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oai:repisalud.isciii.es:20.500.12105/262242025-12-18T12:54:36Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Ortega-Molina, Ana author Deleyto-Seldas, Nerea author Carreras, Joaquim author Sanz, Alba author Lebrero-Fernández, Cristina author Menéndez, Camino author Vandenberg, Andrew author Fernández-Ruiz, Beatriz author Marín-Arraiza, Leyre author de la Calle Arregui, Celia author Belén Plata-Gómez, Ana author Caleiras, Eduardo author de Martino, Alba author Martínez-Martín, Nuria author Troulé, Kevin author Piñeiro-Yáñez, Elena author Nakamura, Naoya author Araf, Shamzah author Victora, Gabriel D author Okosun, Jessica author Fitzgibbon, Jude author Efeyan, Alejo author 2019-08 The humoral immune response demands 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 harbor point, activating mutations in , an essential activator of mTORC1 downstream of the sensing of cellular nutrients. The impact of recurrent mutations in B cell function and lymphoma is unexplored. 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 signaling synergizes with paracrine cues from the supportive T cell microenvironment that activates B cells via the PI3K-Akt-mTORC1 axis. Hence, mutations sustain induced germinal centers 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 signaling pathway foster lymphomagenesis by corrupting a nutrient-dependent control over paracrine signals from the T cell microenvironment. Nat Metab . 2019 Aug;1(8):775-789. Nat Metab https://pmc.ncbi.nlm.nih.gov/articles/PMC6774795/pdf/EMS84435.pdf 31579886 https://hdl.handle.net/20.500.12105/26224 B cell lymphoma B lymphocytes RRAGC T follicular helper apoptosis cell growth germinal center mTOR nutrient signaling rapamycin Oncogenic Rag GTPase signaling enhances B cell activation and drives follicular lymphoma sensitive to pharmacological inhibition of mTOR.