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 Cabon; Nathalie 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

doi:10.1038/s43018-021-00264-y

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

Platform LUXGEN - Micro-Array

Research output: Contribution to journal › Article › Research › peer-review

47 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 language	English
Pages (from-to)	1204-1223
Number of pages	20
Journal	Nature Cancer
Volume	2
Issue number	11
Early online date	11 Nov 2021
DOIs	https://doi.org/10.1038/s43018-021-00264-y
Publication status	Published - Nov 2021

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10.1038/s43018-021-00264-y

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Bosc, C., Saland, E., Bousard, A., Gadaud, N., Sabatier, M., Cognet, G., Farge, T., Boet, E., Gotanègre, M., Aroua, N., Mouchel, P. L., Polley, N., Larrue, C., Kaphan, E., Picard, M., Sahal, A., Jarrou, L., Tosolini, M., Rambow, F., ... Sarry, J. E. (2021). Mitochondrial inhibitors circumvent adaptive resistance to venetoclax and cytarabine combination therapy in acute myeloid leukemia. Nature Cancer, 2(11), 1204-1223. https://doi.org/10.1038/s43018-021-00264-y

@article{119a5c2294d24d2aba7a947239871927,

title = "Mitochondrial inhibitors circumvent adaptive resistance to venetoclax and cytarabine combination therapy in acute myeloid leukemia",

abstract = "Therapy resistance represents a major clinical challenge in acute myeloid leukemia (AML). Here we define a {\textquoteleft}MitoScore{\textquoteright} 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.",

author = "Claudie Bosc and Estelle Saland and Aur{\'e}lie Bousard and No{\'e}mie Gadaud and Marie Sabatier and Guillaume Cognet and Thomas Farge and Emeline Boet and Mathilde Gotan{\`e}gre and Nesrine Aroua and Mouchel, {Pierre Luc} and Nathaniel Polley and Cl{\'e}ment Larrue and El{\'e}onore Kaphan and Muriel Picard and Ambrine Sahal and Latifa Jarrou and Marie Tosolini and Florian Rambow and Florence Cabon and Nathalie Nicot and Laura Poillet-Perez and Yujue Wang and Xiaoyang Su and Quentin Fovez and J{\'e}r{\^o}me Kluza and Arg{\"u}ello, {Rafael Jos{\'e}} and C{\'e}line Mazzotti and Herv{\'e} Avet-Loiseau and Fran{\c c}ois Vergez and J{\'e}r{\^o}me Tamburini and Fourni{\'e}, {Jean Jacques} and Tiong, {Ing S.} and Wei, {Andrew H.} and Tony Kaoma and Marine, {Jean Christophe} and Christian R{\'e}cher and Lucille Stuani and Carine Joffre and Sarry, {Jean Emmanuel}",

note = "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-Pyr{\'e}n{\'e}es Cytoth{\`e}que des h{\'e}mopathies malignes), which is supported by CAPTOR (Cancer Pharmacology of Toulouse-Oncopole and R{\'e}gion). We thank A. Melotti and IGE3 Genomic Platform (Geneva University) as well as F. Pont and F. Lopez (P{\^o}le 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 R{\'e}gion Midi-Pyr{\'e}n{\'e}es, the European Regional Development Fund, the SICOVAL, the Infrastructures en Biologie Sant{\'e} 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{\textquoteright}Avenir PSPC (IMODI), the Laboratoire d{\textquoteright}Excellence Toulouse Cancer (TOUCAN and TOUCAN2.0; contract ANR11-LABEX), INCA (PLBIO 2020-010, DIALAML), the Fondation Toulouse Cancer Sant{\'e}, 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: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2021",

month = nov,

doi = "10.1038/s43018-021-00264-y",

language = "English",

volume = "2",

pages = "1204--1223",

journal = "Nature Cancer",

issn = "2662-1347",

publisher = "Nature Research",

number = "11",

}

Bosc, C, Saland, E, Bousard, A, Gadaud, N, Sabatier, M, Cognet, G, Farge, T, Boet, E, Gotanègre, M, Aroua, N, Mouchel, PL, Polley, N, Larrue, C, Kaphan, E, Picard, M, Sahal, A, Jarrou, L, Tosolini, M, Rambow, F, Cabon, F, Nicot, N, Poillet-Perez, L, Wang, Y, Su, X, Fovez, Q, Kluza, J, Argüello, RJ, Mazzotti, C, Avet-Loiseau, H, Vergez, F, Tamburini, J, Fournié, JJ, Tiong, IS, Wei, AH, Kaoma, T, Marine, JC, Récher, C, Stuani, L, Joffre, C & Sarry, JE 2021, 'Mitochondrial inhibitors circumvent adaptive resistance to venetoclax and cytarabine combination therapy in acute myeloid leukemia', Nature Cancer, vol. 2, no. 11, pp. 1204-1223. https://doi.org/10.1038/s43018-021-00264-y

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.

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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 -

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

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