Document Detail


miRNA deregulation by epigenetic silencing disrupts suppression of the oncogene PLAG1 in chronic lymphocytic leukemia.
MedLine Citation:
PMID:  19692702     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Christian Philipp Pallasch; Michaela Patz; Yoon Jung Park; Susanne Hagist; Daniela Eggle; Rainer Claus; Svenja Debey-Pascher; Alexandra Schulz; Lukas P Frenzel; Julia Claasen; Nadine Kutsch; Günter Krause; Christine Mayr; Andreas Rosenwald; Christoph Plass; Joachim L Schultze; Michael Hallek; Clemens-Martin Wendtner
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-08-19
Journal Detail:
Title:  Blood     Volume:  114     ISSN:  1528-0020     ISO Abbreviation:  Blood     Publication Date:  2009 Oct 
Date Detail:
Created Date:  2009-10-09     Completed Date:  2009-10-27     Revised Date:  2013-05-31    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3255-64     Citation Subset:  AIM; IM    
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.
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MeSH Terms
Descriptor/Qualifier:
3' Untranslated Regions / genetics
B-Lymphocytes / metabolism
DNA-Binding Proteins / biosynthesis*,  genetics
Female
Gene Expression Regulation, Neoplastic*
Gene Silencing*
Humans
Leukemia, Lymphocytic, Chronic, B-Cell / genetics,  metabolism*
Male
MicroRNAs / genetics,  metabolism*
Oncogene Proteins / biosynthesis*,  genetics
Promoter Regions, Genetic / genetics
RNA Stability*
RNA, Neoplasm / genetics,  metabolism*
Transcription, Genetic / genetics
Grant Support
ID/Acronym/Agency:
CA101956/CA/NCI NIH HHS; P01 CA101956/CA/NCI NIH HHS; P01 CA101956-01A20002/CA/NCI NIH HHS; R01 DE013123/DE/NIDCR NIH HHS; R01 DE013123-07/DE/NIDCR NIH HHS
Chemical
Reg. No./Substance:
0/3' Untranslated Regions; 0/DNA-Binding Proteins; 0/MicroRNAs; 0/Oncogene Proteins; 0/PLAG1 protein, human; 0/RNA, Neoplasm
Comments/Corrections

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