Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia
Top Cited Papers
- 19 January 2015
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Medicine
- Vol. 21 (2), 178-184
- https://doi.org/10.1038/nm.3788
Abstract
IDH1 and IDH2 mutations sensitize acute myeloid leukemia cells to the BCL-2 inhibitor ABT-199. 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.Keywords
This publication has 63 references indexed in Scilit:
- In Vivo Expansion of Co-Transplanted T Cells Impacts on Tumor Re-Initiating Activity of Human Acute Myeloid Leukemia in NSG MicePLOS ONE, 2013
- IDH mutation impairs histone demethylation and results in a block to cell differentiationNature, 2012
- 2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomasNature Medicine, 2012
- Revisiting the TCA cycle: signaling to tumor formationTrends in Molecular Medicine, 2011
- Inhibition of Mitochondrial Translation as a Therapeutic Strategy for Human Acute Myeloid LeukemiaCancer Cell, 2011
- Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent DioxygenasesCancer Cell, 2011
- The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations Is a Neomorphic Enzyme Activity Converting α-Ketoglutarate to 2-HydroxyglutarateCancer Cell, 2010
- Cancer-associated IDH1 mutations produce 2-hydroxyglutarateNature, 2009
- Principles of Cancer Therapy: Oncogene and Non-oncogene AddictionCell, 2009
- Cytochrome c oxidase subunit IV is essential for assembly and respiratory function of the enzyme complexJournal of Bioenergetics and Biomembranes, 2006