期刊
EMBO JOURNAL
卷 40, 期 22, 页码 -出版社
WILEY
DOI: 10.15252/embj.2021108125
关键词
angioimmunoblastic T-cell lymphoma; follicular helper T cells; oncogene; peripheral T-cell lymphoma; tumor suppressor
资金
- la Caixa Banking Foundation [HR20-00164]
- Castilla-Leon autonomous government [CSI252P18, CSI145P20, CLC-2017-01]
- Spanish Ministry of Science and Innovation (MSI) [RTI2018-096481-B-100]
- Spanish Association against Cancer [GC16173472GARC]
- Carlos III Health Institute [PI20/01724]
- Programa de Apoyo a Planes Estrategicos de Investigacion de Estructuras de Investigacion de Excelencia of the Castilla-Leon autonomous government [CLC-2017-01]
- Spanish Association against Cancer
- Salamanca local section of the Spanish Association against Cancer
- MSI [BES-2013-063573]
- Spanish Ministry of Education,Culture and Sports [FPU13/02923]
- European Regional Development Fund
Mutations in the VAV1 gene can be classified into five subtypes based on their functional impact on the three main signaling branches, leading to changes in VAV1 signaling output and potential therapeutic vulnerabilities. The most frequent VAV1 mutant subtype drives PTCL formation by engaging downstream signaling branches to promote chronic activation and transformation of follicular helper T cells.
Mutations in VAV1, a gene that encodes a multifunctional protein important for lymphocytes, are found at different frequencies in peripheral T-cell lymphoma (PTCL), non-small cell lung cancer, and other tumors. However, their pathobiological significance remains unsettled. After cataloguing 51 cancer-associated VAV1 mutations, we show here that they can be classified in five subtypes according to functional impact on the three main VAV1 signaling branches, GEF-dependent activation of RAC1, GEF-independent adaptor-like, and tumor suppressor functions. These mutations target new and previously established regulatory layers of the protein, leading to quantitative and qualitative changes in VAV1 signaling output. We also demonstrate that the most frequent VAV1 mutant subtype drives PTCL formation in mice. This process requires the concurrent engagement of two downstream signaling branches that promote the chronic activation and transformation of follicular helper T cells. Collectively, these data reveal the genetic constraints associated with the lymphomagenic potential of VAV1 mutant subsets, similarities with other PTCL driver genes, and potential therapeutic vulnerabilities.
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