RhoA G17V is sufficient to induce autoimmunity and promotes T cell lymphomagenesis in mice

Samuel Y. Ng, Leon Brown, Kristen Stevenson, Tiffany deSouza, Jon C. Aster, Abner Louissaint and David M. Weinstock

Key points

  • Expression of RhoA G17V in CD4+ cells results in cellular and humoral autoimmunity

  • RhoA G17V expression with Tet2 loss induces T cell lymphomas with features of AITL


Patients with angioimmunoblastic T-cell lymphoma (AITL) and other peripheral T-cell lymphomas (PTCL) that harbor features of follicular helper T (TFH) cells have a very poor prognosis. These lymphomas commonly present with paraneoplastic autoimmunity and lymphopenia. RhoA G17V mutation is present in 60% of TFH-like lymphomas but its role in tumorigenesis is poorly understood. We generated transgenic mice that express RhoA G17V under the control of murine CD4 regulatory elements at levels comparable to a heterozygous mutation (tgRhoA mice). These mice had markedly reduced naïve T cells but relatively increased TFH cell populations. Surprisingly, naïve CD4 T-cells expressing RhoA G17V were hyperreactive to T-cell receptor stimulation. All tgRhoA mice developed autoimmunity that included a cellular infiltrate within ears and tails that was recapitulated in wild-type (WT) recipients after bone marrow transplantation. Older tgRhoA mice developed elevated serum titers of anti-double stranded DNA antibodies and renal immune complex deposition. RhoA G17V mice crossed with Tet2fl/fl; Vav-Cre+ mice, which delete Tet2 throughout the hematopoietic compartment, developed T-cell lymphomas that retained histologic and immunophenotypic features of AITL and had transcriptional signatures enriched for mTOR-associated genes. Transplanted tumors were responsive to the mTOR inhibitor everolimus, providing a possible strategy for targeting RhoA G17V. Taken together, these data indicate that RhoA G17V contributes to both neoplastic and paraneoplastic phenotypes like those observed in patients with TFH lymphomas.

  • Submitted November 27, 2017.
  • Accepted May 7, 2018.