TY - JOUR
T1 - Mitochondrial inhibitors circumvent adaptive resistance to venetoclax and cytarabine combination therapy in acute myeloid leukemia
AU - Bosc, Claudie
AU - Saland, Estelle
AU - Bousard, Aurélie
AU - Gadaud, Noémie
AU - Sabatier, Marie
AU - Cognet, Guillaume
AU - Farge, Thomas
AU - Boet, Emeline
AU - Gotanègre, Mathilde
AU - Aroua, Nesrine
AU - Mouchel, Pierre Luc
AU - Polley, Nathaniel
AU - Larrue, Clément
AU - Kaphan, Eléonore
AU - Picard, Muriel
AU - Sahal, Ambrine
AU - Jarrou, Latifa
AU - Tosolini, Marie
AU - Rambow, Florian
AU - Cabon, Florence
AU - Nicot, Nathalie
AU - Poillet-Perez, Laura
AU - Wang, Yujue
AU - Su, Xiaoyang
AU - Fovez, Quentin
AU - Kluza, Jérôme
AU - Argüello, Rafael José
AU - Mazzotti, Céline
AU - Avet-Loiseau, Hervé
AU - Vergez, François
AU - Tamburini, Jérôme
AU - Fournié, Jean Jacques
AU - Tiong, Ing S.
AU - Wei, Andrew H.
AU - Kaoma, Tony
AU - Marine, Jean Christophe
AU - Récher, Christian
AU - Stuani, Lucille
AU - Joffre, Carine
AU - Sarry, Jean Emmanuel
N1 - Funding Information:
We thank all members of mice core facilities (UMS006, ANEXPLO, Inserm) in particular M. Lulka, C. Campi and all members of the CREFRE for their support and technical assistance and V. De Mas and E. Delabesse for the management of the Biobank BRC-HIMIP (Biological Resources Centres-Inserm Midi-Pyrénées Cytothèque des hémopathies malignes), which is supported by CAPTOR (Cancer Pharmacology of Toulouse-Oncopole and Région). We thank A. Melotti and IGE3 Genomic Platform (Geneva University) as well as F. Pont and F. Lopez (Pôle Technologique du CRCT, Inserm/U1037) and F. Martins (GET, GENOToul) for bulk DNA/RNA sequencing and single-cell RNA-seq procedures, respectively. We are grateful to the GENOToul Bioinformatics Platform Toulouse Midi-Pyrenees (Bioinfo Genotoul) for providing computing resources. This work was granted access to the HPC resources of CALMIP supercomputing center under the allocation 2019-T19001. 13C-isotope-tracing experiments were carried out at the Rutgers Cancer Institute of New Jersey. Metabolomics was performed at the MetaToul-MetaboHUB core facility (National Infrastructure of Metabolomics and Fluxomics) under supervision of L. Peyriga, F. Bellvert and J.-C. Portais. MetaToul is part of the national infrastructure MetaboHUB-ANR-11-INBS-0010 (French National infrastructure for Metabolomics and Fluxomics; www.metabohub.fr). MetaToul is supported by grants from the Région Midi-Pyrénées, the European Regional Development Fund, the SICOVAL, the Infrastructures en Biologie Santé et Agronomie, the Centre National de la Recherche Scientifique and the Institut National de la Recherche Agronomique Team. J.-E.S. is a member of OPALE Carnot Institute at the Organization for Partnerships in Leukemia. We thank A.-M. Benot, M. Serthelon and S. Nevouet for their daily help on the administrative and financial management of our team. The authors also thank N. Mazure for fruitful discussion about mitochondrial VDAC, M. Konopleva, I. Majewski and M. Selak for critical reading of the manuscript. This work was also supported by grants from the Programme Investissement d’Avenir PSPC (IMODI), the Laboratoire d’Excellence Toulouse Cancer (TOUCAN and TOUCAN2.0; contract ANR11-LABEX), INCA (PLBIO 2020-010, DIALAML), the Fondation Toulouse Cancer Santé, the Fondation ARC, the Ligue National de Lutte Contre le Cancer, the association Prolific and the association GAEL. A.S. is a fellow of the European Regional Development Fund through the Interreg V-A Spain-France-Andorra program, project PROTEOblood (EFA360/19). C.B. has a fellowship from the Fondation ARC.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/11
Y1 - 2021/11
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85118842657
UR - https://pubmed.ncbi.nlm.nih.gov/35122057
U2 - 10.1038/s43018-021-00264-y
DO - 10.1038/s43018-021-00264-y
M3 - Article
C2 - 35122057
AN - SCOPUS:85118842657
SN - 2662-1347
VL - 2
SP - 1204
EP - 1223
JO - Nature Cancer
JF - Nature Cancer
IS - 11
ER -