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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • GTP Phosphohydrolases / metabolism*
  • Humans
  • Lymphocyte Activation*
  • Lymphoma, Follicular / drug therapy*
  • Lymphoma, Follicular / pathology
  • Mice
  • Mice, Transgenic
  • Signal Transduction*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*


  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • GTP Phosphohydrolases