Cell Reports
Volume 36, Issue 2, 13 July 2021, 109372
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Inhibition of Rag GTPase signaling in mice suppresses B cell responses and lymphomagenesis with minimal detrimental trade-offs

https://doi.org/10.1016/j.celrep.2021.109372Get rights and content
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Highlights

  • Knockin mice expressing a hypomorphic form of the RagC GTPase (Q119L) are viable

  • RagCQ119L/+ mice show attenuated nutrient signaling-mTORC1 activity

  • Lymphomagenesis and self-reactivity are delayed when induced in RagCQ119L/+ mice

  • Aside from B cells, RagCQ119L/+ mice show minimal defects and a normal lifespan

Summary

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
germinal center
lymphocytes
mTOR
RRAGC
nutrient signaling
cell growth
aging
longevity
Rag GTPase

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