TET2 mutations are associated with hypermethylation at key regulatory enhancers in normal and malignant hematopoiesis

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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.

TidsskriftNature Communications
Udgave nummer1
Antal sider10
StatusUdgivet - 2021

Bibliografisk note

Funding Information:
M.T. and L.G. are supported by the Research Foundation at Rigshospitalet. The Danish Twin Registry is supported by the Odense University Hospital AgeCare program (Academy of Geriatric Cancer Research). The Danish Twin Registry has been supported by The National Program for Research Infrastructure 2007 grant 09-063256 from the Danish Agency for Science Technology and Innovation, the Velux Foundation, and the National Institutes of Health, National Institute on Aging grant P01 AG08761. K.G., J.W., and K.H. are supported by the Novo Nordisk Foundation (Novo Nordisk Foundation Center for Stem Cell Biology, DanStem; grant NNF17CC0027852). J.W. is also supported by the Novo Nordisk Foundation grant NNF200C0060141. K.G. is supported by The Danish Cancer Society (Danish Research Center for Precision Medicine in Blood Cancer; grant 223-A13071-18-S68) and from Greater Copenhagen Health Science Partners (Clinical Academic Group in Blood Cancers).

Publisher Copyright:
© 2021, The Author(s).

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