TitleGenetic and epigenetic inactivation of controls mTORC1 and response to EZH2 inhibition in follicular lymphoma.
Publication TypeJournal Article
Year of Publication2017
AuthorsOricchio, Elisa, Katanayeva Natalya, Donaldson Maria Christine, Sungalee Stephanie, Pasion Joyce P., B├ęguelin Wendy, Battistello Elena, Sanghvi Viraj R., Jiang Man, Jiang Yanwen, Teater Matt, Parmigiani Anita, Budanov Andrei V., Chan Fong Chun, Shah Sohrab P., Kridel Robert, Melnick Ari M., Ciriello Giovanni, and Wendel Hans-Guido
JournalSci Transl Med
Volume9
Issue396
Date Published2017 Jun 28
ISSN1946-6242
KeywordsAnimals, Chromosome Deletion, Chromosomes, Human, Pair 6, Enhancer of Zeste Homolog 2 Protein, Epigenesis, Genetic, Gene Silencing, Genetic Testing, Genome, Human, Heat-Shock Proteins, Humans, Lymphoma, Follicular, Mechanistic Target of Rapamycin Complex 1, Mice, Mutation, Protein Biosynthesis, RNA, Messenger
Abstract

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

DOI10.1126/scitranslmed.aak9969
Alternate JournalSci Transl Med
PubMed ID28659443
PubMed Central IDPMC5559734
Grant ListR01 CA190384 / CA / NCI NIH HHS / United States
R01 CA187109 / CA / NCI NIH HHS / United States
159637 / SNSF_ / Swiss National Science Foundation / Switzerland
P30 CA008748 / CA / NCI NIH HHS / United States
R01 CA207217 / CA / NCI NIH HHS / United States
R01 CA172660 / CA / NCI NIH HHS / United States
R01 CA183876 / CA / NCI NIH HHS / United States
P50 CA192937 / CA / NCI NIH HHS / United States