PT  - JOURNAL ARTICLE
AU  - Lucille Stuani
AU  - Marie Sabatier
AU  - Feng Wang
AU  - Nathalie Poupin
AU  - Claudie Bosc
AU  - Estelle Saland
AU  - Florence Castelli
AU  - Lara Gales
AU  - Camille Montersino
AU  - Emeline Boet
AU  - Evgenia Turtoi
AU  - Tony Kaoma
AU  - Thomas Farge
AU  - Nicolas Broin
AU  - Clément Larrue
AU  - Natalia Baran
AU  - Marc Conti
AU  - Sylvain Loric
AU  - Pierre-Luc Mouchel
AU  - Mathilde Gotanègre
AU  - Cédric Cassan
AU  - Laurent Fernando
AU  - Guillaume Cognet
AU  - Aliki Zavoriti
AU  - Mohsen Hosseini
AU  - Héléna Boutzen
AU  - Kiyomi Morita
AU  - Andrew Futreal
AU  - Emeline Chu-Van
AU  - Laurent Le Cam
AU  - Martin Carroll
AU  - Mary A. Selak
AU  - Norbert Vey
AU  - Claire Calmettes
AU  - Arnaud Pigneux
AU  - Audrey Bidet
AU  - Rémy Castellano
AU  - Francois Fenaille
AU  - Andrei Turtoi
AU  - Guillaume Cazals
AU  - Pierre Bories
AU  - Yves Gibon
AU  - Brandon Nicolay
AU  - Sébastien Ronseaux
AU  - Joe Marszalek
AU  - Courtney D. DiNardo
AU  - Marina Konopleva
AU  - Yves Collette
AU  - Laetitia K. Linares
AU  - Floriant Bellvert
AU  - Fabien Jourdan
AU  - Koichi Takahashi
AU  - Christian Récher
AU  - Jean-Charles Portais
AU  - Jean-Emmanuel Sarry
TI  - Combinatory therapy targeting mitochondrial oxidative phosphorylation improves efficacy of IDH mutant inhibitors in acute myeloid leukemia
AID  - 10.1101/749580
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 749580
4099  - http://biorxiv.org/content/early/2019/08/28/749580.short
4100  - http://biorxiv.org/content/early/2019/08/28/749580.full
AB  - Isocitrate dehydrogenases (IDH) are involved in redox control and central metabolism. Mutations in IDH induce epigenetic and transcriptional reprogramming, differentiation bias, BCL-2 dependence and susceptibility to mitochondrial inhibitors in cancer cells. Here we show that high sensitivity to mitochondrial oxidative phosphorylation (OxPHOS) inhibitors is due to an enhanced mitochondrial oxidative metabolism in cell lines, PDX and patients with acute myeloid leukemia (AML) harboring IDH mutation. Along with an increase in TCA cycle intermediates, this AML-specific metabolic behavior mechanistically occurs through the increase in methylation-driven CEBPα- and CPT1a-induced fatty acid oxidation, electron transport chain complex I activity and mitochondrial respiration in IDH1 mutant AML. Furthermore, an IDH mutant inhibitor that significantly and systematically reduces 2-HG oncometabolite transiently reverses mitochondrial FAO and OxPHOS gene signature and activities in patients who responded to the treatment and achieved the remission. However, at relapse or in patients who did not respond, IDH mutant inhibitor failed to block these mitochondrial properties. Accordingly, OxPHOS inhibitors such as IACS-010759 improve anti-AML efficacy of IDH mutant inhibitors alone and in combination with chemotherapy in vivo. This work provides a scientific rationale for combinatory mitochondrial-targeted therapies to treat IDH mutant-positive AML patients, especially those unresponsive to or relapsing from IDH mutant-specific inhibitors.