RHOA G17V Induces T Follicular Helper Cell Specification and Promotes Lymphomagenesis

Publication date: Available online 2 February 2018
Source:Cancer Cell
Author(s): Jose R. Cortes, Alberto Ambesi-Impiombato, Lucile Couronné, S. Aidan Quinn, Christine S. Kim, Ana C. da Silva Almeida, Zachary West, Laura Belver, Marta Sanchez Martin, Laurianne Scourzic, Govind Bhagat, Olivier A. Bernard, Adolfo A. Ferrando, Teresa Palomero
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.

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Teaser

Cortes et al. show that expression of Rhoa G17V in CD4⁺ T cells drives proliferation and Tfh polarization, and they develop an angioimmunoblastic T cell lymphoma model by combining Rhoa G17V expression and Tet2 loss. These tumors show increased ICOS and PI3K/MAPK signaling and are sensitive to pathway inhibition.


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