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

Elisa Oricchio, Natalya Katanayeva, Maria Christine Donaldson, Stephanie Sungalee, Pasion P. Joyce, Wendy Béguelin, Elena Battistello, Viraj R. Sanghvi, Man Jiang, Yanwen Jiang, Matt Teater, Anita Parmigiani, Andrei V. Budanov, Fong Chun Chan, Sohrab P. Shah, Robert Kridel, Ari M. Melnick, Giovanni Ciriello, Hans Guido Wendel

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

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.

Original languageEnglish (US)
Article numbereaak9969
JournalScience Translational Medicine
Volume9
Issue number396
DOIs
StatePublished - Jun 28 2017
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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