Epigenetic alterations occur frequently in leukaemia and might account for differences in clinical phenotype and response to treatment. Despite the consistent presence of the BCR-ABL1 fusion gene in Philadelphia-positive chronic myeloid leukaemia (CML), the clinical course of patients treated with tyrosine kinase inhibitors (TKI) is heterogeneous. This might be due to differing DNA methylation profiles between patients. Therefore, a validated, epigenome-wide survey in CML CD34+ progenitor cells was performed in newly diagnosed chronic phase patients using array-based DNA methylation and gene expression profiling. In practice, the CML DNA methylation signature was remarkably homogeneous; it differed from CD34+ cells of normal persons and did not correlate with an individual patient’s response to TKI therapy. Using a meta-analysis tool it was possible to demonstrate that this signature was highly enriched for developmentally dynamic regions of the human methylome and represents a combination of CML-unique, myeloid leukemia-specific and pan-cancer sub-signatures. The CML profile involved aberrantly methylated genes in signaling pathways already implicated in CML leukaemogenesis, including TGF-beta, Wnt, Jak-STAT and MAPK. Furthermore, a core set of differentially methylated promoters were identified that likely have a role in modulating gene expression levels. In conclusion, the findings are consistent with the notion that CML starts with the acquisition of a BCR-ABL1 fusion gene by a haematopoietic stem cell, which then either causes or cooperates with a series of DNA methylation changes that are specific for CML.Open Acces
