The C/EBPdelta tumor suppressor is silenced by hypermethylation in acute myeloid leukemia.
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.
Agrawal
Shuchi
S
Department of Medicine, Hematology and Oncology, University of Münster, Domagkstrasse 3, 48129 Münster, Germany.
Hofmann
Wolf-Karsten
WK
Tidow
Nicola
N
Ehrich
Mathias
M
van den Boom
Dirk
D
Koschmieder
Steffen
S
Berdel
Wolfgang E
WE
Serve
Hubert
H
Müller-Tidow
Carsten
C
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000235:genetics / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D020298:U937 Cells
D000964:Antimetabolites, Antineoplastic; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D025521:Tumor Suppressor Proteins; D051743:CCAAT-Enhancer-Binding Protein-delta; D000077209:Decitabine; D001374:Azacitidine