RHOA G17V Induces T Follicular Helper Cell Specification and Promotes Lymphomagenesis.
Cancer Cell, 2018/02/12;33(2):259-273.e7.
Cortes JR[1], Ambesi-Impiombato A[1], Couronné L[2], Quinn SA[1], Kim CS[1], da Silva Almeida AC[1], West Z[1], Belver L[1], Martin MS[1], Scourzic L[3], Bhagat G[4], Bernard OA[3], Ferrando AA[5], Palomero T[6]
Affiliations
PMID: 29398449DOI: 10.1016/j.ccell.2018.01.001
Impact factor: 38.585
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, 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.
Keywords: ICOS; RHOA G17V; T follicular helper cells; TET2; angioimmunoblastic T cell lymphoma
MeSH terms
Animals; Biomarkers, Tumor; DNA-Binding Proteins; Dioxygenases; Immunoblastic Lymphadenopathy; Lymphoma, T-Cell; Mice, Knockout; Mutation; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins; T-Lymphocytes, Helper-Inducer; rhoA GTP-Binding Protein
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