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 A 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 y 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 A 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 R Marszalek (7) , Koichi Takahashi (7) , Courtney D Dinardo (7) , Marina Konopleva (7) , Véra Pancaldi (1) , Yves Collette (6) , Floriant Bellvert (4) , Fabien Jourdan (2) , Laetitia K Linares (5) , Christian Récher (1) , Jean-Charles Portais (4) , Jean-Emmanuel Sarry (1)

1 CRCT - Centre de Recherches en Cancérologie de Toulouse
2 ToxAlim-MeX - Métabolisme et Xénobiotiques
3 LEMM - Laboratoire d'Etude du Métabolisme des Médicaments
4 TBI - Toulouse Biotechnology Institute
5 IRCM - U1194 Inserm - UM - Institut de Recherche en Cancérologie de Montpellier
6 CRCM - Centre de Recherche en Cancérologie de Marseille
7 MD Anderson Cancer Center [Houston]
8 INSERM - Institut National de la Santé et de la Recherche Médicale
9 LIH - Luxembourg Institute of Health
10 BFP - Biologie du fruit et pathologie
11 ToxAlim - ToxAlim
12 University of Pennsylvania [Philadelphia]
13 UM - Université de Montpellier
14 Réseau régional de cancérologie Onco-Occitanie
15 Agios Pharmaceuticals

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.

Domains: Life Sciences [q-bio]

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, 2021, 218 (5), pp.e20200924. ⟨10.1084/jem.20200924⟩. ⟨hal-03563454⟩