Mitochondrial inhibitors circumvent adaptive resistance to venetoclax and cytarabine combination therapy in acute myeloid leukemia

Claudie Bosc, Estelle Saland, Aurélie Bousard, Noémie Gadaud, Marie Sabatier, Guillaume Cognet, Thomas Farge, Emeline Boet, Mathilde Gotanègre, Nesrine Aroua, Pierre Luc Mouchel, Nathaniel Polley, Clément Larrue, Eléonore Kaphan, Muriel Picard, Ambrine Sahal, Latifa Jarrou, Marie Tosolini, Florian Rambow, Florence CabonNathalie Nicot, Laura Poillet-Perez, Yujue Wang, Xiaoyang Su, Quentin Fovez, Jérôme Kluza, Rafael José Argüello, Céline Mazzotti, Hervé Avet-Loiseau, François Vergez, Jérôme Tamburini, Jean Jacques Fournié, Ing S. Tiong, Andrew H. Wei, Tony Kaoma, Jean Christophe Marine, Christian Récher, Lucille Stuani, Carine Joffre, Jean Emmanuel Sarry*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

8 Citations (Scopus)

Abstract

Therapy resistance represents a major clinical challenge in acute myeloid leukemia (AML). Here we define a ‘MitoScore’ signature, which identifies high mitochondrial oxidative phosphorylation in vivo and in patients with AML. Primary AML cells with cytarabine (AraC) resistance and a high MitoScore relied on mitochondrial Bcl2 and were highly sensitive to venetoclax (VEN) + AraC (but not to VEN + azacytidine). Single-cell transcriptomics of VEN + AraC-residual cell populations revealed adaptive resistance associated with changes in oxidative phosphorylation, electron transport chain complex and the TP53 pathway. Accordingly, treatment of VEN + AraC-resistant AML cells with electron transport chain complex inhibitors, pyruvate dehydrogenase inhibitors or mitochondrial ClpP protease agonists substantially delayed relapse following VEN + AraC. These findings highlight the central role of mitochondrial adaptation during AML therapy and provide a scientific rationale for alternating VEN + azacytidine with VEN + AraC in patients with a high MitoScore and to target mitochondrial metabolism to enhance the sensitivity of AML cells to currently approved therapies.

Original languageEnglish
Pages (from-to)1204-1223
Number of pages20
JournalNature Cancer
Volume2
Issue number11
Early online date11 Nov 2021
DOIs
Publication statusPublished - Nov 2021

Fingerprint

Dive into the research topics of 'Mitochondrial inhibitors circumvent adaptive resistance to venetoclax and cytarabine combination therapy in acute myeloid leukemia'. Together they form a unique fingerprint.

Cite this