Rho guanine exchange factors (GEFs), the enzymes that stimulate Rho GTPases, are deemed as potential therapeutic targets owing to their protumorigenic functions. However, the understanding of the spectrum of their pathobiological roles in tumors is still very limited. We report here that the GEF Vav1 unexpectedly possesses tumor-suppressor functions in immature T cells. This function entails the noncatalytic nucleation of complexes between the ubiquitin ligase Cbl-b and the intracellular domain of Notch1 (ICN1) that favors ICN1 ubiquitinylation and degradation. Ablation of Vav1 promotes ICN1 signaling and the development of T cell acute lymphoblastic leukemia (T-ALL). The downregulation of Vav1 is essential for the pathogenesis of human T-ALL of the TLX⁺ clinical subtype, further underscoring the suppressor role of this pathway.

中文翻译：

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Rac1 交换因子 Vav1 在 T 细胞急性淋巴细胞白血病中的矛盾肿瘤抑制作用。

Rho 鸟嘌呤交换因子 (GEF) 是一种刺激 Rho GTP 酶的酶，由于其促癌功能，被认为是潜在的治疗靶点。然而，对其在肿瘤中的病理生物学作用谱的理解仍然非常有限。我们在此报告 GEF Vav1 在未成熟 T 细胞中意外地具有肿瘤抑制功能。该功能需要泛素连接酶 Cbl-b 和 Notch1 (ICN1) 的胞内结构域之间的复合物的非催化成核，这有利于 ICN1 泛素化和降解。Vav1 的消融促进 ICN1 信号传导和 T 细胞急性淋巴细胞白血病 (T-ALL) 的发展。Vav1 的下调对于 TLX ^{+的人类 T-ALL 的发病机制至关重要}临床亚型，进一步强调了该途径的抑制作用。