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