Several strategies, such as monoclonal antibodies against Notch ligands and receptors, as well as small-molecule γ-secretase inhibitors (GSIs), have been developed to interfere with Notch receptor activation at proximal points in the pathway. However, the use of drug-like small molecules to target the downstream mediators of Notch signaling, the Notch transcription activation complex, remains largely unexplored. Here, we report the discovery of an orally active small-molecule inhibitor (termed CB-103) of the Notch transcription activation complex. We show that CB-103 inhibits Notch signaling in primary human T cell acute lymphoblastic leukemia and other Notch-dependent human tumor cell lines, and concomitantly induces cell cycle arrest and apoptosis, thereby impairing proliferation, including in GSI-resistant human tumor cell lines with chromosomal translocations and rearrangements in Notch genes. CB-103 produces Notch loss-of-function phenotypes in flies and mice and inhibits the growth of human breast cancer and leukemia xenografts, notably without causing the dose-limiting intestinal toxicity associated with other Notch inhibitors. Thus, we describe a pharmacological strategy that interferes with Notch signaling by disrupting the Notch transcription complex and shows therapeutic potential for treating Notch-driven cancers.
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McQueen, Teresa, Marina Konopleva, and Michael Andreeff. "Activity of Targeted Molecular Therapeutics Against Primary AML Cells: Putative Role of the Bone Marrow Microenvironment." Blood 106, no. 11 (November 16, 2005): 2304. http://dx.doi.org/10.1182/blood.v106.11.2304.2304.
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Abstract In hematological malignancies, there are reciprocal interactions between leukemic cells and cells of the bone marrow (BM) microenvironment such as mesenchymal stem cells (MSC). It is speculated that specific BM niches may provide a sanctuary for subpopulations of leukemic cells to evade chemotherapy-induced death and allow acquisition of a drug-resistant phenotype. In this study, we compared anti-leukemia effects of Ara-C and various signal transduction and apoptosis inhibitors in a co-culture system of primary AML and human bone marrow-derived MSC. AML blasts from 11 primary AML samples with high (>70%) blast count were co-cultured with MSC for 24 hours, after which they were exposed to the indicated concentrations of inhibitors for 48–96 hrs. Concentrations were selected on the basis of preliminary cell line studies which determined efficient inhibition of drug targets. Induction of apoptosis was analyzed by Annexin V flow cytometry after gating on the CD90 APC(−) (non-MSC) population. MSC protected leukemic blasts from spontaneous apoptosis in all 11 samples studied (mean annexinV positivity, 49.5±7.2% vs 25.3±4.8%, p<0.001) and from Ara-C-induced cytotoxicity in 6 out of 11 samples (p=0.02). No difference in the degree of protection was noted when MSC from older vs. younger donors were used (not shown). Co-culture of leukemic cells with MSC resulted in significant (p<0.03) suppression of inhibitor-induced apoptosis for all agents tested (Table 1), however PI3K/AKT inhibitors seemed to overcome MSC-mediated resistance. In addition, specific inhibitors of Bcl-2 and MDM2 induced apoptosis not only in suspension, but also in the MSC co-culture system, while Raf-1/MEK inhibitors were less effective. The AKT inhibitor A443654 caused apoptosis induction not only in leukemic cells, but also in MSC, which likely accounted for its high efficacy in stromal co-cultures (53±6% annexin V+). In a different study (Tabe et al, ASH 2005), we report that interactions of leukemic and BM stromal cells result in the activation of PI3K/ILK/AKT signaling in both, leukemic and stromal cells. We therefore propose that disruption of these interactions by specific PI3K/AKT inhibitors represents a novel therapeutic approach to eradicate leukemia in the BM microenvironment via direct effects on leukemic cells and by targeting activated BM stromal cells. Furthermore, Bcl-2 and MDM2 inhibitors appear to retain their efficacy in stroma-cocultured AML cells, while the efficacy of chemotherapy and Raf/MEK inhibitors in these conditions may be reduced. Further studies are aimed at the elucidation of the role of the BM microenvironment and its ability to activate specific signaling pathways in the pathogenesis of leukemias and on efforts to disrupt the MSC/leukemia interaction (Zeng et al, ASH 2005). Focus on this stroma-leukemia-stroma crosstalk may result in the development of strategies that enhance the efficacy of therapies in hematological malignancies and prevent the acquisition of a chemoresistant phenotype. Table 1. Leukemia Cell Apoptosis in a MSC/AML Co-Culture System Target Bcl-2/XL MDM2 PI3K AKT Raf-1 MEK Apoptosis was determined as percentage of Annexin V(+)CD90(−) cells, and calculated by the formula: % specific apoptosis = (test − control) x 100 / (100 − control). Compound, concentration Ara-C, 1 μM ABT-737, 0.1 μM Nutlin-3A, 2.5 μM LY294002, 10 μM A443654, 1 μM BAY43-9006, 2.5 μM CI1040, 3 μM AML 28±7 69±7 45±7 53.8±13.3 75±7 35±11 27±11 AML + MSC 16±4 38±6 28±6 31.2±6.9 53±6 18±8 15±5
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Huang, Hao, Xi Jiang, Jinhua Wang, Yuanyuan Li, Ping Chen, Stephen Arnovitz, Shenglai Li, et al. "Identification of MLL-Fusion/Myc⊣miR-26a/Mir-29a⊣Tet1 Signaling Circuit in MLL-Rearranged Leukemia." Blood 124, no. 21 (December 6, 2014): 1011. http://dx.doi.org/10.1182/blood.v124.21.1011.1011.
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Abstract Approximately 10% of human acute leukemias are involved in chromosomal translocations between the mixed lineage leukemia (MLL) gene and over 50 partner genes. MLL-rearranged leukemias occur preferentially in infant and young children and are often associated with poor outcome. MicroRNAs (miRNAs) are an abundant class of small noncoding RNAs which repress gene expression and mRNA stability by base pairing with target mRNAs usually at the 3’-untranslated regions (UTRs). The ten-eleven translocation 1 (TET1), the founding member of the TET family of enzymes (TET1/2/3) that convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), was first identified in MLL-rearranged leukemia. But its definitive role in leukemia was unclear until our recent report published in PNAS (Huang H. et al. 2013). In contrast to the frequent repression and tumor-suppressor roles of the three TET genes observed in various cancers, we showed that TET1 is a direct target of MLL-fusion proteins and significantly up-regulated in MLL-rearranged leukemia, leading to a global increase of 5hmC level. Furthermore, Tet1 plays an indispensable oncogenic role in MLL-rearranged leukemia, through coordination with MLL-fusion proteins in regulating their critical co-targets including Hoxa/Meis1/Pbx3 genes. However, whether TET1 is also post-transcriptionally regulated by miRNAs in hematopoietic cells remains unknown. In the present report, through genome-wide miRNA expression profiling assays, we found that miR-26a and miR-29a were expressed at a significantly lower level in MLL-rearranged AML than in normal controls. The down-regulation of miR-26a and miR-29a is, at least in part, attributed to the transcriptional repression mediated by MLL-fusion proteins and MYC. Interestingly, both miR-26a and miR-29a target TET1 directly at the post-transcriptional level. More importantly, we showed that miR-26a or miR-29a significantly inhibited MLL-fusion-mediated cell transformation in vitro and leukemogenesis in vivo down regulating expression of Tet1 and its downstream target genes. Thus, our data suggest that the transcriptional repression of miR-26a and miR-29a is required for the aberrant overexpression and potent oncogenic role of TET1 in MLL-rearranged leukemia, and that miR-26a and miR-29a play important tumor-suppressor role in leukemogenesis. Taken together, our data reveals a previously unappreciated signaling pathway involving the MLL-fusion/Myc⊣miR-26a/miR-29a⊣Tet1 circuit in MLL-rearranged leukemia. Our data not only provides novel insight into our understanding of the complex molecular mechanisms underlying the pathogenesis of MLL-rearranged leukemia, but also may lead to the development of novel, more effective therapeutic strategies to treat this type of dismal disease. Disclosures No relevant conflicts of interest to declare.
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Gupta, Rohit, Jason H. Rogers, Xin Long, Geraldo Medrano, Jaime M. Reyes, Michele Redell, Zachary T. Ball, Margaret Goodell, and Rachel E. Rau. "Targeting Activated Signaling Pathways for the Treatment of IKZF1-Deleted B Lymphoblastic Leukemia." Blood 134, Supplement_1 (November 13, 2019): 3789. http://dx.doi.org/10.1182/blood-2019-127209.
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In B lymphoblastic leukemia (B-ALL), genome-wide association studies have revealed that deletions and mutations of the gene IKAROS family zinc finger 1 (IKZF1) are present in nearly 30% of patients. These lesions are most prevalent in high-risk subsets, including greater than 60% of patients with Philadelphia chromosome positive (Ph+) and Ph-like ALL. IKZF1 deletions are associated with an increased risk of relapse, therapy resistance, and inferior survival. It is therefore imperative to devise new treatment strategies for this poor-prognosis subset of patients. To this regard, using novel CRISPR-Cas9 genome editing strategies, we developed a series of human B-ALL cell lines with IKZF1 deletions. These robust model systems have allowed us to investigate the underlying biology of IKZF1-deleted B-ALL. Our studies have thus far shown that IKZF1 deletion results in a stem cell-like gene expression profile, enhanced bone marrow homing and engraftment, and cell-intrinsic chemoresistance, consistent with the relapsing disease phenotype observed in affected patients. We are using these model systems to explore possible mechanisms of chemoresistance and delineate new strategies to improve response to therapy. Global gene expression analysis of the engineered Nalm-6 IKZF1-deleted cells by RNA-seq revealed potential therapeutic vulnerabilities. IKZF1-deleted cells are characterized by increased activation of the JAK/STAT pathway with overexpression of JAK1, JAK3, STAT3, and STAT5. Aberrant activation of this pro-survival, anti-apoptosis pathway is associated with poor-prognosis leukemia; thus, we postulated this is a contributor to the chemoresistance inherent to IKZF1-deleted B-ALL. We explored the therapeutic potential of targeting the JAK/STAT pathway by treating IKZF1-deleted cells with selective inhibitors of JAK1/3 (tofacitinib) and STAT3 (MM-206) and calculated the IC50 by Annexin V/7-AAD double-negative population after 48 to 72 hours of treatment. The IKZF1 wild-type cells were sensitive to both compounds, suggesting activated JAK/STAT signaling is critical to cell survival. In comparison, the IKZF1-deleted cells were relatively resistant to both compounds (MM-206 IC50 : 5.6 µM vs. 8.2 µM, p < 0.001; tofacitinib IC50 : 43 nM vs. 55 nM, p = 0.05) similar to the relative resistance to ABL1-tyrosine kinase inhibition observed in Ph+ B-ALL cells with loss of function IKZF1 mutations. However, we postulated that inhibition of the JAK/STAT pathway could still augment the effects of standard chemotherapy. Indeed, whereas IKZF1-deleted Nalm-6 cells are highly resistant to glucocorticoid chemotherapy alone, when the cells were also treated with sub-IC50 levels of MM-206, we observed a significant re-sensitization to dexamethasone-induced apoptosis. A similar pattern of re-sensitization was seen with the combination of sub-IC50 MM-206 and vincristine treatment. Additionally, our gene expression analysis of the IKZF1-deleted Nalm-6 cells revealed significantly increased expression of the receptor tyrosine kinase, FLT3. Overexpression was confirmed at the protein level by flow cytometry for cell-surface FLT3. We treated our engineered cell lines with the potent and selective FLT3 inhibitor quizartinib and again found that the IKZF1-deleted cells were relatively resistant compared to the wild type cells (IC50 : 240 nM vs. 282 nM, p < 0.01). Postulating that parallel activation of the JAK/STAT pathway may contribute to this resistance, we treated our cells with pacritinib, a combined JAK/FLT3 inhibitor. The IKZF1-deleted cells were as sensitive to this compound as the wild type cells, suggesting dual targeting of FLT3 and JAK may be efficacious for the treatment of IKZF1-deleted B-ALL. Our data support that IKZF1-deleted B-ALL is an aggressive disease characterized by cell-intrinsic chemoresistance. We found that loss of IKAROS amplifies pro-survival, anti-apoptotic signaling pathways, a likely contributing mechanism to chemoresistance. IKZF1 deletion confers relative resistance to targeted inhibitors of these pathways. However, the combined JAK/FLT3 inhibition exhibits therapeutic efficacy. Additionally, the combination of a JAK/STAT pathway inhibitor with conventional chemotherapy including dexamethasone and vincristine may be a promising strategy to overcome the chemoresistance inherent to this poor-prognosis subset of B-ALL. Disclosures No relevant conflicts of interest to declare.
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Jimenez-Del-Rio, Marlene, and Carlos Velez-Pardo. "The Bad, the Good, and the Ugly about Oxidative Stress." Oxidative Medicine and Cellular Longevity 2012 (2012): 1–13. http://dx.doi.org/10.1155/2012/163913.
Full textAbstract:
Alzheimer’s disease (AD), Parkinson’s disease (PD), and cancer (e.g., leukemia) are the most devastating disorders affecting millions of people worldwide. Except for some kind of cancers, no effective and/or definitive therapeutic treatment aimed to reduce or to retard the clinic and pathologic symptoms induced by AD and PD is presently available. Therefore, it is urgently needed to understand the molecular basis of these disorders. Since oxidative stress (OS) is an important etiologic factor of the pathologic process of AD, PD, and cancer, understanding how intracellular signaling pathways respond to OS will have a significant implication in the therapy of these diseases. Here, we propose a model of minimal completeness of cell death signaling induced by OS as a mechanistic explanation of neuronal and cancer cell demise. This mechanism might provide the basis for therapeutic design strategies. Finally, we will attempt to associate PD, cancer, and OS. This paper critically analyzes the evidence that support the “oxidative stress model” in neurodegeneration and cancer.
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Riether, Carsten, Christian M. Schürch, Ramin Radpour, Magdalena Hinterbrandner, Anne-Laure Huguenin, and Adrian F. Ochsenbein. "CD70/CD27 Signaling Mediates Resistance of Chronic Myeloid Leukemia Stem Cells to Tyrosine Kinase Inhibitors By Compensatory Activation of the Wnt Pathway." Blood 124, no. 21 (December 6, 2014): 400. http://dx.doi.org/10.1182/blood.v124.21.400.400.
Full textAbstract:
Abstract The introduction of BCR/ABL-specific tyrosine kinase inhibitors (TKIs) a decade ago revolutionized chronic myelogenous leukemia (CML) therapy. However, disease-initiating leukemia stem cells (LSCs) in CML are resistant to TKIs despite BCR/ABL inhibition. Therefore, CML will ultimately relapse upon drug discontinuation. We have previously shown that blocking CD70/CD27 signaling targets LSCs by inhibiting the activation of the Wnt pathway. Here, we investigated a combination therapy of TKIs and CD70/CD27 blocking monoclonal antibodies in human and murine CML. We demonstrate that TKI-mediated BCR/ABL inhibition down-regulates miR-29, leading to increased expression of specificity protein 1 (SP1), a transcription factor with binding site in the CD70 promoter. In addition, TKI treatment reduced the expression of DNA methyltransferases resulting in de-methylation of the CD70 promoter. These combined effects resulted in CD70 up-regulation on LSCs, enhanced CD70/CD27 signaling and compensatory Wnt pathway activation. Combined BCR/ABL and CD70/CD27 inhibition synergistically reduced Wnt signaling and eradicated leukemia cells in vitro. More importantly, combination therapy effectively eliminated CD34+ CML stem/progenitor cells in murine xenografts and LSCs in a murine CML model. Therefore, TKI-induced CD70 up-regulation triggers CD70/CD27 signaling leading to compensatory Wnt activation. These findings identify an important targetable TKI resistance mechanism of CML LSCs and may lead to new therapeutic strategies to directly target LSCs to overcome treatment resistance. Disclosures No relevant conflicts of interest to declare.
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Rodriguez-Rodriguez, Sonia, Lin Wang, Huajia Zhang, Amy Zollman, Angelo Cardoso, and Nadia Carlesso. "Absence Of The E3 Ubiquitin Ligase SKP2 Attenuates Notch-Induced T-Cell Leukemogenesis." Blood 122, no. 21 (November 15, 2013): 1272. http://dx.doi.org/10.1182/blood.v122.21.1272.1272.
Full textAbstract:
Abstract Acute Lymphoblastic Leukemia (ALL) is the most common malignancy in childhood, accounting for almost 30% of pediatric cancers. In pediatric T-cell acute lymphoblastic leukemia (T-ALL), around 30% of the children still undergo disease relapse, which is associated with poor prognosis. Hence, novel therapeutic strategies for the treatment of T-ALL are necessary, since conventional therapies still fail to cure a significant number of patients. Notch signaling contributes to the regulation of normal T-cells homeostasis, whereas oncogenic, activated form of Notch is present in the majority of the T-ALL cases. Previous studies in our laboratory demonstrated that Notch1 signaling induces transcriptional activation of SKP2, the F-box protein of the SCF E3-ubiquitin ligase complex. SKP2 targets the major cell cycle inhibitors, the CKIs p21Cip1, p27Kip1, p57Kip2 and p130, for proteasome-mediated degradation. Increased Skp2 expression accelerates cell cycle progression in hematopoietic cells, and its overexpression is frequently found in cancers, in particular lymphomas and leukemias, in which is associated with poor prognosis. We found that Skp2 expression is dynamically regulated during T-cell differentiation coinciding with the Notch expression pattern. Moreover, primary thymocytes cultured in vitro responded to Notch stimulation by the Delta1 ligand increasing their Skp2 expression and their cell cycle activity. As anticipated, we found that Skp2 expression is increased in T-ALL patient samples. Our hypothesis is that Notch activation promotes T-cell leukemogenesis by altering the cell cycle control through upregulation of SKP2. To better define the role of SKP2 in T-ALL, we analyzed the Skp2 expression in a murine model of Notch-induced T-cell leukemia. Mice transplanted with stem/progenitor cells transduced with the constitutive active form of Notch (ICN), developed T-ALL and died by week 12 after transplant. Analysis of T-ALL cells revealed a 5 fold upregulation of Skp2 expression compared to controls. Next, we tested whether SKP2 was required for T-ALL development. To this end, we evaluated leukemia development in mice transplanted with SKP2 deficient cells overexpressing ICN. Stem/progenitor cells derived from Skp2+/+, Skp2+/- or Skp2-/- mice were transduced with ICN and then transplanted into WT recipients. Loss of SKP2 significantly delayed the development of T-cell leukemia in transplanted mice and increased their survival by 60% at 12 weeks. Taken together, these results demonstrate a previously unrecognized role for SKP2 in the initiation and progression of T-ALL and its potential role as a therapeutic target. Disclosures: No relevant conflicts of interest to declare.
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Michmerhuizen, Nicole L., Jeffery M. Klco, and Charles G. Mullighan. "Mechanistic insights and potential therapeutic approaches for NUP98-rearranged hematologic malignancies." Blood 136, no. 20 (November 12, 2020): 2275–89. http://dx.doi.org/10.1182/blood.2020007093.
Full textAbstract:
Abstract Nucleoporin 98 (NUP98) fusion oncoproteins are observed in a spectrum of hematologic malignancies, particularly pediatric leukemias with poor patient outcomes. Although wild-type full-length NUP98 is a member of the nuclear pore complex, the chromosomal translocations leading to NUP98 gene fusions involve the intrinsically disordered and N-terminal region of NUP98 with over 30 partner genes. Fusion partners include several genes bearing homeodomains or having known roles in transcriptional or epigenetic regulation. Based on data in both experimental models and patient samples, NUP98 fusion oncoprotein–driven leukemogenesis is mediated by changes in chromatin structure and gene expression. Multiple cofactors associate with NUP98 fusion oncoproteins to mediate transcriptional changes possibly via phase separation, in a manner likely dependent on the fusion partner. NUP98 gene fusions co-occur with a set of additional mutations, including FLT3–internal tandem duplication and other events contributing to increased proliferation. To improve the currently dire outcomes for patients with NUP98-rearranged malignancies, therapeutic strategies have been considered that target transcriptional and epigenetic machinery, cooperating alterations, and signaling or cell-cycle pathways. With the development of more faithful experimental systems and continued study, we anticipate great strides in our understanding of the molecular mechanisms and therapeutic vulnerabilities at play in NUP98-rearranged models. Taken together, these studies should lead to improved clinical outcomes for NUP98-rearranged leukemia.
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Chiriches, Claudia, Nathalie Guillen, Michal Rokicki, Carol Guy, Afsar Mian, Oliver G. Ottmann, and Martin Ruthardt. "Subtractive Interaction Proteomics Reveal a Network of Signaling Pathways Activated By an Oncogenic Transcription Factor in High Risk AML." Blood 132, Supplement 1 (November 29, 2018): 3917. http://dx.doi.org/10.1182/blood-2018-99-116631.
Full textAbstract:
Abstract Acute myeloid leukemias (AML) are characterized by recurrent genomic alterations, often in transcriptional regulators, which form the basis on which current prognostication and therapeutic intervention is overlaid. Three subtypes of AML carrying specific translocations, namely t(15;17), t(11;17) and t(6;9), are notable for being associated with a smaller number of co-existing driver mutations than e.g. AML with normal karyotype. This strongly suggests that the function of their aberrant gene products, PML/RAR and DEK/CAN, respectively, may subsume the functions of other driver mutations. Thus we hypothesized that these functions, while as yet elusive, not necessarily require sequential acquisition of secondary genomic alterations. We elected to study AML with the t(6;9), defined as a distinct entity by the WHO classification, because of its particular biological and high risk clinical features and unmet clinical needs. Most t(6;9)-AML patients are young, with a median age of 23-40 years, complete remission rates do not exceed 50% and median survival after diagnosis is only about 1 year. We used a novel "subtractive interaction proteomics" (SIP) approach to understand the mechanisms by which the t(6;9)-DEK/CAN nuclear oncogene induces this highly resistant leukemic phenotype. Based on Tandem Affinity Precipitation (TAP) for the enrichment of proteins complexes associated with SILAC-technology followed by LC-MS/MS we developed SIP as a comparison between the interactome of an oncogene and those of its functionally inactive mutants in order to obtain eventually only relevant interaction partners (exclusive binders) in the same genetic background. This is achieved by the subtraction of binders that are common to four functionally inactive mutants classifying them as not relevant. Bioinformatic network analysis of the 9 exclusive binders of DEK/CAN revealed by SIP (RAB1A, RAB6A, S100A7, PCBD1, Clusterin, RPS14 and 19, IDH3A, SerpinB3) using BioGrid, IntAct and String together with Ingenuity© Pathway Analysis (IPA), indicated a functional relationship with ABL1-, AKT/mTOR-, MYC- and SRC family kinases-dependent signaling. Interestingly, we found all these signaling pathways strongly activated in an autonomous manner in four DEK/CAN-positive leukemia models, DEK/CAN expressing U937 cells, t(6;9)-positive FKH-1 cells, primary syngeneic murine DEK/CAN-driven leukemias, and t(6;9)-positive patient samples. Bioinformatic analysis of the phopshoproteomic profile of FKH1 cells upon molecular targeting of single pathways (imatinib for ABL1, PP2 for SFKs, dasatinib for ABL1/SFK and Torin1 or NVP-BEZ-235 for mTOR/AKT) revealed that these signaling pathways were organized in clusters creating a network with nodes that are credible candidates for combinatorial therapeutic interventions. On the other hand inhibition of individual outputs had the potential to activate interconnected pathways in a detrimental manner with consequential clinical impact e.g. the activation of STAT5 by the inhibition of mTOR/AKT in these cells. Treatment of mice injected with primary syngeneic DEK/CAN-induced leukemic cells with dasatinib (10mg/kg) and NVP-BEZ-235 (45mg/kg) alone and in combination for 14 days led to a strong reduction of leukemia burden in all cohorts (each cohort n=7). In fact, as compared to untreated controls (146.6 +/- 36mg), mice treated with NVP-BEZ 235 alone and in combination (61.7 +/-4.7mg and 65.3+/- 4.6mg, respectively) showed a statistically significant reduction of spleen size whereas those treated with dasatinib alone (77.5 8 +/- 5.4mg) did not reach statistical significance. Taken together the here presented results reveal specific interdependencies between a nuclear oncogene and kinase driven cancer signaling pathways providing a foundation for the design of therapeutic strategies to better address the complexity of cancer signaling. In addition, it provides evidence for the need of a more in depth analysis of indirect effects of molecular targeting strategies in a preclinical setting not only in AML but in all cancer types. Disclosures Ottmann: Novartis: Consultancy; Pfizer: Consultancy; Fusion Pharma: Consultancy, Research Funding; Amgen: Consultancy; Celgene: Consultancy, Research Funding; Takeda: Consultancy; Incyte: Consultancy, Research Funding.