The C/EBP tumor suppressor is silenced by hypermethylation in acute myeloid leukemia
نویسندگان
چکیده
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-azadeoxy-cytidine. Overall, 274 transcripts were significantly induced. Interestingly, C/EBP expression was significantly induced (more than 10-fold) by demethylation whereas expression of all other C/EBP family members remained unchanged. The C/EBP 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 ( , , , , , ) in bone marrow samples from AML patients (n 80) and controls (n 15) by mass spectrometry revealed that C/EBP 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/EBP promoter and low expression of C/EBP in AML patients. C/EBP promoter activity was strongly repressed by methylation in vitro, and transcriptional repression partially depended on MeCP2 activity. C/EBP exhibited growth-inhibitory properties in primary progenitor cells as well as in Flt3ITD–transformed cells. Taken together, C/EBP is a novel tumor suppressor gene in AML that is silenced by promoter methylation. (Blood. 2007;109:3895-3905)
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