Data from Epigenetic Modification of CCAAT/Enhancer Binding Protein α Expression in Acute Myeloid Leukemia

Abstract

<div>Abstract<p>Functional loss of <i>CCAAT/enhancer binding protein α</i> (<i>C/EBPα</i>), a master regulatory transcription factor in the hematopoietic system, can result in a differentiation block in granulopoiesis and thus contribute to leukemic transformation. Here, we show the effect of epigenetic aberrations in regulating C/EBPα expression in acute myeloid leukemia (AML). Comprehensive DNA methylation analyses of the CpG island of <i>C/EBPα</i> identified a densely methylated upstream promoter region in 51% of AML patients. Aberrant DNA methylation was strongly associated with two generally prognostically favorable cytogenetic subgroups: inv(16) and t(15;17). Surprisingly, while epigenetic treatment increased <i>C/EBPα</i> mRNA levels <i>in vitro</i>, C/EBPα protein levels decreased. Using a computational microRNA (miRNA) prediction approach and functional studies, we show that <i>C/EBPα</i> mRNA is a target for miRNA-124a. This miRNA is frequently silenced by epigenetic mechanisms in leukemia cell lines, becomes up-regulated after epigenetic treatment, and targets the <i>C/EBPα</i> 3′ untranslated region. In this way, C/EBPα protein expression is reduced in a posttranscriptional manner. Our results indicate that epigenetic alterations of <i>C/EBPα</i> are a frequent event in AML and that epigenetic treatment can result in down-regulation of a key hematopoietic transcription factor. [Cancer Res 2008;68(9):3142–51]</p></div>