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 CEBPα-induced fatty acid β-oxidation of IDH1 mutant cells. While IDH1 mutant inhibitor reduced 2-HG oncometabolite and CEBPα 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-γ coactivator-1 PGC1α 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.
Mitochondrial metabolism supports resistance to IDH mutant inhibitors in acute myeloid leukemia
Disclosures: B. Nicolay reported "other" from Agios Pharmaceuticals outside the submitted work and is an employee and shareholder of Agios Pharmaceuticals. J.R. Marszalek reported a patent to IACS-010759 issued. K. Takahashi reported personal fees from Celgene during the conduct of the study; and personal fees from Symbio Pharmaceuticals, GSK, and Novartis outside the submitted work. C.D. DiNardo reported personal fees from Agios Pharmaceuticals, Celgene, and AbbVie outside the submitted work. M. Konopleva reported "other" from Amgen, Kisoji, and Reata Pharmaceutical; and grants from AbbVie, Genentech, and Stemline Therapeutics, F. Hoffman La-Roche, Forty Seven, Eli Lilly, Cellectis, Calithera, Ablynx, Agios, Ascentage, Astra Zeneca, Rafael Pharmaceutical, and Sanofi outside the submitted work. In addition, M. Konopleva had a patent to Novartis pending (62/993,166), a patent to Eli Lilly issued, and a patent to Reata Pharmaceutical issued (7,795,305 B2 CDDO). C. Récher reported grants from Celgene, Amgen, Novartis, Jazz, AbbVie, Astellas, MaatPharma, Agios, Daiichi-Sankyo, and Roche; personal fees from Incyte, Macrogenics, Otsuka, Janssen, Pfizer, and Takeda; and non-financial support from Sanofi and Gilead outside the submitted work. No other disclosures were reported.
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Lucille Stuani, Marie Sabatier, Estelle Saland, Guillaume Cognet, Nathalie Poupin, Claudie Bosc, Florence A. Castelli, Lara Gales, Evgenia Turtoi, Camille Montersino, Thomas Farge, Emeline Boet, Nicolas Broin, Clément Larrue, Natalia Baran, Madi Y. Cissé, Marc Conti, Sylvain Loric, Tony Kaoma, Alexis Hucteau, Aliki Zavoriti, Ambrine Sahal, Pierre-Luc Mouchel, Mathilde Gotanègre, Cédric Cassan, Laurent Fernando, Feng Wang, Mohsen Hosseini, Emeline Chu-Van, Laurent Le Cam, Martin Carroll, Mary A. Selak, Norbert Vey, Rémy Castellano, François Fenaille, Andrei Turtoi, Guillaume Cazals, Pierre Bories, Yves Gibon, Brandon Nicolay, Sébastien Ronseaux, Joseph R. Marszalek, Koichi Takahashi, Courtney D. DiNardo, Marina Konopleva, Véra Pancaldi, Yves Collette, Floriant Bellvert, Fabien Jourdan, Laetitia K. Linares, Christian Récher, Jean-Charles Portais, Jean-Emmanuel Sarry; Mitochondrial metabolism supports resistance to IDH mutant inhibitors in acute myeloid leukemia. J Exp Med 3 May 2021; 218 (5): e20200924. doi: https://doi.org/10.1084/jem.20200924
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