MLL-Rearranged Acute Lymphoblastic Leukemias Activate BCL-2 through H3K79 Methylation and Are Sensitive to the BCL-2-Specific Antagonist ABT-199

Benito, Juliana; Godfrey, Laura; Kojima, Kensuke; Hogdal, Leah J.; Wunderlich, Mark; Geng, Huimin; Marzo, Isabel; Harutyunyan, Karine G.; Golfman, Leonard S.; North, Phillip; Kerry, Jon; Ballabio, Erica; Chonghaile, Tríona Ní; Gonzalo, Óscar; Qiu, Yihua; Jeremias, Irmela; Debose, La Kiesha; O’Brien, Eric; Ma, Helen; Zhou, Ping; Jácamo, Rodrigo; Park, Eugene; Coombes, Kevin R.; Zhang, Nianxiang; Thomas, Deborah A.; O’Brien, Susan; Kantarjian, Hagop M.; Leverson, Joel D.; Kornblau, Steven M.; Andreeff, Michael; Müschen, Markus; Zweidler‐McKay, Patrick A.; Mulloy, James C.; Letaï, Anthony; Milne, Thomas A.; Konopleva, Marina

doi:10.1016/j.celrep.2015.12.003

Cited by 115 publications

(140 citation statements)

References 45 publications

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“…In MLL-r ALL xenografts, venetoclax was associated with a higher response rate of 50%, compared with 26% in non-MLL-ALL xenografts, suggesting that BCL-2 inhibition, in conjunction with chemotherapeutics, is effective in this sub-group (93,94). These data support the trial of the introduction of BCL-2-inhibitor drugs into therapeutic regimens for MLL-r leukemias (84).…”

Section: Minireview: Leukemia Fusions and Apoptosissupporting

confidence: 70%

Dysregulation of BCL-2 family proteins by leukemia fusion genes

Brown

Hanna

Khaw

et al. 2017

Journal of Biological Chemistry

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The genomic lesions that characterize acute lymphoblastic leukemia in childhood include recurrent translocations that result in the expression of fusion proteins that typically involve genes encoding tyrosine kinases, cytokine receptors, and transcription factors. These genetic rearrangements confer phenotypic hallmarks of malignant transformation, including unrestricted proliferation and a relative resistance to apoptosis. In this Minireview, we discuss the molecular mechanisms that link these fusions to the control of cell death. We examine how these fusion genes dysregulate the BCL-2 family of proteins, preventing activation of the apoptotic effectors, BAX and BAK, and promoting cell survival. Recurrent fusion genes in acute lymphoblastic leukemiaAcute lymphoblastic leukemia (ALL) 2 is the most common form of childhood malignancy. Therapy for ALL is one of the great success stories of modern chemotherapy, and overall cure rates are now Ͼ90% in developed countries, depending on molecular subtypes and clinical features (1). The extraordinary improvements in outcomes in ALL have unquestionably been driven by the treatment of patients on international collaborative clinical trials (2), which have made it possible to rapidly recruit sufficient numbers of patients to studies of new treatment regimes. The analysis of treatment responses, based on measurement of minimal residual disease, has allowed the early identification of treatment failure or relapse and the consequent adjustment of treatment intensity.The next revolution in our understanding of ALL biology is being driven by many studies, involving thousands of patient samples, characterizing the genomic landscape of ALL through genome and transcriptome sequencing (3-7). This has led to the recognition of novel molecular subtypes of ALL, defined by the genomic lesions that drive them. Characterization of leukemic genomes provides insight into the key molecular pathways involved in ALL subtypes.Many recently identified genomic lesions in ALL are fusion genes, arising from chromosomal translocations (8). These include fusions that activate tyrosine kinases, cytokine receptors, and transcription factors. The presence of these fusions has important prognostic and treatment implications. In this Minireview, we consider how these genomic lesions promote resistance to apoptosis in ALL. Gene fusions in ALLChromosomal translocations, resulting in the expression of fusion genes, are a hallmark of B-cell malignancies. This likely arises as fusion partners are mistakenly juxtaposed during periods of genomic editing and recombinase-activating gene (RAG1 and RAG2) activation or somatic hypermutation during B-cell development (9). Recurrent chromosomal translocations have been recognized and detected in ALL, initially by staining of metaphases and microscopy, and more recently by fluorescent in situ hybridization (FISH). The detection of a small number of recurrent translocations is a standard component of ALL diagnosis and risk assessment. For example, t(12;21) ETV6-RUNX1 ...

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Section: Minireview: Leukemia Fusions and Apoptosissupporting

confidence: 70%

Dysregulation of BCL-2 family proteins by leukemia fusion genes

Brown

Hanna

Khaw

et al. 2017

Journal of Biological Chemistry

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“…This observation extends a recent published finding that MLL rearrangement directly induces BCL-2 expression in ALL cells by promoting H3K79 methylation at the BCL2 locus. 62 In that study, single-agent efficacy was observed in 1 of 2 MLLr-ALL xenografts treated with venetoclax in vivo. Notably, even within the MLLr-ALL subgroup, we found Figure 5.…”

Section: Discussionmentioning

confidence: 99%

Venetoclax responses of pediatric ALL xenografts reveal sensitivity of MLL-rearranged leukemia

Khaw

Suryani

Evans

et al. 2016

Blood

148

137

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Key Points• Venetoclax demonstrates potent in vitro and in vivo single-agent activity in MLLrearranged ALL xenografts.• Clinically efficacious BH3-mimetic therapy for other high-risk ALL subtypes is likely to require concurrent BCL-2 and BCL-X L inhibition.The clinical success of the BCL-2-selective BH3-mimetic venetoclax in patients with poor prognosis chronic lymphocytic leukemia (CLL) highlights the potential of targeting the BCL-2-regulated apoptotic pathway in previously untreatable lymphoid malignancies. By selectively inhibiting BCL-2, venetoclax circumvents the dose-limiting, BCL-X L -mediated thrombocytopenia of its less selective predecessor navitoclax, while enhancing efficacy in CLL. We have previously reported the potent sensitivity of many high-risk childhood acute lymphoblastic leukemia (ALL) xenografts to navitoclax. Given the superior tolerability of venetoclax, here we have investigated its efficacy in childhood ALL. We demonstrate that in contrast to the clear dependence of CLL on BCL-2 alone, effective antileukemic activity in the majority of ALL xenografts requires concurrent inhibition of both BCL-2 and BCL-X L . We identify BCL-X L expression as a key predictor of poor response to venetoclax and demonstrate that concurrent inhibition of both BCL-2 and BCL-X L results in synergistic killing in the majority of ALL xenografts. A notable exception is mixed lineage leukemia-rearranged infant ALL, where venetoclax largely recapitulates the activity of navitoclax, identifying this subgroup of patients as potential candidates for clinical trials of venetoclax in childhood ALL. Conversely, our findings provide a clear basis for progressing navitoclax into trials ahead of venetoclax in other subgroups. (Blood. 2016;128(10):1382-1395

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“…BH3 profiling and studies using the LOUCY cell line indicate that venetoclax, alone or in combination with chemotherapeutic agents, may represent a powerful new therapeutic strategy for ETP T-ALL (117–119). Benito and colleagues found that blasts from mixed lineage leukemia-rearranged (MLLr) ALL express high levels of BCL-2, and ChIP sequencing analysis demonstrated that the BCL2 gene is a direct MLL-AF4 target (120). MLL-AF4 maintains BCL2 gene expression through H3K79 methylation, which translates into high sensitivity of MLLr cell lines and primary cells to venetoclax, alone or in combination with standard induction chemotherapeutics or H3K79 methylation inhibitors.…”

Section: Future Considerations and Conclusionmentioning

confidence: 99%

Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax

Sampath²,

et al. 2017

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Since the discovery of apoptosis as a form of programmed cell death, targeting the apoptosis pathway to induce cancer cell death has been a high priority goal for cancer therapy. After decades of effort, drug discovery scientists have succeeded in generating small-molecule inhibitors of antiapoptotic BCL-2 family proteins. Innovative medicinal chemistry and structure-based drug design, coupled with a strong fundamental understanding of BCL-2 biology, were essential to the development of BH3 mimetics such as the BCL-2-selective inhibitor venetoclax. We review a number of preclinical studies that have deepened our understanding of BCL-2 biology and facilitated the clinical development of venetoclax.

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MLL-Rearranged Acute Lymphoblastic Leukemias Activate BCL-2 through H3K79 Methylation and Are Sensitive to the BCL-2-Specific Antagonist ABT-199

Cited by 115 publications

References 45 publications

Dysregulation of BCL-2 family proteins by leukemia fusion genes

Dysregulation of BCL-2 family proteins by leukemia fusion genes

Venetoclax responses of pediatric ALL xenografts reveal sensitivity of MLL-rearranged leukemia

Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax

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