Cell Reports (Jun 2015)
Co-activation of AMPK and mTORC1 Induces Cytotoxicity in Acute Myeloid Leukemia
- Pierre Sujobert,
- Laury Poulain,
- Etienne Paubelle,
- Florence Zylbersztejn,
- Adrien Grenier,
- Mireille Lambert,
- Elizabeth C. Townsend,
- Jean-Marie Brusq,
- Edwige Nicodeme,
- Justine Decrooqc,
- Ina Nepstad,
- Alexa S. Green,
- Johanna Mondesir,
- Marie-Anne Hospital,
- Nathalie Jacque,
- Alexandra Christodoulou,
- Tiffany A. Desouza,
- Olivier Hermine,
- Marc Foretz,
- Benoit Viollet,
- Catherine Lacombe,
- Patrick Mayeux,
- David M. Weinstock,
- Ivan C. Moura,
- Didier Bouscary,
- Jerome Tamburini
Affiliations
- Pierre Sujobert
- INSERM U1016, Institut Cochin, 75014 Paris, France
- Laury Poulain
- INSERM U1016, Institut Cochin, 75014 Paris, France
- Etienne Paubelle
- INSERM UMR 1163, Laboratory of cellular and molecular mechanisms of hematological disorders and therapeutic implications, 75015 Paris, France
- Florence Zylbersztejn
- INSERM UMR 1163, Laboratory of cellular and molecular mechanisms of hematological disorders and therapeutic implications, 75015 Paris, France
- Adrien Grenier
- INSERM U1016, Institut Cochin, 75014 Paris, France
- Mireille Lambert
- INSERM U1016, Institut Cochin, 75014 Paris, France
- Elizabeth C. Townsend
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA
- Jean-Marie Brusq
- GlaxoSmithKline Research Center, 91490 Les Ulis, France
- Edwige Nicodeme
- GlaxoSmithKline Research Center, 91490 Les Ulis, France
- Justine Decrooqc
- INSERM UMR 1163, Laboratory of cellular and molecular mechanisms of hematological disorders and therapeutic implications, 75015 Paris, France
- Ina Nepstad
- Division for Hematology, Department of Medicine, Haukeland University Hospital, N-5021 Bergen, Norway
- Alexa S. Green
- INSERM U1016, Institut Cochin, 75014 Paris, France
- Johanna Mondesir
- INSERM U1016, Institut Cochin, 75014 Paris, France
- Marie-Anne Hospital
- INSERM U1016, Institut Cochin, 75014 Paris, France
- Nathalie Jacque
- INSERM U1016, Institut Cochin, 75014 Paris, France
- Alexandra Christodoulou
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA
- Tiffany A. Desouza
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA
- Olivier Hermine
- INSERM UMR 1163, Laboratory of cellular and molecular mechanisms of hematological disorders and therapeutic implications, 75015 Paris, France
- Marc Foretz
- INSERM U1016, Institut Cochin, 75014 Paris, France
- Benoit Viollet
- INSERM U1016, Institut Cochin, 75014 Paris, France
- Catherine Lacombe
- INSERM U1016, Institut Cochin, 75014 Paris, France
- Patrick Mayeux
- INSERM U1016, Institut Cochin, 75014 Paris, France
- David M. Weinstock
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA
- Ivan C. Moura
- INSERM UMR 1163, Laboratory of cellular and molecular mechanisms of hematological disorders and therapeutic implications, 75015 Paris, France
- Didier Bouscary
- INSERM U1016, Institut Cochin, 75014 Paris, France
- Jerome Tamburini
- INSERM U1016, Institut Cochin, 75014 Paris, France
- DOI
- https://doi.org/10.1016/j.celrep.2015.04.063
- Journal volume & issue
-
Vol. 11,
no. 9
pp. 1446 – 1457
Abstract
AMPK is a master regulator of cellular metabolism that exerts either oncogenic or tumor suppressor activity depending on context. Here, we report that the specific AMPK agonist GSK621 selectively kills acute myeloid leukemia (AML) cells but spares normal hematopoietic progenitors. This differential sensitivity results from a unique synthetic lethal interaction involving concurrent activation of AMPK and mTORC1. Strikingly, the lethality of GSK621 in primary AML cells and AML cell lines is abrogated by chemical or genetic ablation of mTORC1 signaling. The same synthetic lethality between AMPK and mTORC1 activation is established in CD34-positive hematopoietic progenitors by constitutive activation of AKT or enhanced in AML cells by deletion of TSC2. Finally, cytotoxicity in AML cells from GSK621 involves the eIF2α/ATF4 signaling pathway that specifically results from mTORC1 activation. AMPK activation may represent a therapeutic opportunity in mTORC1-overactivated cancers.
