Mitochondrial metabolism supports resistance to IDH mutant inhibitors in acute myeloid leukemia

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, Clement Larrue, Natalia Baran, Madi Y. Cisse, Marc Conti, Sylvain Loric, Tony Kaoma, Alexis HucteauAliki Zavoriti, Ambrine Sahal, Pierre Luc Mouchel, Mathilde Gotanègre, Cedric Cassan, Laurent Fernando, Feng Wang, Mohsen Hosseini, Emeline Chu-Van, Laurent Le Cam, Martin Carroll, Mary A. Selak, Norbert Vey, Remy Castellano, François Fenaille, Andrei Turtoi, Guillaume Cazals, Pierre Bories, Yves Gibon, Brandon Nicolay, Sebastien Ronseaux, Joseph R. Marszalek, Koichi Takahashi, Courtney D. DiNardo, Marina Konopleva, Vera Pancaldi, Yves Collette, Floriant Bellvert, Fabien Jourdan, Laetitia K. Linares, Christian Recher, Jean Charles Portais, Jean Emmanuel Sarry*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

24 Citations (Scopus)

Abstract

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 IDH1mutant 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 mitochondrialtargeted therapies to treat IDH mutant AML patients, especially those unresponsive to or relapsing from IDHmutant inhibitors.

Original languageEnglish
Article numbere20200924
JournalJournal of Experimental Medicine
Volume218
Issue number5
DOIs
Publication statusPublished - 3 May 2021

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