Epigenetic modification of CCAAT/enhancer binding protein alpha expression in acute myeloid leukemia.
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.
Hackanson
Björn
B
Department of Molecular Virology, Immunology and Medical Genetics, Division of Human Cancer Genetics, College of Pharmacy, Ohio State University, Columbus, Ohio, USA. bjoern.hackanson@uniklinik-freiburg.de
Bennett
Kristi L
KL
Brena
Romulo M
RM
Jiang
Jinmai
J
Claus
Rainer
R
Chen
Shih-Shih
SS
Blagitko-Dorfs
Nadya
N
Maharry
Katie
K
Whitman
Susan P
SP
Schmittgen
Thomas D
TD
Lübbert
Michael
M
Marcucci
Guido
G
Bloomfield
Clara D
CD
Plass
Christoph
C
D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics* / Q000378:metabolism; D016000:Cluster Analysis; D020732:Cytogenetic Analysis; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015973:Gene Expression Regulation, Leukemic; D018922:HL-60 Cells; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000145:classification / Q000235:genetics*; D035683:MicroRNAs / Q000502:physiology; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D014407:Tumor Cells, Cultured; D020298:U937 Cells
D022763:CCAAT-Enhancer-Binding Protein-alpha; C509207:MIRN124 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger