Epigenetic modification of CCAAT/enhancer binding protein alpha expression in acute myeloid leukemia

Authors:
Hackanson B, Bennett KL, Brena RM, Jiang J, Claus R, Chen SS, Blagitko-Dorfs N, Maharry K, Whitman SP, Schmittgen TD, L├╝bbert M, Marcucci G, Bloomfield CD, Plass C
In:
Source: Cancer Res
Publication Date: (2008)
Issue: 68(9): 3142-51
Research Area:
Cancer Research/Cell Biology
Immunotherapy / Hematology
Cells used in publication:
HL-60
Species: human
Tissue Origin: blood
Platform:
Nucleofector® I/II/2b
Abstract
Functional loss of CCAAT/enhancer binding protein alpha (C/EBP alpha), 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/EBP alpha expression in acute myeloid leukemia (AML). Comprehensive DNA methylation analyses of the CpG island of C/EBP alpha 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 C/EBP alpha mRNA levels in vitro, C/EBP alpha protein levels decreased. Using a computational microRNA (miRNA) prediction approach and functional studies, we show that C/EBP alpha 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 C/EBP alpha 3' untranslated region. In this way, C/EBP alpha protein expression is reduced in a posttranscriptional manner. Our results indicate that epigenetic alterations of C/EBP alpha are a frequent event in AML and that epigenetic treatment can result in down-regulation of a key hematopoietic transcription factor.