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

Abstract

Patients with angioimmunoblastic T-cell lymphoma (AITL) and other peripheral T-cell lymphomas that harbor features of follicular helper T (T_FH) cells have a very poor prognosis. These lymphomas commonly present with paraneoplastic autoimmunity and lymphopenia. RhoA G17V mutation is present in 60% of T_FH-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 naive T cells but relatively increased T_FH-cell populations. Surprisingly, naive 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 Tet2^fl/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 mechanistic target of rapamycin (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 similar to those observed in patients with T_FH lymphomas.