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Genomic impact of transient low-dose decitabine treatment on primary AML cells.
- Source :
-
Blood [Blood] 2013 Feb 28; Vol. 121 (9), pp. 1633-43. Date of Electronic Publication: 2013 Jan 07. - Publication Year :
- 2013
-
Abstract
- Acute myeloid leukemia (AML) is characterized by dysregulated gene expression and abnormal patterns of DNA methylation; the relationship between these events is unclear. Many AML patients are now being treated with hypomethylating agents, such as decitabine (DAC), although the mechanisms by which it induces remissions remain unknown. The goal of this study was to use a novel stromal coculture assay that can expand primary AML cells to identify the immediate changes induced by DAC with a dose (100nM) that decreases total 5-methylcytosine content and reactivates imprinted genes (without causing myeloid differentiation, which would confound downstream genomic analyses). Using array-based technologies, we found that DAC treatment caused global hypomethylation in all samples (with a preference for regions with higher levels of baseline methylation), yet there was limited correlation between changes in methylation and gene expression. Moreover, the patterns of methylation and gene expression across the samples were primarily determined by the intrinsic properties of the primary cells, rather than DAC treatment. Although DAC induces hypomethylation, we could not identify canonical target genes that are altered by DAC in primary AML cells, suggesting that the mechanism of action of DAC is more complex than previously recognized.
- Subjects :
- Animals
Antimetabolites, Antineoplastic administration & dosage
Antimetabolites, Antineoplastic pharmacology
Azacitidine administration & dosage
Azacitidine pharmacology
Cells, Cultured
CpG Islands drug effects
CpG Islands genetics
DNA Methylation drug effects
DNA Methylation genetics
Decitabine
Dose-Response Relationship, Drug
Gene Expression Profiling
Genome, Human drug effects
Humans
Leukemia, Myeloid, Acute pathology
Mice
Microarray Analysis
Primary Cell Culture
Time Factors
Azacitidine analogs & derivatives
Gene Expression Regulation, Leukemic drug effects
Leukemia, Myeloid, Acute genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 121
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 23297133
- Full Text :
- https://doi.org/10.1182/blood-2012-09-459313