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Blood, 8 October 2009, Vol. 114, No. 15, pp. 3255-3264. Prepublished online as a Blood First Edition Paper on August 19, 2009; DOI 10.1182/blood-2009-06-229898. This Article Full Text Full Text (PDF) Supplemental Tables and Figures All Versions of this Article: blood-2009-06-229898v1 114/15/3255    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Pallasch, C. P. Articles by Wendtner, C.-M. PubMed PubMed Citation Articles by Pallasch, C. P. Articles by Wendtner, C.-M. Related Collections Lymphoid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA miRNA deregulation by epigenetic silencing disrupts suppression of the oncogene PLAG1 in chronic lymphocytic leukemia Christian Philipp Pallasch1, Michaela Patz1, Yoon Jung Park2, Susanne Hagist1, Daniela Eggle1, Rainer Claus2, Svenja Debey-Pascher3, Alexandra Schulz1, Lukas P. Frenzel1, Julia Claasen1, Nadine Kutsch1, Günter Krause1, Christine Mayr4, Andreas Rosenwald5, Christoph Plass2, Joachim L. Schultze3, Michael Hallek1, and Clemens-Martin Wendtner1 1 Department I of Internal Medicine, Center of Integrated Oncology and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany; 2 Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany; 3 Institute for Life and Medical Sciences, Genomics and Immunoregulation, University of Bonn, Bonn, Germany; 4 Whitehead Institute, Massachusetts Institute of Technology, Cambridge; and 5 Institute of Pathology, University of Würzburg, Würzburg, Germany MicroRNAs (miRNA) play a key role in cellular regulation and, if deregulated, in the development of neoplastic disorders including chronic lymphocytic leukemia (CLL). RNAs from primary cells of 50 treatment-naive CLL patients and peripheral B cells of 14 healthy donors were applied to miRNA expression profiling using bead chip technology. In CLL cells, a set of 7 up- and 19 down-regulated miRNAs was identified. Among the miRNAs down-regulated in CLL cells, 6 of 10 miRNA promoters examined showed gain of methylation compared with normal B-cell controls. Subsequent target prediction of deregulated miRNAs revealed a highly significant binding prediction at the 3' untranslated region of the pleomorphic adenoma gene 1 (PLAG1) oncogene. Luciferase reporter assays including site-directed mutagenesis of binding sites revealed a significant regulation of PLAG1 by miR-181a, miR-181b, miR-107, and miR-424. Although expression of PLAG1 mRNA was not affected, PLAG1 protein expression was shown to be significantly elevated in CLL cells compared with the levels in healthy donor B cells. In summary, we could demonstrate disruption of miRNA-mediated translational control, partly due to epigenetic transcriptional silencing of miRNAs, with subsequent overexpression of the oncogenic transcription factor PLAG1 as a putative novel mechanism of CLL pathogenesis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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