Epigenomic profiling of myelofibrosis reveals widespread DNA methylation changes in enhancer elements and as a potential tumor suppressor gene that is epigenetically regulated.

In this study we interrogated the DNA methylome of myelofibrosis patients using high-density DNA methylation arrays. We detected 35,215 differentially methylated CpG, corresponding to 10,253 genes, between myelofibrosis patients and healthy controls. These changes were present both in primary and secondary myelofibrosis, which showed no differences between them. Remarkably, most differentially methylated CpG were located outside gene promoter regions and showed significant association with enhancer regions. This aberrant enhancer hypermethylation was negatively correlated with the expression of 27 genes in the myelofibrosis cohort. Of these, we focused on the gene and validated its decreased expression and enhancer DNA hypermethylation in an independent cohort of patients and myeloid cell-lines. reporter assay and 5'-azacitidine treatment confirmed the functional relevance of hyper-methylation of enhancer. Furthermore, rescue of expression had an impact on cell proliferation and induced apoptosis in SET-2 cell line indicating a possible role of as a tumor suppressor gene in myelofibrosis. Collectively, we describe the DNA methylation profile of myelofibrosis, identifying extensive changes in enhancer elements and revealing as a novel candidate tumor suppressor gene.