부산대학교 도서관

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. Synopsis: VAV1 encodes a multifunctional signaling protein involved in both RAC1 GTPase activation and adaptor‐like functions. Mutations in this gene have recently been found in PTCL and other tumor types. Here, we have catalogued 51 VAV1 tumor‐associated mutations according to their functional impact on the downstream signaling branches of the protein. Our work has revealed that: The VAV1 gain‐of‐function mutations belong to different subclasses according to impact on VAV1 downstream signaling.These mutations target both expected and hitherto unknown VAV1 regulatory layers.A VAV1 mutation representative of the most frequent functional subclass drives PTCL formation in mice.VAV1‐driven lymphomagenesis requires cooperating signals from the catalytic‐dependent and independent pathways of the mutant protein.The molecular features of VAV1‐driven lymphomas resemble those found in PTCL patients. [ABSTRACT FROM AUTHOR]