Cancer-associated mutations in VAV1 trigger variegated signaling outputs and T-cell lymphomagenesis
[EN]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 c...
| Autores: | , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2021 |
| País: | España |
| Institución: | Universidad de Salamanca (USAL) |
| Repositorio: | GREDOS. Repositorio Institucional de la Universidad de Salamanca |
| OAI Identifier: | oai:gredos.usal.es:10366/168546 |
| Acceso en línea: | http://hdl.handle.net/10366/168546 |
| Access Level: | acceso abierto |
| Palabra clave: | Angioimmunoblastic T-cell lymphoma Follicular helper T cells Oncogene Peripheral T-cell lymphoma Tumor suppressor GTPases Lymphoma Animals Humans CD4-Positive T-Lymphocytes rac1 GTP-Binding Protein Cell Proliferation COS Cells 3201.01 Oncología linfoma linfocitos T CD4-positivos animales humanos proteína de unión al GTP rac1 proliferación celular células COS |
| Sumario: | [EN]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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