期刊
BLOOD
卷 132, 期 9, 页码 935-947出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2017-11-818617
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资金
- American Cancer Society-Kirby Foundation Postdoctoral Fellowship [PF-16-149-01-TBG]
- Harvard Medical School CMeRIT Award
- Conquer Cancer Foundation of ASCO Young Investigator Award [11489]
- Leukemia and Lymphoma Society Specialized Center of Research award
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.
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