The humoral immune response requires 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 harbour 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 signalling synergizes 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 centres 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 signalling pathway foster lymphomagenesis by corrupting a nutrient-dependent control over paracrine signals from the T cell microenvironment.
Some follicular B cell lymphomas harbour activating mutations in RRAGC, activator of the nutrient sensor mTORC1. Here the authors show that these mutations confer insensitivity to nutrient deprivation and synergize with paracrine cues from the supportive T cell microenvironment to accelerate lymphomagenesis, but impose vulnerability to inhibition of mTORC1.