Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 218, Issue 5, Pages -Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20200924
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Funding
- Region Midi-Pyrenees (FLEXAML)
- Plan Cancer Biologie des Systemes 2014 (FLEXAML)
- Laboratoire d'Excellence Toulouse Cancer (TOUCAN) [ANR11-LABEX]
- MetaboCancerGSO
- Program Hospitalo-Universitaire en Cancerologie (CAPTOR) [ANR11-PHUC0001]
- La Ligue Nationale de Lutte Contre le Cancer
- Fondation ARC
- Fondation Toulouse Cancer Sante
- Association G.A.E.L
- French National Infrastructure for Metabolomics and Fluxomics [ANR-11-INBS-0010]
- Region Midi-Pyrenees
- European Regional Development Fund
- SICOVAL
- Infrastructures en Biologie Sante et Agronomie (France)
- Centre National de la Recherche Scientifique
- Institut National de la Recherche Agronomique
- Canceropole PACA, SIRIC [INCa-Inserm-DGOS 6038 2012-2017]
- Canceropole-SIRIC EmA [INCA 2017-024-COLLETTE, INCa 2017-024-MAL]
- SIRIC [INCa-Inserm-DGOS 6038 2012-2017]
- SIRIC-Montpellier Cancer Program [INCa-Inserm-DGOS_12553]
- Leukemia Spore grant P50 [CA100632-16]
- chair of Bioinformatics in Oncology of the CRCT
- Laboratoire d'Excellence Toulouse Cancer
- SIRIC Montpellier Cancer Grant [INCa_Inserm_DGOS_12553]
- Foundation de France [00078461]
- LabEx MabImprove Starting Grant
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Mutations in IDH lead to enhanced mitochondrial oxidative metabolism in AML, involving increased electron transport chain activity and fatty acid oxidation. IDH1 mutant inhibitors reduce 2-HG levels and CEBPα methylation, but do not reverse fatty acid oxidation and OxPHOS. Targeting mitochondrial activities may improve anti-AML efficacy of IDH mutant inhibitors.
Mutations in IDH induce epigenetic and transcriptional reprogramming, differentiation bias, and susceptibility to mitochondrial inhibitors in cancer cells. Here, we first show that cell lines, PDXs, and patients with acute myeloid leukemia (AML) harboring an IDH mutation displayed an enhanced mitochondrial oxidative metabolism. Along with an increase in TCA cycle intermediates, this AML-specific metabolic behavior mechanistically occurred through the increase in electron transport chain complex I activity, mitochondrial respiration, and methylation-driven CEBP alpha-induced fatty acid beta-oxidation of IDH1 mutant cells. While IDH1 mutant inhibitor reduced 2-HG oncometabolite and CEBP alpha methylation, it failed to reverse FAO and OxPHOS. These mitochondrial activities were maintained through the inhibition of Akt and enhanced activation of peroxisome proliferator-activated receptor-gamma coactivator-1 PGC1 alpha upon IDH1 mutant inhibitor. Accordingly, OxPHOS inhibitors improved anti-AML efficacy of IDH mutant inhibitors in vivo. This work provides a scientific rationale for combinatory mitochondrial-targeted therapies to treat IDH mutant AML patients, especially those unresponsive to or relapsing from IDH mutant inhibitors.
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