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.
Highlights
This is the first study to compare genome-wide DNA methylation profiles of sorted blood cells from myelofibrosis (MF) patients and healthy controls
By comparison of individual MF cell populations to their normal counterparts isolated from healthy donors, we initially identified differentially methylated CpG sites within MF granulocytes, MF mononuclear cells and MF CD34+ cells, respectively
A previous study has shown correlation of ASXL1 mutations to a higher overall DNA methylation level and leukemic transformation in MF, whereas TET2 mutations correlated with increased DNA methylation levels of a distinct set of genes[11], that study was based on the analyses of only 12 cases and needs confirmation in a larger cohort
Summary
This is the first study to compare genome-wide DNA methylation profiles of sorted blood cells from myelofibrosis (MF) patients and healthy controls. Few differentially methylated CpG sites were common among the three cell populations. In a supervised analysis of ASXL1 mutated versus wild-type cases, differentially methylated CpG sites were enriched in regions marked by histone H3K4me[1], histone H3K27me[3], and the bivalent histone mark H3K27me3 + H3K4me[3] in human CD34+ cells. 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. Eight to 11% of JAK2V617F negative MF patients carry MPL mutations[4], and both JAK2 and MPL mutations cause constitutive activation of the JAK/STAT pathway that promotes cell survival and proliferation[5]. In addition to causing constitutive activation of the JAK/STAT pathway[7], mutated CALR lose the. Mutations in JAK2, MPL, and CALR are recurrent in MPN, they alone explain neither the pathogenesis nor the clinical manifestations associated with the distinctive MPN subgroups
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