Characterization of the spectrum of trivalent VAV1 mutation-driven tumors using a gene-edited mouse model

VAV1 mutations have been recently found in peripheral T cell lymphoma and non-small cell lung cancer. To understand their pathogenic potential, we generated a gene-edited mouse model that expresses a Vav1 mutant protein that recapitulates the signaling alterations present the VAV1 mutant subclass most frequently found in tumors. We could not detect any overt tumorigenic process in those mice. However, the concurrent elimination of the Trp53 tumor suppressor gene in them drives T cell lymphomagenesis. This process represents an exacerbation of the normal functions that wild-type Vav1 plays in follicular helper T cells. We also found that, in combination with an oncogenic Kras mutation, the Vav1 mutant version favors progression of non-small cell lung cancer. These data indicate that VAV1 mutations play critical, although highly cell typespecific roles in tumorigenesis. They also indicate that such functions are contingent on the mutational landscape of the tumors involved. Splenocytes from control (Trp53KI/KI) and lymphoma-bearing animals (Trp53KI/KI;Vav1DC/DC)

研究人员近期在外周T细胞淋巴瘤（peripheral T cell lymphoma）与非小细胞肺癌（non-small cell lung cancer）中发现了VAV1基因突变。为阐明此类突变的致病潜能，我们构建了表达Vav1突变蛋白的基因编辑小鼠模型，该模型可复现肿瘤中最常见的VAV1突变亚型所携带的信号通路异常改变。我们未在该类小鼠中观察到明显的致瘤过程。然而，若同时敲除该模型小鼠的Trp53抑癌基因，则可诱发T细胞淋巴瘤发生。该过程实则是野生型Vav1在滤泡辅助性T细胞（follicular helper T cells）中正常功能的异常增强。我们还发现，当与致癌性Kras突变共存时，Vav1突变体可促进非小细胞肺癌的进展。上述研究结果表明，VAV1基因突变在肿瘤发生过程中发挥关键作用，但其功能具有高度的细胞类型特异性；同时也提示，此类功能依赖于所涉及肿瘤的突变谱特征。对照组（Trp53KI/KI）与荷瘤动物（Trp53KI/KI;Vav1DC/DC）的脾脏淋巴细胞