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

Abstract

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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Acknowledgements

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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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). https://doi.org/10.1038/nm.3788

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