Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma

Follicular lymphoma is an incurable B cell malignancy characterized by the t(14;18) translocation and mutations affecting the epigenome. Although frequent gene mutations in key signaling pathways, including JAK-STAT, NOTCH and NF-κB, have also been defined, the spectrum of these mutations typically...

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Main Authors: Sabatini, David, Wolfson, Rachel Laura, Efeyan, Alejo
Other Authors: Massachusetts Institute of Technology. Department of Biology
Format: Article
Language:en_US
Published: Nature Publishing Group 2017
Online Access:http://hdl.handle.net/1721.1/106517
https://orcid.org/0000-0002-1446-7256
https://orcid.org/0000-0002-9535-7664
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author Sabatini, David
Wolfson, Rachel Laura
Efeyan, Alejo
author2 Massachusetts Institute of Technology. Department of Biology
author_facet Massachusetts Institute of Technology. Department of Biology
Sabatini, David
Wolfson, Rachel Laura
Efeyan, Alejo
author_sort Sabatini, David
collection MIT
description Follicular lymphoma is an incurable B cell malignancy characterized by the t(14;18) translocation and mutations affecting the epigenome. Although frequent gene mutations in key signaling pathways, including JAK-STAT, NOTCH and NF-κB, have also been defined, the spectrum of these mutations typically overlaps with that in the closely related diffuse large B cell lymphoma (DLBCL). Using a combination of discovery exome and extended targeted sequencing, we identified recurrent somatic mutations in RRAGC uniquely enriched in patients with follicular lymphoma (17%). More than half of the mutations preferentially co-occurred with mutations in ATP6V1B2 and ATP6AP1, which encode components of the vacuolar H+-ATP ATPase (V-ATPase) known to be necessary for amino acid−induced activation of mTORC1. The RagC variants increased raptor binding while rendering mTORC1 signaling resistant to amino acid deprivation. The activating nature of the RRAGC mutations, their existence in the dominant clone and their stability during disease progression support their potential as an excellent candidate for therapeutic targeting.
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spelling mit-1721.1/1065172022-10-01T20:01:11Z Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma Sabatini, David Wolfson, Rachel Laura Efeyan, Alejo Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Koch Institute for Integrative Cancer Research at MIT Sabatini, David Wolfson, Rachel Laura Efeyan, Alejo Follicular lymphoma is an incurable B cell malignancy characterized by the t(14;18) translocation and mutations affecting the epigenome. Although frequent gene mutations in key signaling pathways, including JAK-STAT, NOTCH and NF-κB, have also been defined, the spectrum of these mutations typically overlaps with that in the closely related diffuse large B cell lymphoma (DLBCL). Using a combination of discovery exome and extended targeted sequencing, we identified recurrent somatic mutations in RRAGC uniquely enriched in patients with follicular lymphoma (17%). More than half of the mutations preferentially co-occurred with mutations in ATP6V1B2 and ATP6AP1, which encode components of the vacuolar H+-ATP ATPase (V-ATPase) known to be necessary for amino acid−induced activation of mTORC1. The RagC variants increased raptor binding while rendering mTORC1 signaling resistant to amino acid deprivation. The activating nature of the RRAGC mutations, their existence in the dominant clone and their stability during disease progression support their potential as an excellent candidate for therapeutic targeting. Experimental Cancer Medicine Centres 2017-01-17T21:22:37Z 2017-01-17T21:22:37Z 2015-12 2015-10 Article http://purl.org/eprint/type/JournalArticle 1061-4036 1546-1718 http://hdl.handle.net/1721.1/106517 Okosun, Jessica et al. “Recurrent mTORC1-Activating RRAGC Mutations in Follicular Lymphoma.” Nature Genetics 48.2 (2015): 183–188. https://orcid.org/0000-0002-1446-7256 https://orcid.org/0000-0002-9535-7664 en_US http://dx.doi.org/10.1038/ng.3473 Nature Genetics Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Nature Publishing Group PMC
spellingShingle Sabatini, David
Wolfson, Rachel Laura
Efeyan, Alejo
Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma
title Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma
title_full Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma
title_fullStr Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma
title_full_unstemmed Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma
title_short Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma
title_sort recurrent mtorc1 activating rragc mutations in follicular lymphoma
url http://hdl.handle.net/1721.1/106517
https://orcid.org/0000-0002-1446-7256
https://orcid.org/0000-0002-9535-7664
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