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 <i>EZH2</i> Using a focused genetic screen, we identified <i>SESTRIN1</i> as a relevant target of the 6q deletion and demonstrate tumor suppression by <i>SESTRIN1</i> in vivo. Moreover, <i>SESTRIN1</i> is a direct target of the lymphoma-specific <i>EZH2</i> gain-of-function mutation (<i>EZH2</i>^<i>Y641X</i> ). <i>SESTRIN1</i> inactivation disrupts p53-mediated control of mammalian target of rapamycin complex 1 (mTORC1) and enables mRNA translation under genotoxic stress. <i>SESTRIN1</i> loss represents an alternative to <i>RRAGC</i> 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, <i>EZH2</i>^<i>Y641X</i> 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.