The gene behind follicular lymphoma

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

Elisa Oricchio1,*, Natalya Katanayeva1, Maria Christine Donaldson1, Stephanie Sungalee1, Pasion P. Joyce2, Wendy Béguelin3, Elena Battistello1,4, Viraj R. Sanghvi2, Man Jiang2, Yanwen Jiang5, Matt Teater5, Anita Parmigiani6, Andrei V. Budanov6,7, Fong Chun Chan8,9, Sohrab P. Shah10,11, Robert Kridel8,12, Ari M. Melnick3, Giovanni Ciriello4 and Hans-Guido Wendel2

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

Science Translational Medicine  28 Jun 2017:
Vol. 9, Issue 396, eaak9969
DOI: 10.1126/scitranslmed.aak9969

 

Lymphoma’s loss is a therapeutic gain

Follicular lymphoma is a relatively common and difficult-to-treat hematologic malignancy, for which no specific targeted therapy is available. Knowing that deletions of chromosome 6q are common in this tumor type, Oricchio et al. examined the genes on this chromosome and identified SESTRIN1 as a likely tumor suppressor. The authors examined the mechanism by which the loss of SESTRIN1 contributes to tumorigenesis and identified a mechanistic connection between SESTRIN1 and EZH2, an epigenetic modifier that plays a role in multiple cancer types. The authors demonstrated that the effectiveness of targeting EZH2 depends on SESTRIN1 genetic and epigenetic status and also reported that mutations in EZH2 itself can sensitize cancer cells to additional targeted therapies.

 

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.

 

Read the full publication at the Science Translational Medicine journal