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Sci Rep. 2017 Jul 28;7(1):6774. doi: 10.1038/s41598-017-07057-3.

Epigenetic changes in myelofibrosis: Distinct methylation changes in the myeloid compartments and in cases with ASXL1 mutations.

Author information

1
Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
2
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
3
Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
4
Department of Hematology, Roskilde Hospital, Roskilde, Denmark.
5
Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark.
6
Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
7
Department of Hematology, Odense University Hospital, Odense, Denmark.
8
Division of Hematology, Keck School of Medicine, University of Southern California, Los Angeles, United States.
9
Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. kirsten.groenbaek@regionh.dk.
10
Danish Stem Cell Centre (DanStem) Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. kirsten.groenbaek@regionh.dk.

Abstract

This is the first study to compare genome-wide DNA methylation profiles of sorted blood cells from myelofibrosis (MF) patients and healthy controls. We found that differentially methylated CpG sites located to genes involved in 'cancer' and 'embryonic development' in MF CD34+ cells, in 'inflammatory disease' in MF mononuclear cells, and in 'immunological diseases' in MF granulocytes. Only few differentially methylated CpG sites were common among the three cell populations. Mutations in the epigenetic regulators ASXL1 (47%) and TET2 (20%) were not associated with a specific DNA methylation pattern using an unsupervised approach. However, in a supervised analysis of ASXL1 mutated versus wild-type cases, differentially methylated CpG sites were enriched in regions marked by histone H3K4me1, histone H3K27me3, and the bivalent histone mark H3K27me3 + H3K4me3 in human CD34+ cells. Hypermethylation of selected CpG sites was confirmed in a separate validation cohort of 30 MF patients by pyrosequencing. Altogether, we show that individual MF cell populations have distinct differentially methylated genes relative to their normal counterparts, which likely contribute to the phenotypic characteristics of MF. Furthermore, differentially methylated CpG sites in ASXL1 mutated MF cases are found in regulatory regions that could be associated with aberrant gene expression of ASXL1 target genes.

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