Inhibition of Rag GTPase signaling in mice suppresses B cell responses and lymphomagenesis with minimal detrimental trade-offs

Cell Rep. 2021 Jul 13;36(2):109372. doi: 10.1016/j.celrep.2021.109372.


B lymphocytes are exquisitely sensitive to fluctuations in nutrient signaling by the Rag GTPases, and 15% of follicular lymphomas (FLs) harbor activating mutations in RRAGC. Hence, a potential therapeutic approach against malignant B cells is to inhibit Rag GTPase signaling, but because such inhibitors are still to be developed, efficacy and safety remain unknown. We generated knockin mice expressing a hypomorphic variant of RagC (Q119L); RagCQ119L/+ mice are viable and show attenuated nutrient signaling. B lymphocyte activation is cell-intrinsically impaired in RagCQ119L/+ mice, which also show significant suppression of genetically induced lymphomagenesis and autoimmunity. Surprisingly, no overt systemic trade-offs or phenotypic alterations caused by partial suppression of nutrient signaling are seen in other organs, and RagCQ119L/+ mice show normal longevity and normal age-dependent health decline. These results support the efficacy and safety of moderate inhibition of nutrient signaling against pathological B cells.

Keywords: B cell lymphoma; RRAGC; Rag GTPase; aging; cell growth; germinal center; longevity; lymphocytes; mTOR; nutrient signaling.

Publication types

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

MeSH terms

  • Animals
  • B-Lymphocytes / immunology*
  • Carcinogenesis / immunology*
  • Carcinogenesis / pathology*
  • Female
  • Gene Knock-In Techniques
  • Heterozygote
  • Immunity, Humoral
  • Longevity
  • Lymphoma / immunology*
  • Lymphoma / pathology*
  • Male
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice, Mutant Strains
  • Monomeric GTP-Binding Proteins / metabolism*
  • Mutation / genetics
  • Signal Transduction*


  • Mechanistic Target of Rapamycin Complex 1
  • Monomeric GTP-Binding Proteins