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Leukemia. 2017 Nov;31(11):2326-2335. doi: 10.1038/leu.2017.81. Epub 2017 Mar 10.

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

Poulain L1,2,3,4, Sujobert P1,2,3,4, Zylbersztejn F5,6, Barreau S1,2,3,4, Stuani L7,8, Lambert M1,2,3,4, Palama TL8,9, Chesnais V1,2,3,4, Birsen R1,2,3,4, Vergez F7,8, Farge T7,8, Chenevier-Gobeaux C10, Fraisse M7,8, Bouillaud F1,2,3, Debeissat C11, Herault O11, Récher C7,8, Lacombe C1,2,3,4, Fontenay M1,2,3,4,12, Mayeux P1,2,3,4, Maciel TT5,6, Portais JC8,9, Sarry JE7,8, Tamburini J1,2,3,4,13, Bouscary D1,2,3,4,13, Chapuis N1,2,3,4,13.

Author information

1
INSERM U1016, Institut Cochin, Paris, France.
2
CNRS UMR8104, Paris, France.
3
Faculté de Médecine Sorbonne Paris Cité, Université Paris Descartes, Paris, France.
4
Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC), Paris, France.
5
INSERM UMR1163, Laboratory of Cellular and Molecular Mechanisms of Haematological Disorders and Therapeutic Implications, Paris, France.
6
Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
7
INSERM, UMR1037, Cancer Research Center of Toulouse, Toulouse, France.
8
Université de Toulouse III Paul Sabatier, INSA, UPS, INP, LISBP, Toulouse, France.
9
LISBP, Université de Toulouse, CNRS, INRA, INSA, Toulouse, France.
10
Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre, Service de Diagnostic Biologique Automatisé, Paris, France.
11
CNRS UMR7292, Tours, France.
12
Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre, Service d'Hématologie biologique, F-75014 Paris, France.
13
Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre, Service d'Hématologie clinique, F-75014 Paris, France.

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.

PMID:
28280275
DOI:
10.1038/leu.2017.81
[Indexed for MEDLINE]

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