Assessing the impact of TET2 and TET3 deletion in TCRa and TCRb expression and repertoire in murine CD4 T cells in physiological and pathological conditions [TCR-seq]

TET proteins are tumor suppressors that through their catalytic activity oxidize 5-methylcytosine to 5-hydroxymethylcytosine, to promote DNA demethylation and to regulate gene expression. Notably, TET2 is one of the most frequently mutated genes in hematological malignancies, including T cell lymphomas. However, murine models with deletion of TET2 do not exhibit T cell expansion, presumably due to redundancy with other members of the TET family of proteins. In order to gain insight on the TET mediated molecular events that safeguard T cells from aberrant proliferation we performed serial adoptive transfers of murine CD4 T cells that lack concomitantly TET2 and TET3 to fully immunocompetent congenic mice. Our data reveal a progressive acquisition of malignant traits upon loss of TET2 and TET3 that is characterized by loss of genomic integrity, acquisition of aneuploidy and upregulation of the protooncogene Myc. Overall design: We evaluated TCRa and TCRb chain repertoire to assess clonality in control, Tet2/3 DKO CD4 SP, Tet2/3 DKO CD4 peripheral T cells as well as transferred and expanded cells