RHOA G17V Induces T Follicular Helper Cell Specification and Promotes Lymphomagenesis

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, 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers, Tumor / genetics
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Immunoblastic Lymphadenopathy / genetics*
  • Lymphoma, T-Cell / metabolism
  • Mice, Knockout
  • Mutation / genetics*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • T-Lymphocytes, Helper-Inducer / immunology*
  • rhoA GTP-Binding Protein / metabolism*

Substances

  • Biomarkers, Tumor
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • Tet2 protein, mouse
  • Phosphatidylinositol 3-Kinases
  • rhoA GTP-Binding Protein