title: miRNA deregulation by epigenetic silencing disrupts suppression of the oncogene PLAG1 in chronic lymphocytic leukemia.
abstract: 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.
authors.affiliation: 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.
authors.forename: Christian Philipp
authors.initials: CP
authors.lastname: Pallasch
authors.forename: Michaela
authors.initials: M
authors.lastname: Patz
authors.forename: Yoon Jung
authors.initials: YJ
authors.lastname: Park
authors.forename: Susanne
authors.initials: S
authors.lastname: Hagist
authors.forename: Daniela
authors.initials: D
authors.lastname: Eggle
authors.forename: Rainer
authors.initials: R
authors.lastname: Claus
authors.forename: Svenja
authors.initials: S
authors.lastname: Debey-Pascher
authors.forename: Alexandra
authors.initials: A
authors.lastname: Schulz
authors.forename: Lukas P
authors.initials: LP
authors.lastname: Frenzel
authors.forename: Julia
authors.initials: J
authors.lastname: Claasen
authors.forename: Nadine
authors.initials: N
authors.lastname: Kutsch
authors.forename: Günter
authors.initials: G
authors.lastname: Krause
authors.forename: Christine
authors.initials: C
authors.lastname: Mayr
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.forename: Joachim L
authors.initials: JL
authors.lastname: Schultze
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
authors.forename: Clemens-Martin
authors.initials: CM
authors.lastname: Wendtner
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D001402:B-Lymphocytes / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D020871:RNA Stability; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D004268:DNA-Binding Proteins; D035683:MicroRNAs; D015513:Oncogene Proteins; C104382:PLAG1 protein, human; D012334:RNA, Neoplasm
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