Oncogenic Rag GTPase signaling enhances B cell activation and drives follicular lymphoma sensitive to pharmacological inhibition of mTOR.
dc.contributor.author | Ortega-Molina, A | en_US |
dc.contributor.author | Deleyto-Seldas, N | en_US |
dc.contributor.author | Carreras, J | en_US |
dc.contributor.author | Sanz, A | en_US |
dc.contributor.author | Lebrero-Fernández, C | en_US |
dc.contributor.author | Menéndez, C | en_US |
dc.contributor.author | Vandenberg, A | en_US |
dc.contributor.author | Fernández-Ruiz, B | en_US |
dc.contributor.author | Marín-Arraiza, L | en_US |
dc.contributor.author | de la Calle Arregui, C | en_US |
dc.contributor.author | Belén Plata-Gómez, A | en_US |
dc.contributor.author | Caleiras, E | en_US |
dc.contributor.author | de Martino, A | en_US |
dc.contributor.author | Martínez-Martín, N | en_US |
dc.contributor.author | Troulé, K | en_US |
dc.contributor.author | Piñeiro-Yáñez, E | en_US |
dc.contributor.author | Nakamura, N | en_US |
dc.contributor.author | Araf, S | en_US |
dc.contributor.author | Victora, GD | en_US |
dc.contributor.author | Okosun, J | en_US |
dc.contributor.author | Fitzgibbon, J | en_US |
dc.contributor.author | Efeyan, A | en_US |
dc.date.accessioned | 2019-12-16T09:54:42Z | |
dc.date.issued | 2019-08 | en_US |
dc.identifier.uri | https://qmro.qmul.ac.uk/xmlui/handle/123456789/61999 | |
dc.description.abstract | 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 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 signaling synergizes with paracrine cues from the supportive T cell microenvironment that activates 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. 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. | en_US |
dc.format.extent | 775 - 789 | en_US |
dc.language | eng | en_US |
dc.language.iso | en | en_US |
dc.relation.ispartof | Nat Metab | en_US |
dc.subject | B cell lymphoma | en_US |
dc.subject | B lymphocytes | en_US |
dc.subject | RRAGC | en_US |
dc.subject | T follicular helper | en_US |
dc.subject | apoptosis | en_US |
dc.subject | cell growth | en_US |
dc.subject | germinal center | en_US |
dc.subject | mTOR | en_US |
dc.subject | nutrient signaling | en_US |
dc.subject | rapamycin | en_US |
dc.title | Oncogenic Rag GTPase signaling enhances B cell activation and drives follicular lymphoma sensitive to pharmacological inhibition of mTOR. | en_US |
dc.type | Article | |
dc.identifier.doi | 10.1038/s42255-019-0098-8 | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/31579886 | en_US |
pubs.issue | 8 | en_US |
pubs.notes | Not known | en_US |
pubs.publication-status | Published | en_US |
pubs.volume | 1 | en_US |
rioxxterms.funder | Default funder | en_US |
rioxxterms.identifier.project | Default project | en_US |