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Genome-wide DNA methylation in chronic myeloid leukaemia

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Title: Genome-wide DNA methylation in chronic myeloid leukaemia
Authors: Bazeos, Alexandra
Item Type: Thesis or dissertation
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.
Content Version: Open Access
Issue Date: Feb-2016
Date Awarded: Mar-2017
URI: http://hdl.handle.net/10044/1/67646
DOI: https://doi.org/10.25560/67646
Supervisor: Apperley, Jane
Foroni, Letizia
Sponsor/Funder: Medical Research Council (Great Britain)
Department: Department of Medicine
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses

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