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.

中文翻译：

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VAV1 中与癌症相关的突变触发多样化的信号输出和 T 细胞淋巴瘤发生

在外周 T 细胞淋巴瘤 (PTCL)、非小细胞肺癌和其他肿瘤中发现VAV1突变，这是一种编码对淋巴细胞重要的多功能蛋白的基因。然而，它们的病理生物学意义仍未确定。在对 51 个与癌症相关的VAV1突变进行编目后，我们在这里表明，它们可以根据对三个主要 VAV1 信号分支的功能影响、RAC1 的 GEF 依赖性激活、GEF 非依赖性适配器样和肿瘤抑制功能分为五个亚型. 这些突变针对蛋白质的新的和以前建立的调节层，导致 VAV1 信号输出的数量和质量变化。我们还证明了最常见的VAV1突变亚型驱动小鼠 PTCL 的形成。这个过程需要两个下游信号分支的同时参与，这些分支促进滤泡辅助 T 细胞的慢性激活和转化。总的来说，这些数据揭示了与VAV1突变子集的淋巴瘤发生潜力相关的遗传限制、与其他 PTCL 驱动基因的相似性以及潜在的治疗漏洞。