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Nucleic Acids Research 2005 33(21):6895-6905; doi:10.1093/nar/gki1001
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Published online 7 December 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oxfordjournals.org

Article

Down-regulation of interferon regulatory factor 4 gene expression in leukemic cells due to hypermethylation of CpG motifs in the promoter region

Christina A. Ortmann, Andreas Burchert, Katharina Hölzle, Andreas Nitsche1, Burghardt Wittig2,3, Andreas Neubauer and Manuel Schmidt2,*

Klinik für Hämatologie, Onkologie and Immunologie, Zentrum Innere Medizin, Klinikum der Philipps-Universität Marburg, Germany 1Robert-Koch-Institut Berlin, Germany 2MOLOGEN AG Berlin, Germany 3Abteilung Molekularbiologie und Bioinformatik, Universitätsmedizin Berlin Charité–Campus Benjamin Franklin, Berlin, Germany

*To whom correspondence should be addressed. Tel: +49 30 8417 156; Fax: +49 30 8445 1516; Email: maschmidt{at}mologen.com

Received August 23, 2005. Revised October 10, 2005. Accepted November 15, 2005.

Although the bcr-abl translocation has been shown to be the causative genetic aberration in chronic myeloid leukemia (CML), there is mounting evidence that the deregulation of other genes, such as the transcription factor interferon regulatory factor 4 (IRF-4), is also implicated in the pathogenesis of CML. Promoter methylation of CpG target sites or direct deletions/insertions of genes are mechanisms of a reversible or permanent silencing of gene expression, respectively. Therefore, we investigated whether IRF-4 promoter methylation or mutation may be involved in the regulation of IRF-4 expression in leukemia cells. Whereas promoter mutations or structural rearrangements could be excluded as a cause of altered IRF-4 expression in hematopoietic cells, the IRF-4 promoter methylation status was found to significantly influence IRF-4 transcription. First, treatment of IRF-4-negative lymphoid, myeloid and monocytic cell lines with the methylation-inhibitor 5-aza-2-deoxycytidine resulted in a time- and concentration-dependent increase of IRF-4 mRNA and protein levels. Second, using a restriction-PCR-assay and bisulfite-sequencing we identified specifically methylated CpG sites in IRF-4-negative but not in IRF-4-positive cells. Third, we clearly determined promoter methylation as a mechanism for IRF-4 down-regulation via reporter gene assays, but did not detect an association of methylational status and mRNA expression of DNA methyltransferases or methyl-CpG-binding proteins. Together, these data suggest CpG site-specific IRF-4 promoter methylation as a putative mechanism of down-regulated IRF-4 expression in leukemia.


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