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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.

Mutations in 5-methylcytosine oxidase TET2 and RhoA cooperatively disrupt T cell homeostasis