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RHOA G17V Induces T Follicular Helper Cell Specification and Promotes Lymphomagenesis

2018; Cell Press; Volume: 33; Issue: 2 Linguagem: Inglês

10.1016/j.ccell.2018.01.001

1878-3686

José R. Cortés, Alberto Ambesi‐Impiombato, Lucile Couronné, S. Aidan Quinn, Christine S. Kim, Ana Carolina da Silva Almeida, Zachary J. West, Laura Belver, Marta Sanchez Martin, Laurianne Scourzic, Govind Bhagat, Olivier Bernard, Adolfo A. Ferrando, Teresa Palomero,

Cancer-related molecular mechanisms research

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.