TET2 protects the genome from mutagenicity through interacting with MSH6. Mus musculus

Ten eleven translocation 2 (TET2) is a member of dioxygenases that catalyze the multi-step 5-methylcytosine oxidation. Loss-of-function TET2 mutations frequently occur in various types of hematological malignancies; however, the underlying mechanism remains poorly understood. Here, we show that Tet2-/- mice develop spontaneous myeloid, T- and B-cell malignancies. Exome sequencing of Tet2-/- tumors reveals acquisition of numerous mutations. The mutational frequency in Tet2-/- tumors is significantly greater at loci containing Tet2-dependent active demethylation sites. In addition, the analyses of TET2-interacting protein unveil the association between TET2 and MutS Homolog 6 (MSH6). TET2-depleted cells display elevated spontaneous mutational frequencies and increased microsatellite instability, characteristics of mismatch repair deficient cells. Furthermore, myelodysplastic syndrome (MDS) patients with mutant TET2 have significantly higher mutational events than patients with wild-type TET2. Our findings reveal genomic hypermutability driven by the loss of TET2 as a novel contributing mechanism for TET2 loss-mediated pathogenesis of diverse hematological malignancies. Overall design: Given the role of Tet proteins in 5mC oxidation, we employed a previously established chemical labeling and affinity purification method coupled with high-throughput sequencing (hMe-Seal) to profile the genome-wide distribution of 5hmC. Furthremore, we used an established MEL cell line to perform ChIP-seq to identify the Tet2-binding sites across the genome.