Abstract IA13: Oncogenic Rag GTPase signaling links cellular nutrients with the FL microenvironment

During the humoral response, B cells undergo a sudden anabolic shift that requires high cellular nutrient levels 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 have selected for point, activating mutations in RRAGC, a member of the Rag GTPase family that controls the activation of the mechanistic target of rapamycin complex 1 downstream of the sensing of cellular nutrients. S74C and T89N, two of the most frequent activating single-amino acid changes in RRAGC, when targeted to the endogenous Rragc locus in mice, confer only a partial insensitivity to nutrient deprivation but strongly exacerbate B-cell responses and accelerate lymphomagenesis. Surprisingly, this moderate increase in nutrient signaling affected the interaction of B cells with the cellular microenvironment, synergizing their effects on mTORC1 activation with paracrine cues from the supportive T-cell microenvironment that activate 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. From a therapeutic standpoint, Rragc mutations impose a selective vulnerability to pharmacologic inhibition of mTORC1. 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. While pharmacologic inhibition of mTORC1 with rapamycin yielded exciting preclinical responses in murine lymphomas with activating mutations in Rragc, targeting the nutrient signaling cascade itself, instead of using such allosteric, partial inhibition of mTOR, may constitute a more efficacious intervention. Because nutrient signaling inhibitors are still in development phase, their efficacy and safety remain unproven. Previous genetic approaches to investigate the consequences of inhibition of Rag GTPase signaling relied on deletion of the Rags in mice and led to severe phenotypes and death. Incomplete inhibition of nutrient signaling, an approach that would mirror more closely the effect of small molecules, has not been pursued to support both their efficacy and safety. We have generated knock-in mice endogenously expressing a point-mutant form of RagC (Q119L) that partially suppresses nutrient signaling. RagCQ119L/Q119L mice are not viable, but RagCQ119L/+ mice sh