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Acute myeloid leukemia

High mTORC1 activity drives glycolysis addiction and sensitivity to G6PD inhibition in acute myeloid leukemia cells

Leukemia volume 31, pages 2326–2335 (2017)Cite this article

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Abstract

Alterations in metabolic activities are cancer hallmarks that offer a wide range of new therapeutic opportunities. Here we decipher the interplay between mTORC1 activity and glucose metabolism in acute myeloid leukemia (AML). We show that mTORC1 signaling that is constantly overactivated in AML cells promotes glycolysis and leads to glucose addiction. The level of mTORC1 activity determines the sensitivity of AML cells to glycolysis inhibition as switch-off mTORC1 activity leads to glucose-independent cell survival that is sustained by an increase in mitochondrial oxidative phosphorylation. Metabolic analysis identified the pentose phosphate pathway (PPP) as an important pro-survival pathway for glucose metabolism in AML cells with high mTORC1 activity and provided a clear rational for targeting glucose-6-phosphate dehydrogenase (G6PD) in AML. Indeed, our analysis of the cancer genome atlas AML database pinpointed G6PD as a new biomarker in AML, as its overexpression correlated with an adverse prognosis in this cohort. Targeting the PPP using the G6PD inhibitor 6-aminonicotinamide induces in vitro and in vivo cytotoxicity against AML cells and synergistically sensitizes leukemic cells to chemotherapy. Our results demonstrate that high mTORC1 activity creates a specific vulnerability to G6PD inhibition that may work as a new AML therapy.

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Acknowledgements

This work was supported by grant from the Institut National du Cancer (Projet Recherche Translationnelle TRANSLA13-087), Ligue Nationale Contre le Cancer (Equipe Labellisée EL2014. No Projet: R14077KK), Plan Cancer BioSys 2014 (Project FLEXAML; J-CP and J-ES), INCa-Cancéropôle GSO (TLP) and from Région Midi-Pyrénées 2014 (Project CRLE; J-CP and J-ES). MetaToul (Metabolomics & Fluxomics Facitilies, Toulouse, France, http://file:///D:/preeditjobs/npg/leu/leu201781/www.metatoul.fr) is gratefully acknowledged for carrying out metabolome analysis. MetaToul is part of the national infrastructure MetaboHUB-ANR-11-INBS-0010 (The 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 Sante et Agronomie (IBiSa, France), the Centre National de la Recherche Scientifique (CNRS) and the Institut National de la Recherche Agronomique (INRA). We thank Dr Olivier Kosmider (Service d’Hématologie Biologique, Hôpital Cochin, Paris) for genotyping AML samples.

Author contributions

LP designed and performed the experiments, analyzed the data and wrote the manuscript; PS designed the experiments, analyzed the data and wrote the manuscript; SB, LS, ML, RB, CG, CD and MF performed experiments; TLP and J-CP performed glucose flux experiments and analyzed the data; FZ and TTM performed in vivo experiments; VC, FV and TF performed bioinformatics analyses. OH, CR, J-ES, FB, PM and MFo analyzed the data; CL and JT analyzed the data and wrote the manuscript, NC and DB designed and supervised the research program, analyzed the data and wrote the manuscript; and all authors approved the final version of the manuscript.

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Author notes

  1. D Bouscary and N Chapuis: These authors contributed equally to this work.

Authors and Affiliations

  1. INSERM U1016, Institut Cochin, Paris, France

    L Poulain, P Sujobert, S Barreau, M Lambert, V Chesnais, R Birsen, F Bouillaud, C Lacombe, M Fontenay, P Mayeux, J Tamburini, D Bouscary & N Chapuis

  2. CNRS UMR8104, Paris, France

    L Poulain, P Sujobert, S Barreau, M Lambert, V Chesnais, R Birsen, F Bouillaud, C Lacombe, M Fontenay, P Mayeux, J Tamburini, D Bouscary & N Chapuis

  3. Faculté de Médecine Sorbonne Paris Cité, Université Paris Descartes, Paris, France

    L Poulain, P Sujobert, S Barreau, M Lambert, V Chesnais, R Birsen, F Bouillaud, C Lacombe, M Fontenay, P Mayeux, J Tamburini, D Bouscary & N Chapuis

  4. Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC), Paris, France

    L Poulain, P Sujobert, S Barreau, M Lambert, V Chesnais, R Birsen, C Lacombe, M Fontenay, P Mayeux, J Tamburini, D Bouscary & N Chapuis

  5. INSERM UMR1163, Laboratory of Cellular and Molecular Mechanisms of Haematological Disorders and Therapeutic Implications, Paris, France

    F Zylbersztejn & T T Maciel

  6. Paris Descartes–Sorbonne Paris Cité University, Imagine Institute, Paris, France

    F Zylbersztejn & T T Maciel

  7. INSERM, UMR1037, Cancer Research Center of Toulouse, Toulouse, France

    L Stuani, F Vergez, T Farge, M Fraisse, C Récher & J-E Sarry

  8. Université de Toulouse III Paul Sabatier, INSA, UPS, INP, LISBP, Toulouse, France

    L Stuani, T L Palama, F Vergez, T Farge, M Fraisse, C Récher, J-C Portais & J-E Sarry

  9. LISBP, Université de Toulouse, CNRS, INRA, INSA, Toulouse, France

    T L Palama & J-C Portais

  10. Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre, Service de Diagnostic Biologique Automatisé, Paris, France

    C Chenevier-Gobeaux

  11. CNRS UMR7292, Tours, France

    C Debeissat & O Herault

  12. Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre, Service d'Hématologie biologique, F-75014 Paris, France

    M Fontenay

  13. Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre, Service d'Hématologie clinique, F-75014 Paris, France

    J Tamburini, D Bouscary & N Chapuis

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  1. L Poulain
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  2. P Sujobert
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Correspondence to D Bouscary or N Chapuis.

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Poulain, L., Sujobert, P., Zylbersztejn, F. et al. High mTORC1 activity drives glycolysis addiction and sensitivity to G6PD inhibition in acute myeloid leukemia cells. Leukemia 31, 2326–2335 (2017). https://doi.org/10.1038/leu.2017.81

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