Journal
NATURE CANCER
Volume 2, Issue 11, Pages 1204-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s43018-021-00264-y
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Funding
- CAPTOR (Cancer Pharmacology of Toulouse-Oncopole and Region)
- French National infrastructure for Metabolomics and Fluxomics [ANR-11-INBS-0010]
- Region Midi-Pyrenees
- European Regional Development Fund
- SICOVAL
- Infrastructures en Biologie Sante et Agronomie
- Centre National de la Recherche Scientifique
- Institut National de la Recherche Agronomique Team
- Programme Investissement d'Avenir PSPC (IMODI)
- Laboratoire d'Excellence Toulouse Cancer (TOUCAN)
- Laboratoire d'Excellence Toulouse Cancer (TOUCAN2.0) [ANR11-LABEX]
- INCA [PLBIO 2020-010]
- Fondation Toulouse Cancer Sante
- Fondation ARC
- Ligue National de Lutte Contre le Cancer
- association Prolific
- association GAEL
- European Regional Development Fund through the Interreg V-A Spain-France-Andorra program, project PROTEOblood [EFA360/19]
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Therapy resistance in AML is linked to high mitochondrial oxidative phosphorylation identified by MitoScore. Targeting mitochondrial metabolism can delay AML relapse, highlighting the central role of mitochondrial adaptation in AML therapy.
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. Sarry and colleagues demonstrate that adaptive resistance to venetoclax + cytarabine therapy in acute myeloid leukemia relies on mitochondrial respiration and show that combination with electron transport chain complex inhibitors delays relapse in patient-derived xenograft models in vivo.
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