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Sci Transl Med. 2017 Jun 28;9(396). pii: eaak9969. doi: 10.1126/scitranslmed.aak9969.

Genetic and epigenetic inactivation of SESTRIN1 controls mTORC1 and response to EZH2 inhibition in follicular lymphoma.

Author information

1
Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland. elisa.oricchio@epfl.ch.
2
Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
3
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
4
Division of Hematology/Oncology, Weill Cornell Medical College, Cornell University, 1300 York Avenue, New York, NY 10065, USA.
5
Department of Computational Biology, University of Lausanne, 1005 Lausanne, Switzerland.
6
Institute for Computational Biomedicine, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.
7
Department of Human and Molecular Genetics, Goodwin Research Laboratories, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
8
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Pearse Street, Dublin 2, Ireland.
9
Centre for Lymphoid Cancer, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
10
Bioinformatics Graduate Program, University of British Columbia, Vancouver, British Columbia, Canada.
11
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
12
Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada.
13
Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

Abstract

Follicular lymphoma (FL) is an incurable form of B cell lymphoma. Genomic studies have cataloged common genetic lesions in FL such as translocation t(14;18), frequent losses of chromosome 6q, and mutations in epigenetic regulators such as EZH2 Using a focused genetic screen, we identified SESTRIN1 as a relevant target of the 6q deletion and demonstrate tumor suppression by SESTRIN1 in vivo. Moreover, SESTRIN1 is a direct target of the lymphoma-specific EZH2 gain-of-function mutation (EZH2Y641X ). SESTRIN1 inactivation disrupts p53-mediated control of mammalian target of rapamycin complex 1 (mTORC1) and enables mRNA translation under genotoxic stress. SESTRIN1 loss represents an alternative to RRAGC mutations that maintain mTORC1 activity under nutrient starvation. The antitumor efficacy of pharmacological EZH2 inhibition depends on SESTRIN1, indicating that mTORC1 control is a critical function of EZH2 in lymphoma. Conversely, EZH2Y641X mutant lymphomas show increased sensitivity to RapaLink-1, a bifunctional mTOR inhibitor. Hence, SESTRIN1 contributes to the genetic and epigenetic control of mTORC1 in lymphoma and influences responses to targeted therapies.

PMID:
28659443
PMCID:
PMC5559734
DOI:
10.1126/scitranslmed.aak9969
[Indexed for MEDLINE]
Free PMC Article

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