Angioimmunoblastic T cell lymphoma (AITL) is an aggressive tumor derived from malignant transformation of T follicular helper (Tfh) cells. AITL is characterized by loss-of-function mutations in Ten-Eleven Translocation 2 (TET2) epigenetic tumor suppressor and a highly recurrent mutation (p.Gly17Val) in the RHOA small GTPase. Yet, the specific role of RHOA G17V in AITL remains unknown. Expression of Rhoa G17V in CD4⁺ T cells induces Tfh cell specification; increased proliferation associated with inducible co-stimulator (ICOS) upregulation and increased phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase signaling. Moreover, RHOA G17V expression together with Tet2 loss resulted in development of AITL in mice. Importantly, Tet2^-/-RHOA G17V tumor proliferation in vivo can be inhibited by ICOS/PI3K-specific blockade, supporting a driving role for ICOS signaling in Tfh cell transformation.

中文翻译：

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RHOA G17V 诱导 T 滤泡辅助细胞规范并促进淋巴瘤发生。

血管免疫母细胞性 T 细胞淋巴瘤 (AITL) 是一种侵袭性肿瘤，源自 T 滤泡辅助 (Tfh) 细胞的恶性转化。AITL 的特征是 10-11 易位 2 (TET2) 表观遗传肿瘤抑制基因中的功能丧失突变和 RHOA 小 GTPase 中的高度复发性突变 (p.Gly17Val)。然而，RHOA G17V 在 AITL 中的具体作用仍然未知。Rhoa G17V 在 CD4 ⁺ T 细胞中的表达诱导 Tfh 细胞特化；与诱导型共刺激剂 (ICOS) 上调相关的增殖增加和磷酸肌醇 3-激酶 (PI3K) 和丝裂原活化蛋白激酶信号传导增加。此外，RHOA G17V 表达与 Tet2 缺失一起导致小鼠 AITL 的发展。重要的是，Tet2 ^-/-体内 RHOA G17V 肿瘤增殖可以被 ICOS/PI3K 特异性阻断抑制，支持 ICOS 信号在 Tfh 细胞转化中的驱动作用。