Somatic G17V RHOA mutations were found in 50-70% of angioimmunoblastic T-cell lymphoma (AITL). The mutant RHOA lacks GTP binding capacity, suggesting defects in the classical RHOA signaling. Here, we discovered the novel function of the G17V RHOA: VAV1 was identified as a G17V RHOA-specific binding partner via high-throughput screening. We found that binding of G17V RHOA to VAV1 augmented its adaptor function through phosphorylation of 174Tyr, resulting in acceleration of T-cell receptor (TCR) signaling. Enrichment of cytokine and chemokine-related pathways was also evident by the expression of G17V RHOA. We further identified VAV1 mutations and a new translocation, VAV1-STAP2, in seven of the 85 RHOA mutation-negative samples (8.2%), whereas none of the 41 RHOA mutation-positive samples exhibited VAV1 mutations. Augmentation of 174Tyr phosphorylation was also demonstrated in VAV1-STAP2. Dasatinib, a multikinase inhibitor, efficiently blocked the accelerated VAV1 phosphorylation and the associating TCR signaling by both G17V RHOA and VAV1-STAP2 expression. Phospho-VAV1 staining was demonstrated in the clinical specimens harboring G17V RHOA and VAV1 mutations at a higher frequency than those without. Our findings indicate that the G17V RHOA-VAV1 axis may provide a new therapeutic target in AITL.

中文翻译：

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RHOA-VAV1信号在血管免疫母细胞性T细胞淋巴瘤中的激活。

在50-70％的血管免疫母细胞性T细胞淋巴瘤（AITL）中发现了体细胞G17V RHOA突变。突变体RHOA缺乏GTP结合能力，表明经典RHOA信号传导中存在缺陷。在这里，我们发现了G17V RHOA的新颖功能：通过高通量筛选，VAV1被鉴定为G17V RHOA特异性结合伴侣。我们发现，G17V RHOA与VAV1的结合通过174Tyr的磷酸化增强了其衔接子功能，从而加速了T细胞受体（TCR）信号传导。G17V RHOA的表达也证明了细胞因子和趋化因子相关途径的富集。我们在85个RHOA突变阴性样品中的7个（8.2％）中进一步鉴定了VAV1突变和一个新的易位VAV1-STAP2，而41个RHOA突变阳性样品中没有一个显示VAV1突变。在VAV1-STAP2中也证实了174Tyr磷酸化的增强。多激酶抑制剂达沙替尼通过G17V RHOA和VAV1-STAP2表达有效地阻断了加速的VAV1磷酸化和相关的TCR信号传导。在带有G17V RHOA和VAV1突变的临床标本中证明了磷酸VAV1染色的频率比没有突变的频率高。我们的发现表明，G17V RHOA-VAV1轴可能为AITL提供了新的治疗靶标。