HAL will be down for maintenance from Friday, June 10 at 4pm through Monday, June 13 at 9am. More information
Skip to Main content Skip to Navigation
Journal articles

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

Lucille Stuani 1 Marie Sabatier 1 Estelle Saland 1 Guillaume Cognet 1 Nathalie Poupin 2 Claudie Bosc 1 Florence Castelli 3 Lara Gales 4 Evgenia Turtoi 5 Camille Montersino 6 Thomas Farge 1 Emeline Boet 1 Nicolas Broin 1 Clément Larrue 1 Natalia Baran 7 Madi Cissé 5 Marc Conti 8 Sylvain Loric 8 Tony Kaoma 9 Alexis Hucteau 1 Aliki Zavoriti 1 Ambrine Sahal 1 Pierre-Luc Mouchel 1 Mathilde Gotanègre 1 Cédric Cassan 10 Laurent Fernando 11 Feng Wang 7 Mohsen Hosseini 1 Emeline Chu-Van 3 Laurent Le Cam 8 Martin Carroll 12 Mary Selak 12 Norbert Vey 6 Rémy Castellano 6 François Fenaille 3 Andrei Turtoi 5 Guillaume Cazals 13 Pierre Bories 14 Yves Gibon 10 Brandon Nicolay 15 Sébastien Ronseaux 15 Joseph Marszalek 7 Koichi Takahashi 7 Courtney Dinardo 7 Marina Konopleva 7 Véra Pancaldi 1 Yves Collette 6 Floriant Bellvert 4 Fabien Jourdan 2 Laetitia Linares 5 Christian Récher 1 Jean-Charles Portais 4 Jean-Emmanuel Sarry 1
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 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 mitochondrialtargeted therapies to treat IDH mutant AML patients, especially those unresponsive to or relapsing from IDH mutant inhibitors.
Document type :
Journal articles
Complete list of metadata

Contributor : Yves Collette Connect in order to contact the contributor
Submitted on : Wednesday, February 9, 2022 - 4:59:12 PM
Last modification on : Thursday, May 19, 2022 - 3:00:04 PM
Long-term archiving on: : Tuesday, May 10, 2022 - 7:10:40 PM


Publisher files allowed on an open archive


Distributed under a Creative Commons Attribution 4.0 International License



Lucille Stuani, Marie Sabatier, Estelle Saland, Guillaume Cognet, Nathalie Poupin, et al.. Mitochondrial metabolism supports resistance to IDH mutant inhibitors in acute myeloid leukemia. Journal of Experimental Medicine, Rockefeller University Press, 2021, 218 (5), pp.e20200924. ⟨10.1084/jem.20200924⟩. ⟨hal-03563454⟩



Record views


Files downloads