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Journal Articles Journal of Experimental Medicine Year : 2021

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

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Nathalie Poupin
Lara Gales
Natalia Baran
Tony Kaoma
Cédric Cassan
Laurent Fernando
Feng Wang
Mary A Selak
Guillaume Cazals
Yves Gibon
Brandon Nicolay
Sébastien Ronseaux
Joseph R Marszalek
Koichi Takahashi
Courtney D Dinardo
Marina Konopleva
Floriant Bellvert
Fabien Jourdan
Jean-Charles Portais

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.
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Dates and versions

hal-03563454 , version 1 (09-02-2022)

Licence

Attribution - CC BY 4.0

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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⟩
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