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The C/EBPdelta tumor suppressor is silenced by hypermethylation in acute myeloid leukemia.
- Source :
-
Blood [Blood] 2007 May 01; Vol. 109 (9), pp. 3895-905. Date of Electronic Publication: 2007 Jan 18. - Publication Year :
- 2007
-
Abstract
- Aberrant DNA methylation is the most frequent molecular alteration in acute myeloid leukemia (AML). To identify methylation-silenced genes in AML, we performed microarray analyses in U937 cells exposed to the demethylating agent 5-aza-deoxy-cytidine. Overall, 274 transcripts were significantly induced. Interestingly, C/EBPdelta expression was significantly induced (more than 10-fold) by demethylation whereas expression of all other C/EBP family members remained unchanged. The C/EBPdelta promoter was strongly methylated in different leukemic cell lines and showed signs of a repressed chromatin state. Analyses of the promoter regions of the entire C/EBP family (alpha, beta, gamma, delta, epsilon, zeta) in bone marrow samples from AML patients (n = 80) and controls (n = 15) by mass spectrometry revealed that C/EBPdelta is the most commonly hypermethylated C/EBP gene in AML. Hypermethylation occurred in more than 35% of AML patients at primary diagnosis. A significant correlation (P = .016) was observed between hypermethylation of the C/EBPdelta promoter and low expression of C/EBPdelta in AML patients. C/EBPdelta promoter activity was strongly repressed by methylation in vitro, and transcriptional repression partially depended on MeCP2 activity. C/EBPdelta exhibited growth-inhibitory properties in primary progenitor cells as well as in Flt3-ITD-transformed cells. Taken together, C/EBPdelta is a novel tumor suppressor gene in AML that is silenced by promoter methylation.
- Subjects :
- Antimetabolites, Antineoplastic pharmacology
Azacitidine analogs & derivatives
Azacitidine pharmacology
CCAAT-Enhancer-Binding Protein-delta genetics
Chromatin Assembly and Disassembly drug effects
Chromatin Assembly and Disassembly genetics
Decitabine
Female
Gene Expression Profiling
Humans
Leukemia, Myeloid, Acute genetics
Male
Methyl-CpG-Binding Protein 2 metabolism
Oligonucleotide Array Sequence Analysis
Promoter Regions, Genetic genetics
Tumor Suppressor Proteins genetics
U937 Cells
CCAAT-Enhancer-Binding Protein-delta metabolism
DNA Methylation drug effects
Gene Expression Regulation, Leukemic drug effects
Gene Silencing drug effects
Leukemia, Myeloid, Acute metabolism
Tumor Suppressor Proteins biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 0006-4971
- Volume :
- 109
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 17234736
- Full Text :
- https://doi.org/10.1182/blood-2006-08-040147