RHOA G17V 诱导滤泡辅助性 T 细胞的特征，并促进淋巴瘤的发生。
RHOA G17V Induces T Follicular Helper Cell Specification and Promotes Lymphomagenesis.
机构信息
Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
Department of Adult Hematology, Necker Hospital, Paris 75993, France; INSERM U 1163, CNRS ERL 8254, Institut Imagine, Paris 75015, France; Paris Descartes University, Paris 75006, France.
出版信息
Cancer Cell. 2018 Feb 12;33(2):259-273.e7. doi: 10.1016/j.ccell.2018.01.001. Epub 2018 Feb 2.
Abstract
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, Tet2RHOA G17V tumor proliferation in vivo can be inhibited by ICOS/PI3K-specific blockade, supporting a driving role for ICOS signaling in Tfh cell transformation.
摘要
血管免疫母细胞性 T 细胞淋巴瘤 (AITL) 是一种源自滤泡辅助性 T 细胞 (Tfh) 恶性转化的侵袭性肿瘤。AITL 的特征是 TET2 表观遗传肿瘤抑制因子功能丧失突变和 RHOA 小 GTPase 的高度复发突变 (p.Gly17Val)。然而，RHOA G17V 在 AITL 中的具体作用仍不清楚。Rhoa G17V 在 CD4 T 细胞中的表达诱导 Tfh 细胞的特化；与诱导共刺激因子 (ICOS) 上调和磷酸肌醇 3-激酶 (PI3K) 和丝裂原活化蛋白激酶信号转导增加相关的增殖。此外，RHOA G17V 的表达与 Tet2 的缺失一起导致了小鼠 AITL 的发生。重要的是，ICOS/PI3K 特异性阻断可抑制 Tet2RHOA G17V 肿瘤在体内的增殖，这支持了 ICOS 信号在 Tfh 细胞转化中的驱动作用。
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