Send to

Choose Destination
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

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


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.


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

[Available on 2020-02-01]

Supplemental Content

Loading ...
Support Center