BCL2 Is Synthetic Lethal to IDH1/2 Mutations in AML

Approximately 15% of patients with acute myeloid leukemia (AML) harbor mutations in the citric acid cycle enzymes isocitrate dehydrogenase 1 (IDH1) or IDH2, resulting in accumulation of the oncometabolite (R)-2-hydroxyglutarate (2-HG) and an altered epigenetic landscape. To identify non-oncogenes that are synthetic lethal to mutant IDH and that may represent potential therapeutic targets, Chan and colleagues performed an RNA interference screen in AML cells. Intriguingly, IDH1^R132H-mutant AML cells exhibited increased dependence on the anti-apoptotic gene BCL2 for survival compared with AML cells expressing wild-type IDH1. Intracellular accumulation of 2-HG was sufficient to render wild-type AML cells sensitive to BCL2 depletion, indicating that the activity of mutant IDH induces synthetic lethality to BCL2. Consistent with this finding, IDH1/2 mutation enhanced the sensitivity of AML cell lines and primary human AML blasts to pharmacologic BCL2 inhibition with ABT-199, a specific BCL2 inhibitor currently in clinical trials. Treatment with ABT-199 reduced the engraftment of IDH1-mutant, but not wild-type IDH1/2, human AML cells in mice and targeted IDH1-mutant AML blasts as well as leukemic stem cells in vivo. Mechanistically, 2-HG accumulation inhibited the enzymatic activity of cytochrome c oxidase (COX), which comprises complex IV of the mitochondrial electron transport chain (ETC), mimicking a state of oxygen deprivation and resulting in a decreased mitochondrial threshold for the induction of apoptosis. COX inhibition was both necessary and sufficient to confer increased dependence on BCL2 for cell viability and sensitized AML cells to ABT-199, which triggered cytochrome c release and mitochondrial outer membrane permeabilization to induce apoptosis in IDH1/2-mutant AML cells. These results suggest that mutant IDH–mediated dysregulation of mitochondrial function may promote leukemogenesis and that IDH1/2 mutations may identify patients most likely to respond to treatment with ABT-199. In addition, combined treatment with drugs that disrupt ETC function may enhance the efficacy of ABT-199.

Chan SM, Thomas D, Corces-Zimmerman MR, Xavy S, Rastogi S, Hong WJ, et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat Med 2015;21:178–84.

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