RHOA G17V Induces T Follicular Helper Cell Specification and Promotes Lymphomagenesis

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. [Display omitted] •RHOA G17V expression in CD4+ T cells induces Tfh lineage specification•RHOA G17V expression in a Tet2−/− null background results in AITL development•Tet2−/−RHOA G17V tumor proliferation is suppressed by ICOS/PI3K inhibition in vivo 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.