Concomitant loss of TET2 and TET3 results in T cell expansion and genomic instability in mice
Marianthi Gioulbasani, Tarmo Äijö, Siyao Liu, Stephanie A. Montgomery, Nathan D. Montgomery, David L. Corcoran, Ageliki Tsagaratou
Abstract
Ten eleven translocation (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. Here we show 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. Concomitant deletion of TET2 and TET3 in murine CD4 T cells results in acquisition of malignant traits, including loss of genomic integrity, acquisition of aneuploidy and upregulation of the protooncogene Myc.