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The C/EBPδ tumor suppressor is silenced by hypermethylation in acute myeloid leukemia
File(s)
zh800907003895.pdf (549.97 KB)
Published version
Author(s)
Agrawal, Shuchi
Hofmann, Wolf-Karsten
Tidow, Nicola
Ehrich, Mathias
Boom, Dirk van den
Type
Journal Article
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/EBPδ expression was significantly induced (more than 10-fold) by demethylation whereas expression of all other C/EBP family members remained unchanged. The C/EBPδ 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 (α, β, γ, δ, ϵ, ζ) in bone marrow samples from AML patients (n = 80) and controls (n = 15) by mass spectrometry revealed that C/EBPδ 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/EBPδ promoter and low expression of C/EBPδ in AML patients. C/EBPδ promoter activity was strongly repressed by methylation in vitro, and transcriptional repression partially depended on MeCP2 activity. C/EBPδ exhibited growth-inhibitory properties in primary progenitor cells as well as in Flt3-ITD–transformed cells. Taken together, C/EBPδ is a novel tumor suppressor gene in AML that is silenced by promoter methylation.
Date Issued
2007-05-01
Date Acceptance
2006-12-26
Citation
Blood, 2007, 109 (9), pp.3895-3905
URI
URL
DOI
ISSN
0006-4971
Publisher
American Society of Hematology
Start Page
3895
End Page
3905
Journal / Book Title
Blood
Volume
109
Issue
9
Copyright Statement
"This research was originally published in Blood. Shuchi Agrawal, Wolf-Karsten Hofmann, Nicola Tidow, Mathias Ehrich, Dirk van den Boom, Steffen Koschmieder, Wolfgang E. Berdel, Hubert Serve, Carsten Müller-Tidow; The C/EBPδ tumor suppressor is silenced by hypermethylation in acute myeloid leukemia. Blood 2007; 109 (9): 3895–3905. doi: https://doi.org/10.1182/blood-2006-08-040147. © the American Society of Hematology."
Identifier
10.1182/blood-2006-08-040147
Publication Status
Published
Date Publish Online
2007-01-18