title: 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 IDH1(R132H) 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.
authors.affiliation: 1] Department of Medicine, Stanford University School of Medicine, Stanford, California, USA. [2] Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Chan
authors.affiliation: Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Thomas
authors.affiliation: Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: M Ryan
authors.initials: MR
authors.lastname: Corces-Zimmerman
authors.affiliation: Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Seethu
authors.initials: S
authors.lastname: Xavy
authors.affiliation: Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Suchita
authors.initials: S
authors.lastname: Rastogi
authors.affiliation: 1] Department of Medicine, Stanford University School of Medicine, Stanford, California, USA. [2] Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Wan-Jen
authors.initials: WJ
authors.lastname: Hong
authors.affiliation: Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Feifei
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Bruno C
authors.initials: BC
authors.lastname: Medeiros
authors.affiliation: Department of Chemistry, Stanford University, Stanford, California, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Tyvoll
authors.affiliation: 1] Department of Medicine, Stanford University School of Medicine, Stanford, California, USA. [2] Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Ravindra
authors.initials: R
authors.lastname: Majeti
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004579:Electron Transport; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors; D005977:Glutarates / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics*; D009154:Mutation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005977:Glutarates; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C019417:alpha-hydroxyglutarate; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D003576:Electron Transport Complex IV; C579720:venetoclax