miRNA deregulation by epigenetic silencing disrupts suppression of the oncogene PLAG1 in chronic lymphocytic leukemia.
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.
Pallasch
Christian Philipp
CP
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.
Patz
Michaela
M
Park
Yoon Jung
YJ
Hagist
Susanne
S
Eggle
Daniela
D
Claus
Rainer
R
Debey-Pascher
Svenja
S
Schulz
Alexandra
A
Frenzel
Lukas P
LP
Claasen
Julia
J
Kutsch
Nadine
N
Krause
Günter
G
Mayr
Christine
C
Rosenwald
Andreas
A
Plass
Christoph
C
Schultze
Joachim L
JL
Hallek
Michael
M
Wendtner
Clemens-Martin
CM
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
D020413:3' Untranslated Regions; D004268:DNA-Binding Proteins; D035683:MicroRNAs; D015513:Oncogene Proteins; C104382:PLAG1 protein, human; D012334:RNA, Neoplasm
Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3627-32
15738415
Oncogene. 2004 Jan 8;23(1):179-91
14712223
Nucleic Acids Res. 2008 Aug;36(14):e87
18579563
Mol Cancer Res. 2003 Oct;1(12):882-91
14573789
Bioinformatics. 2008 Feb 1;24(3):325-32
18048393
Genome Res. 2004 Oct;14(10A):1902-10
15364901
Science. 2001 Oct 26;294(5543):858-62
11679671
Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15785-90
16243968
Nature. 2008 Sep 4;455(7209):58-63
18668040
Nature. 2005 Jun 9;435(7043):834-8
15944708
Cell. 2005 Jan 14;120(1):15-20
15652477
Immunity. 2008 May;28(5):630-8
18455451
Immunity. 2009 May;30(5):744-52
19446474
Leukemia. 2008 Feb;22(2):330-8
17989717
Blood. 2009 Apr 16;113(16):3801-8
18941118
BMC Bioinformatics. 2008 Dec 22;9:552
19099609
Nat Genet. 2005 May;37(5):495-500
15806104
BMC Bioinformatics. 2007 Aug 06;8:290
17683603
PLoS Biol. 2004 Nov;2(11):e363
15502875
Blood. 2005 Apr 1;105(7):2900-7
15585652
Cell. 2009 Feb 20;136(4):586-91
19239879
Blood. 2006 Jan 15;107(2):742-51
16179374
Science. 2007 Mar 16;315(5818):1576-9
17322030
Mol Cell. 2007 Jul 6;27(1):91-105
17612493
Genes Dev. 2008 Nov 15;22(22):3172-83
19056895
Science. 2007 Apr 27;316(5824):604-8
17463289
N Engl J Med. 2000 Dec 28;343(26):1910-6
11136261
Int J Cancer. 2008 Oct 1;123(7):1593-600
18649356
Nat Genet. 1997 Feb;15(2):170-4
9020842
Blood. 2000 Nov 1;96(9):3181-7
11050001
RNA. 2005 Mar;11(3):241-7
15701730
Int J Oncol. 2007 Apr;30(4):765-74
17332914
Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15524-9
12434020
Cell. 2003 Dec 26;115(7):787-98
14697198
Cell. 2008 Jan 11;132(1):9-14
18191211
Lab Invest. 2009 Jun;89(6):708-16
19349957
Blood. 2007 Jun 1;109(11):4944-51
17327404
J Biol Chem. 1998 Sep 4;273(36):23026-32
9722527
Cancer Res. 2004 Apr 1;64(7):2424-33
15059895
J Pathol. 2008 May;215(1):13-20
18348159