title: TCL1 targeting miR-3676 is codeleted with tumor protein p53 in chronic lymphocytic leukemia.
abstract: B-cell chronic lymphocytic leukemia (CLL) is the most common human leukemia and dysregulation of the T-cell leukemia/lymphoma 1 (TCL1) oncogene is a contributing event in the pathogenesis of the aggressive form of this disease based on transgenic mouse studies. To determine a role of microRNAs on the pathogenesis of the aggressive form of CLL we studied regulation of TCL1 expression in CLL by microRNAs. We identified miR-3676 as a regulator of TCL1 expression. We demonstrated that miR-3676 targets three consecutive 28-bp repeats within 3'UTR of TCL1 and showed that miR-3676 is a powerful inhibitor of TCL1. We further showed that miR-3676 expression is significantly down-regulated in four groups of CLL carrying the 11q deletions, 13q deletions, 17p deletions, or a normal karyotype compared with normal CD19(+) cord blood and peripheral blood B cells. In addition, the sequencing of 539 CLL samples revealed five germ-line mutations in six samples (1%) in miR-3676. Two of these mutations were loss-of-function mutations. Because miR-3676 is located at 17p13, only 500-kb centromeric of tumor protein p53 (Tp53), and is codeleted with Tp53, we propose that loss of miR-3676 causes high levels of TCL1 expression contributing to CLL progression.
authors: Department of Molecular Virology, Immunology and Medical Genetics, and.
authors: Veronica
authors: V
authors: Balatti
authors: Department of Molecular Virology, Immunology and Medical Genetics, and.
authors: Lara
authors: L
authors: Rizzotto
authors: Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210;
authors: Cecelia
authors: C
authors: Miller
authors: Department of Molecular Virology, Immunology and Medical Genetics, and.
authors: Alexey
authors: A
authors: Palamarchuk
authors: Department of Molecular Virology, Immunology and Medical Genetics, and.
authors: Paolo
authors: P
authors: Fadda
authors: Department of Molecular Virology, Immunology and Medical Genetics, and Department of Health Sciences, University "Magna Grecia" of Catanzaro, Catanzaro 88100, Italy; and.
authors: Rosantony
authors: R
authors: Pandolfo
authors: Department of Medicine, University of California, San Diego, La Jolla, CA 92093.
authors: Laura Z
authors: LZ
authors: Rassenti
authors: Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210;
authors: Erin
authors: E
authors: Hertlein
authors: Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210;
authors: Amy S
authors: AS
authors: Ruppert
authors: Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210;
authors: Arletta
authors: A
authors: Lozanski
authors: Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210;
authors: Gerard
authors: G
authors: Lozanski
authors: Department of Medicine, University of California, San Diego, La Jolla, CA 92093.
authors: Thomas J
authors: TJ
authors: Kipps
authors: Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210;
authors: John C
authors: JC
authors: Byrd
authors: Department of Molecular Virology, Immunology and Medical Genetics, and carlo.croce@osumc.edu pekarsky.yuri@osumc.edu.
authors: Carlo M
authors: CM
authors: Croce
authors: Department of Molecular Virology, Immunology and Medical Genetics, and carlo.croce@osumc.edu pekarsky.yuri@osumc.edu.
authors: Yuri
authors: Y
authors: Pekarsky
mesh_terms: D017353:Gene Deletion; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; C090851:TCL1A protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: 17p deletions; CLL; miR-3676
references: Genome Res. 2010 Jun;20(6):710-21
references: 20413673
references: Leukemia. 2010 May;24(5):970-5
references: 20357824
references: Blood. 2010 Nov 4;116(18):3537-46
references: 20530793
references: Semin Cancer Biol. 2010 Dec;20(6):370-6
references: 20863894
references: Hematology Am Soc Hematol Educ Program. 2010;2010:481-8
references: 21239840
references: PLoS One. 2011;6(2):e16403
references: 21346806
references: Blood. 2011 Sep 15;118(11):3072-9
references: 21636858
references: Blood. 2012 Feb 2;119(5):1182-9
references: 22180443
references: Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):2555-60
references: 22308499
references: J Clin Oncol. 2012 Jul 10;30(20):2483-91
references: 22564988
references: Curr Pharm Des. 2012;18(23):3363-72
references: 22591386
references: Blood. 2012 Dec 6;120(24):4783-94
references: 23047824
references: Am J Hematol. 2013 Sep;88(9):803-16
references: 23720127
references: Adv Exp Med Biol. 2013;792:109-31
references: 24014294
references: Trends Immunol. 2013 Dec;34(12):592-601
references: 23928062
references: Leukemia. 2014 Jan;28(1):118-28
references: 23608884
references: Leukemia. 2014 Jan;28(1):98-107
references: 23974981
references: Blood. 2014 Jul 3;124(1):42-8
references: 24868078
references: Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3028-33
references: 10716693
references: N Engl J Med. 2000 Dec 28;343(26):1910-6
references: 11136261
references: Proc Natl Acad Sci U S A. 2002 May 14;99(10):6955-60
references: 12011454
references: Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15524-9
references: 12434020
references: Blood. 2003 Feb 15;101(4):1220-35
references: 12393483
references: Nat Rev Cancer. 2005 Aug;5(8):640-8
references: 16056259
references: Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):13944-9
references: 16166262
references: N Engl J Med. 2005 Oct 27;353(17):1793-801
references: 16251535
references: Leukemia. 2006 Feb;20(2):280-5
references: 16341048
references: Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11713-8
references: 16864779
references: Nat Struct Mol Biol. 2006 Dec;13(12):1097-101
references: 17099701
references: Cancer Res. 2006 Dec 15;66(24):11590-3
references: 17178851
references: Proc Natl Acad Sci U S A. 2008 Apr 1;105(13):5166-71
references: 18362358
references: J Mol Diagn. 2008 Sep;10(5):442-51
references: 18687794
references: Genes Dev. 2008 Nov 15;22(22):3172-83
references: 19056895
references: Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19643-8
references: 19064921
references: Genes Dev. 2009 Jun 1;23(11):1247-69
references: 19487567
references: Genes Dev. 2009 Nov 15;23(22):2639-49
references: 19933153
references: Blood. 2009 Nov 12;114(20):4469-76
references: 19755673
references: RNA. 2010 Apr;16(4):673-95
references: 20181738
references: Proc Natl Acad Sci U S A. 2010 Jul 6;107(27):12210-5
references: 20566844