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

• Published in: Blood 2018-08, Vol.132 (9), p.935-947
• Main Authors: Ng, Samuel Y., Brown, Leon, Stevenson, Kristen, deSouza, Tiffany, Aster, Jon C., Louissaint, Abner, Weinstock, David M.
• Format: Article
• Language: English
• Subjects: Amino Acid Substitution; Animals; Antibodies, Antinuclear - immunology; Autoimmune Diseases; Lymphoid Neoplasia; Lymphoma, Follicular - genetics; Lymphoma, Follicular - immunology; Lymphoma, Follicular - pathology; Lymphoma, T-Cell - genetics; Lymphoma, T-Cell - immunology; Lymphoma, T-Cell - pathology; Mice; Mice, Transgenic; Mutation, Missense; Neoplasm Proteins - genetics; Neoplasm Proteins - immunology; rho GTP-Binding Proteins - genetics; rho GTP-Binding Proteins - immunology; rhoA GTP-Binding Protein; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Helper-Inducer - pathology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2017-11-818617

Patients with angioimmunoblastic T-cell lymphoma (AITL) and other peripheral T-cell lymphomas 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 naive T cells but relatively increased TFH-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 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 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 TFH lymphomas. •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. [Display omitted]