TET2 loss and the lymphoma-associated RHOA mutation cooperate to disrupt CD4+ T cell function through inactivation of FOXO1

Angioimmunoblastic T cell lymphoma (AITL) represents a distinctive form of peripheral T cell lymphoma with a dismissal prognosis. Recent exome sequencing in AITL patients revealed frequent coexistence of somatic mutations in the RHO GTPase (RHOAG17V) and the 5-methylcytosine oxidase TET2. Here we demonstrated that Tet2 loss and RhoAG17V cooperatively caused abnormal CD4+ T cell proliferation and differentiation by perturbing FoxO1 gene expression and its subcellular localization, an abnormality that is also detected in AITL tumor samples. Re-expression of FoxO1 attenuated aberrant immune responses induced by genetic lesions in both Tet2 and RhoA. Our findings suggest that mutational cooperativity between epigenetic factors and GTPases in adult CD4+ T cells may account for immunoinflammatory responses that are commonly associated with AITL. Overall design: Determine the differential expressed genes between WT, Tet2-/-, RhoAG17V, Tet2-/-RhoAG17V mutant CD4+ T cells.

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Zang S, Li J, Yang H, Zeng H, Han W, Zhang J, Lee M, Moczygemba M, Isgandarova S, Yang Y, Zhou Y, Rao A, You MJ, Sun D, Huang Y