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Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia


Mutant isocitrate dehydrogenase (IDH) 1 and 2 proteins alter the epigenetic landscape in acute myeloid leukemia (AML) cells through production of the oncometabolite (R)-2-hydroxyglutarate (2-HG). Here we performed a large-scale RNA interference (RNAi) screen to identify genes that are synthetic lethal to the IDH1R132H mutation in AML and identified the anti-apoptotic gene BCL-2. IDH1- and IDH2-mutant primary human AML cells were more sensitive than IDH1/2 wild-type cells to ABT-199, a highly specific BCL-2 inhibitor that is currently in clinical trials for hematologic malignancies, both ex vivo and in xenotransplant models. This sensitization effect was induced by (R)-2-HG–mediated inhibition of the activity of cytochrome c oxidase (COX) in the mitochondrial electron transport chain (ETC); suppression of COX activity lowered the mitochondrial threshold to trigger apoptosis upon BCL-2 inhibition. Our findings indicate that IDH1/2 mutation status may identify patients that are likely to respond to pharmacologic BCL-2 inhibition and form the rational basis for combining agents that disrupt ETC activity with ABT-199 in future clinical studies.

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Figure 1: Identification of BCL-2 as synthetic lethal to mutant IDH1.
Figure 2: (R)-2-HG sensitizes AML cells to pharmacologic BCL-2 inhibition.
Figure 3: ABT-199 targets IDH1/2 mutant primary human AML cells.
Figure 4: (R)-2-HG–mediated inhibition of cytochrome c oxidase activity induces BCL-2 dependence.

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We acknowledge the Hematology Division Tissue Bank and the patients for donating their samples. We acknowledge A. Giaccia for providing access to the Seahorse extracellular flux analyzer. S.M.C. is supported by a Stanford University School of Medicine Dean's Postdoctoral Fellowship and an American Society of Hematology Scholar Award. R.M. holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund and is a New York Stem Cell Foundation Robertson Investigator. This research was supported by the Burroughs Wellcome Fund, the New York Stem Cell Foundation, and a National Institutes of Health grant (R01CA188055) to R.M.

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S.M.C., D.T. and R.M. designed experiments. S.M.C., D.T., M.R.C.-Z., S.X., S.R., W.-J.H. and F.Z. performed the experiments. S.M.C., B.C.M., D.A.T. and R.M. analyzed and interpreted the data. S.M.C. and R.M. wrote the manuscript.

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Correspondence to Ravindra Majeti.

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The authors declare no competing financial interests.

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Chan, S., Thomas, D., Corces-Zimmerman, M. et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat Med 21, 178–184 (2015).

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