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 javax.xml.bind.JAXBElement@4375628f Using a focused genetic screen, we identified javax.xml.bind.JAXBElement@76a4bdfb as a relevant target of the 6q deletion and demonstrate tumor suppression by javax.xml.bind.JAXBElement@26a2409a in vivo. Moreover, javax.xml.bind.JAXBElement@3203074e is a direct target of the lymphoma-specific javax.xml.bind.JAXBElement@5a0a6a9b gain-of-function mutation ( javax.xml.bind.JAXBElement@9925f44 javax.xml.bind.JAXBElement@3d00687c ). javax.xml.bind.JAXBElement@179321e5 inactivation disrupts p53-mediated control of mammalian target of rapamycin complex 1 (mTORC1) and enables mRNA translation under genotoxic stress. javax.xml.bind.JAXBElement@1e44df3e loss represents an alternative to javax.xml.bind.JAXBElement@5b7cbcd 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, javax.xml.bind.JAXBElement@3bca108f javax.xml.bind.JAXBElement@3558921a 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.