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

Details

Serval ID
serval:BIB_6C1BB5F656C6
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Genetic and epigenetic inactivation of SESTRIN1 controls mTORC1 and response to EZH2 inhibition in follicular lymphoma.
Journal
Science translational medicine
Author(s)
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.
ISSN
1946-6242 (Electronic)
ISSN-L
1946-6234
Publication state
Published
Issued date
28/06/2017
Peer-reviewed
Oui
Volume
9
Number
396
Pages
1-10
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
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 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.

Keywords
Animals, Chromosome Deletion, Chromosomes, Human, Pair 6/genetics, Enhancer of Zeste Homolog 2 Protein/antagonists & inhibitors, Enhancer of Zeste Homolog 2 Protein/metabolism, Epigenesis, Genetic, Gene Silencing, Genetic Testing, Genome, Human, Heat-Shock Proteins/deficiency, Heat-Shock Proteins/genetics, Humans, Lymphoma, Follicular/genetics, Mechanistic Target of Rapamycin Complex 1/metabolism, Mice, Mutation/genetics, Protein Biosynthesis, RNA, Messenger/genetics, RNA, Messenger/metabolism
Pubmed
Web of science
Open Access
Yes
Create date
28/07/2017 13:51
Last modification date
21/08/2019 5:34
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