Genetic and epigenetic inactivation of SESTRIN1 controls mTORC1 and response to EZH2 inhibition in follicular lymphoma Journal Article
| Authors: | Oricchio, E.; Katanayeva, N.; Donaldson, M. C.; Sungalee, S.; Pasion, J. P.; Béguelin, W.; Battistello, E.; Sanghvi, V. R.; Jiang, M.; Jiang, Y.; Teater, M.; Parmigiani, A.; Budanov, A. V.; Chan, F. C.; Shah, S. P.; Kridel, R.; Melnick, A. M.; Ciriello, G.; Wendel, H. G. |
| Article Title: | Genetic and epigenetic inactivation of SESTRIN1 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 (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. © Copyright 2017 The Authors, some rights reserved. |
| Keywords: | s6 kinase; controlled study; treatment response; unclassified drug; human cell; major clinical study; promoter region; gene deletion; drug efficacy; nonhuman; antineoplastic agent; protein function; animal cell; mouse; animal tissue; gene; gene targeting; apoptosis; tumor volume; animal experiment; animal model; rna interference; in vivo study; antineoplastic activity; enzyme activity; mutational analysis; protein p53; dna methylation; cancer inhibition; homozygosity; messenger rna; epigenetics; cpg island; heterozygosity; gene identification; histone h3; membrane protein; rna translation; gene inactivation; gene silencing; chromosome deletion; genetic screening; protein p21; follicular lymphoma; short hairpin rna; concentration response; chromosome 6q; molecularly targeted therapy; genetic regulation; transcription factor ezh2; antiproliferative activity; mammalian target of rapamycin complex 1; gain of function mutation; human; priority journal; article; gsk 126; sestrin1 protein; sestrin2 protein; rragc gene; sestrin1 gene; sestrin2 gene |
| Journal Title: | Science Translational Medicine |
| Volume: | 9 |
| Issue: | 396 |
| ISSN: | 1946-6234 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2017-06-28 |
| Start Page: | eaak9969 |
| Language: | English |
| DOI: | 10.1126/scitranslmed.aak9969 |
| PROVIDER: | scopus |
| PUBMED: | 28659443 |
| PMCID: | PMC5559734 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 August 2017 -- Source: Scopus |
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