TET2 mutations are associated with hypermethylation at key regulatory enhancers in normal and malignant hematopoiesis
Tulstrup, M., Soerensen, M., Hansen, J. W., Gillberg, L., Needhamsen, M., Kaastrup, K., Helin, K., Christensen, K., Weischenfeldt, J., and Grønbæk, K. (2021). TET2 mutations are associated with hypermethylation at key regulatory enhancers in normal and malignant hematopoiesis. Nature Communications, 12(1), 6061. doi: 10.1038/s41467-021-26093-2.
Mutations in the epigenetic modiﬁer TET2 are frequent in myeloid malignancies and clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined signiﬁcance (CCUS). Here, we investigate associations between TET2 mutations and DNA methylation in whole blood in 305 elderly twins, 15 patients with CCUS and 18 healthy controls. We ﬁnd that TET2 mutations are associated with DNA hypermethylation at enhancer sites in whole blood in CHIP and in both granulocytes and mononuclear cells in CCUS. These hypermethylated sites are associated with leukocyte function and immune response and ETS-related and C/EBP-related transcription factor motifs. While the majority of TET2-associated hypermethylation sites are shared between CHIP and in AML, we ﬁnd a set of AML-speciﬁc hypermethylated loci at active enhancer elements in hematopoietic stem cells. In summary, we show that TET2 mutations is associated with hypermethylated enhancers involved in myeloid differentiation in both CHIP, CCUS and AML patients.