Concomitant loss of TET2 and TET3 results in T cell expansion and genomic instability

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 the second most frequently mutated gene 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: In this report, we aim to decipher the impact of TET proteins in controlling in vivo proliferation of peripheral T cells. We employ adoptive transfer of Tet2/3 DKO T cells and we discover that Tet2/3 DKO CD4 cells exhibit upregulation of cell cycle genes upon serial transplantation. This altered gene expression program endows Tet2/3 DKO CD4 cells with increased proliferative capacity and acquisition of malignant traits, such as oligoclonal expansion and chromosomal copy number (CCN) variations, resulting in aggressive lymphoproliferative disorders. In addition, we demonstrate that as the TET deficient cells acquire a hyperproliferative profile they can expand remarkably fast, within 10 days, in recipient mice. During this rapid expansion of transplanted Tet2/3 DKO T cells, by employing an unbiased, single cell transcriptomic approach, we reveal that while the immune environment of the host mice becomes rapidly activated, it fails to annihilate the expansion of the donor T cells.