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

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 (EZH2^Y641X ). 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 t

SUBMITTER: Oricchio E 

PROVIDER: S-EPMC5559734 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature