@article{d57bc2db995f4f3dbe956a24f1eea27f,
title = "Mutations in 5-methylcytosine oxidase TET2 and RhoA cooperatively disrupt T cell homeostasis",
abstract = "Angioimmunoblastic T cell lymphoma (AITL) represents a distinct, aggressive form of peripheral T cell lymphoma with a dismal prognosis. Recent exome sequencing in patients with AITL has revealed the frequent coexistence of somatic mutations in the Rho GTPase RhoA (RhoAG17V) and loss-of-function mutations in the 5-methylcytosine oxidase TET2. Here, we have demonstrated that TET2 loss and RhoAG17V expression in mature murine T cells cooperatively cause abnormal CD4+ T cell proliferation and differentiation by perturbing FoxO1 gene expression, phosphorylation, and subcellular localization, an abnormality that is also detected in human primary AITL tumor samples. Reexpression of FoxO1 attenuated aberrant immune responses induced in mouse models adoptively transferred with T cells and bearing genetic lesions in both TET2 and RhoA. Our findings suggest a mutational cooperativity between epigenetic factors and GTPases in adult CD4+ T cells that may account for immunoinflammatory responses associated with AITL patients.",
author = "Shengbing Zang and Jia Li and Haiyan Yang and Hongxiang Zeng and Wei Han and Jixiang Zhang and Minjung Lee and Margie Moczygemba and Sevinj Isgandarova and Yaling Yang and Yubin Zhou and Anjana Rao and You, {M. James} and Deqiang Sun and Yun Huang",
note = "Funding Information: We thank Margaret Goodell at the Baylor College of Medicine (Houston, Texas, USA) for her advice and sharing of reagents. We are grateful to Jianjun Shen and the MD Anderson Next-Generation Sequencing Core at Smithville for their highthroughput sequencing work (CPRIT RP120348 and RP170002). This work was supported by grants from the Cancer Prevention and Research Institute of Texas (RR140053, to YH); an Innovation Award from the American Heart Association (16IRG27250155, to YH); the John S. Dunn Foundation Collaborative Research Award (to YH); the Translational Research Program (TRP) of the Leukemia and Lymphoma Society (6464-15, to AR); the NIH (R01GM112003, to YZ); the Welch Foundation (BE-1913, to YZ); the American Cancer Society (RSG-16-215-01-TBE, to YZ); and by an allocation from the Texas A&M University Start-up Funds (to YH and DS). MJY was partially supported by grants from the National Cancer Institute, NIH (R01 CA164346 and R01 CA200703) and Developmental Research Awards in Leukemia (SPORE CA100632) and CPRIT RP140402.",
year = "2017",
month = aug,
day = "1",
doi = "10.1172/JCI92026",
language = "English (US)",
volume = "127",
pages = "2998--3012",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "8",
}