Genome-wide DNA methylation in chronic myeloid leukaemia

Abstract

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.