| Literature DB >> 35122057 |
Lucille Stuani1,2,3, Carine Joffre1,2,3, Claudie Bosc1,2,3, Estelle Saland1,2,3, Aurélie Bousard4, Noémie Gadaud1,2,3,5,6, Marie Sabatier1,2,3, Guillaume Cognet1,2,3, Thomas Farge1,2,3, Emeline Boet1,2,3, Mathilde Gotanègre1,2,3, Nesrine Aroua1,2,3, Pierre-Luc Mouchel1,2,3,5,6, Nathaniel Polley1,2,3, Clément Larrue1,2,3, Eléonore Kaphan1,2,3, Muriel Picard7, Ambrine Sahal1,2,3, Latifa Jarrou1,2,3, Marie Tosolini1, Florian Rambow4, Florence Cabon1,2,3, Nathalie Nicot8, Laura Poillet-Perez1,2,3, Yujue Wang9, Xiaoyang Su9, Quentin Fovez10, Jérôme Kluza10, Rafael José Argüello11, Céline Mazzotti1,12, Hervé Avet-Loiseau1,12, François Vergez1,2,3,5,6, Jérôme Tamburini13, Jean-Jacques Fournié1,2, Ing S Tiong14, Andrew H Wei14, Tony Kaoma15, Jean-Christophe Marine4, Christian Récher1,2,3,5,6, Jean-Emmanuel Sarry16,17,18.
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.Entities:
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Year: 2021 PMID： 35122057 DOI： 10.1038/s43018-021-00264-y
Source DB: PubMed Journal: Nat Cancer ISSN： 2662-1347