DNA methylation and 5-azacytidine in myelodysplastic syndromes : Pharmacodynamic, mechanistic and clinical studies
Year: 2007
Type: dissertation
Abstract: Promoter DNA hypermethylation and hence silencing of e.g. tumour \nsuppressor genes is considered to be an important step in carcinogenesis \nand has been associated with poor outcome in patients with \nmyelodysplastic syndromes (MDS). In contrast to many other \nchemotherapeutic agents, the DNA hypomethylating compound 5-azacytidine \nhas a positive therapeutic effect in patients with high-risk \nmyelodysplastic syndromes (MDS), however, the lack of knowledge about its \nmechanism of action hampers clinical development of the drug. \n \n \n \nThe first aim of the thesis was to assess the pharmocodynamic properties \nof 5-azacytidine, and the mechanism of 5-azacytidine-induced apoptosis as \nwell as its link with DNA methylation. Secondly, we investigated the role \nof gene-specific methylation status for the outcome of induction \nchemotherapy in a cohort of patients high-risk MDS and MDS-AML, and \nassessed global and gene-specific (p15INK4B) methylation patterns in \nanother cohort of patients with low and intermediate-risk MDS. \n \n \n \n5-azacytidine induced dose-dependent hypomethylation and growth \ninhibition, as well as a complex pattern of apoptotic mechanisms \nregulated by multiple and separate pathways. Furthermore, we demonstrated \na possible link between apoptosis and hypomethylation. We showed that \noptimal cellular effects of 5-azacytidine could be achieved by shorter \nexposure times than expected. Translated to shorter treatment duration in \npatients, this may eventually lead to superior and more cost-effective \nand convenient clinical treatment schedules. P15INK4B methylation plus \nmethylation of CDH or HIC gene was more frequent in patients with \nconventional high-risk features, such as adverse karyoptype and high \npercentage of marrow blasts. DNA hypermethylation of multiple surrogate \ngenes correlated with the percentage of blasts and marrow CD34 \nexpression, but not with the degree of inefficient haematopoiesis. We \ndemonstrated a significant negative impact of promoter methylation status \non the outcome of conventional induction chemotherapy in high-risk MDS \nand MDS-AML, a finding that may have significant impact on the clinical \nmanagement of patients with high-risk myeloid disease. Global and \ngene-specific DNA methylation pattern in MDS correlated with each other \nin the sense that more advanced MDS, characterized by p15INK4B \nmethylation showed higher global DNA methylation than those with \nunmethylated p15INK4B. Global methylation status did not correlate with \nconventional risk factors, but was more pronounced in patients with \nsevere erythroid failure. Patients with stable disease maintained their \nglobal DNA methylation level over time, and disease progression was \nassociated with an increase in global DNA methylation in only half of the \ncases. \n \n \n \nTo conclude, these studies provide important knowledge about the cellular \nmechanisms of 5-azacytidine and role of DNA methylation in patients with \nMDS and MDS-AML.
Source: Figshare
Author: Rasheed Khan
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1750767751