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

¹ Department of Molecular Virology, Immunology and Medical Genetics, Division of Human Cancer Genetics, ² Department of Molecular Genetics, ³ College of Pharmacy, and ⁴ Department of Internal Medicine, Division of Hematology and Oncology, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio; ⁵ The Cancer and Leukemia Group B Statistical Center, Duke University Medical Center, Durham, North Carolina; ⁶ Department of Hematology and Oncology, University of Freiburg Medical Center, Freiburg, Germany; and ⁷ German Cancer Research Center, Heidelberg, Germany

Requests for reprints: Björn Hackanson, Universitätsklinik Freiburg, Abteilung Hämatologie/Onkologie, Hugstetterstrasse 55, 79106 Freiburg, Germany. Phone: 49-761-2707715; Fax: 49-761-2703697; E-mail: bjoern.hackanson{at}uniklinik-freiburg.de or Christoph Plass, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg. Phone: 49-6221-42-3300; Fax: 49-6221-42-3359; E-mail: c.plass{at}dkfz-heidelberg.de.

Key Words: AML • epigenetic • microRNA

Functional loss of CCAAT/enhancer binding protein (C/EBP), 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 expression in acute myeloid leukemia (AML). Comprehensive DNA methylation analyses of the CpG island of C/EBP 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 mRNA levels in vitro, C/EBP protein levels decreased. Using a computational microRNA (miRNA) prediction approach and functional studies, we show that C/EBP 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 3' untranslated region. In this way, C/EBP protein expression is reduced in a posttranscriptional manner. Our results indicate that epigenetic alterations of C/EBP 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]

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