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

• DOI: 10.1016/j.celrep.2021.109372
• Publication Date: 2021-07-13T15:09:44Z
• Authors: Ana Ortega-Molina; Cristina Lebrero-...; Alba Sanz; Nerea Deleyto-Seldas; Ana Belén Plata-G...; Camino Menéndez; Osvaldo Graña-Castro; Eduardo Caleiras; Alejo Efeyan
• Keywords: Small GTPase; Cell Signaling

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