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Nat Metab. 2019 Aug;1(8):775-789. doi: 10.1038/s42255-019-0098-8. Epub 2019 Aug 19.

Oncogenic Rag GTPase signaling enhances B cell activation and drives follicular lymphoma sensitive to pharmacological inhibition of mTOR.

Author information

1
Metabolism and Cell Signaling Laboratory. Spanish National Cancer Research Center (CNIO). Madrid, Spain.
2
Tokai University, School of Medicine, Department of Pathology. Isehara, Kanagawa, Japan.
3
Histopathology Unit. Spanish National Cancer Research Center (CNIO). Madrid, Spain.
4
Centro de Biología Molecular Severo Ochoa, Madrid, Spain.
5
Bioinformatics Unit. Spanish National Cancer Research Center (CNIO). Madrid, Spain.
6
Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
7
Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY.

Abstract

The humoral immune response demands that B cells undergo a sudden anabolic shift and high cellular nutrient levels which are required to sustain the subsequent proliferative burst. Follicular lymphoma (FL) originates from B cells that have participated in the humoral response, and 15% of FL samples harbor point, activating mutations in RRAGC, an essential activator of mTORC1 downstream of the sensing of cellular nutrients. The impact of recurrent RRAGC mutations in B cell function and lymphoma is unexplored. RRAGC mutations, targeted to the endogenous locus in mice, confer a partial insensitivity to nutrient deprivation, but strongly exacerbate B cell responses and accelerate lymphomagenesis, while creating a selective vulnerability to pharmacological inhibition of mTORC1. This moderate increase in nutrient signaling synergizes with paracrine cues from the supportive T cell microenvironment that activates B cells via the PI3K-Akt-mTORC1 axis. Hence, Rragc mutations sustain induced germinal centers and murine and human FL in the presence of decreased T cell help. Our results support a model in which activating mutations in the nutrient signaling pathway foster lymphomagenesis by corrupting a nutrient-dependent control over paracrine signals from the T cell microenvironment.

KEYWORDS:

B cell lymphoma; B lymphocytes; RRAGC; T follicular helper; apoptosis; cell growth; germinal center; mTOR; nutrient signaling; rapamycin

PMID:
31579886
PMCID:
PMC6774795
[Available on 2020-02-01]
DOI:
10.1038/s42255-019-0098-8

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