title: Micro-RNA response to imatinib mesylate in patients with chronic myeloid leukemia.
abstract: BACKGROUND
  Micro-RNAs (miRNAs) control gene expression by destabilizing targeted transcripts and inhibiting their translation. Aberrant expression of miRNAs has been described in many human cancers, including chronic myeloid leukemia. Current first-line therapy for newly diagnosed chronic myeloid leukemia is imatinib mesylate, which typically produces a rapid hematologic response. However the effect of imatinib on miRNA expression in vivo has not been thoroughly examined.
  
  
  METHODS
  Using a TaqMan Low-Density Array system, we analyzed miRNA expression in blood samples from newly diagnosed chronic myeloid leukemia patients before and within the first two weeks of imatinib therapy. Quantitative real-time PCR was used to validate imatinib-modulated miRNAs in sequential primary chronic myeloid leukemia samples (n=11, plus 12 additional validation patients). Bioinformatic target gene prediction analysis was performed based on changes in miRNA expression.
  
  
  RESULTS
  We observed increased expression of miR-150 and miR-146a, and reduced expression of miR-142-3p and miR-199b-5p (3-fold median change) after two weeks of imatinib therapy. A significant correlation (P<0.05) between the Sokal score and pre-treatment miR-142-3p levels was noted. Expression changes in the same miRNAs were consistently found in an additional cohort of chronic myeloid leukemia patients, as compared to healthy subjects. Peripheral blood cells from chronic phase and blast crisis patients displayed a 30-fold lower expression of miR-150 compared to normal samples, which is of particular interest since c-Myb, a known target of miR-150, was recently shown to be necessary for Bcr-Abl-mediated transformation.
  
  
  CONCLUSIONS
  We found that imatinib treatment of chronic myeloid leukemia patients rapidly normalizes the characteristic miRNA expression profile, suggesting that miRNAs may serve as a novel clinically useful biomarker in this disease.
authors.affiliation: Gene and Stem Cell Therapy Program, Centenary Institute, Locked Bag No 6, Newtown, NSW 2042, Australia.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Flamant
authors.forename: William
authors.initials: W
authors.lastname: Ritchie
authors.forename: Joëlle
authors.initials: J
authors.lastname: Guilhot
authors.forename: Jeff
authors.initials: J
authors.lastname: Holst
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Bonnet
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Chomel
authors.forename: François
authors.initials: F
authors.lastname: Guilhot
authors.forename: Ali G
authors.initials: AG
authors.lastname: Turhan
authors.forename: John E J
authors.initials: JE
authors.lastname: Rasko
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D002478:Cells, Cultured; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D000068877:Imatinib Mesylate; D035683:MicroRNAs; D010879:Piperazines; D011743:Pyrimidines; C533097:MIR150, human
references.citation: Genome Res. 2009 Jan;19(1):92-105
references.pmid: 18955434
references.citation: Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15524-9
references.pmid: 12434020
references.citation: Proc Natl Acad Sci U S A. 2006 May 9;103(19):7444-9
references.pmid: 16651519
references.citation: Proc Natl Acad Sci U S A. 2000 Feb 29;97(5):2145-50
references.pmid: 10681437
references.citation: Cell. 2007 Oct 5;131(1):146-59
references.pmid: 17923094
references.citation: Cell. 2009 Feb 20;136(4):642-55
references.pmid: 19239886
references.citation: Mol Cancer Res. 2008 Dec;6(12):1830-40
references.pmid: 19074828
references.citation: Nat Methods. 2009 Jun;6(6):397-8
references.pmid: 19478799
references.citation: Leukemia. 2009 Jun;23(6):1054-61
references.pmid: 19282833
references.citation: Cell. 2009 Jan 9;136(1):26-36
references.pmid: 19135886
references.citation: Oncogene. 1997 Nov 6;15(19):2267-75
references.pmid: 9393872
references.citation: Dev Cell. 2008 Jun;14(6):843-53
references.pmid: 18539114
references.citation: Blood. 1991 Oct 1;78(7):1826-33
references.pmid: 1912569
references.citation: Blood. 2008 Mar 15;111(6):3183-9
references.pmid: 18187662
references.citation: Blood. 1985 Dec;66(6):1352-7
references.pmid: 3904870
references.citation: Nat Genet. 2000 Sep;26(1):103-5
references.pmid: 10973259
references.citation: Blood. 2007 May 15;109(10):4399-405
references.pmid: 17284533
references.citation: PLoS One. 2009;4(3):e4998
references.pmid: 19308264
references.citation: Nat Immunol. 2008 Apr;9(4):405-14
references.pmid: 18327259
references.citation: Nat Rev Cancer. 2005 Mar;5(3):172-83
references.pmid: 15719031
references.citation: Nature. 2005 Jun 9;435(7043):828-33
references.pmid: 15944707
references.citation: Brain Res. 2009 May 7;1269:158-65
references.pmid: 19265686
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2257-61
references.pmid: 16461460
references.citation: Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15535-40
references.pmid: 18832181
references.citation: Nature. 2007 Sep 13;449(7159):183-8
references.pmid: 17728715
references.citation: Oncogene. 2008 Sep 18;27(42):5643-7
references.pmid: 18504431
references.citation: Mol Cancer Ther. 2008 Feb;7(2):391-7
references.pmid: 18245668
references.citation: N Engl J Med. 2005 Oct 27;353(17):1793-801
references.pmid: 16251535
references.citation: Genes Dev. 2006 Oct 1;20(19):2673-86
references.pmid: 16983145
references.citation: Science. 2004 Jan 2;303(5654):83-6
references.pmid: 14657504
references.citation: Nature. 2006 Aug 17;442(7104):779-85
references.pmid: 16915281
references.citation: Nature. 2005 Jun 9;435(7043):834-8
references.pmid: 15944708
references.citation: Blood. 2008 May 1;111(9):4771-9
references.pmid: 18227349
references.citation: Cell. 2009 Jan 23;136(2):215-33
references.pmid: 19167326
references.citation: Leukemia. 1998 Dec;12(12):1858-65
references.pmid: 9844916
references.citation: Genes Dev. 1998 Apr 1;12(7):968-81
references.pmid: 9531535
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19971-6
references.pmid: 18056805
references.citation: Leuk Res. 2009 Jan;33(1):109-14
references.pmid: 18687467
references.citation: EMBO J. 1996 Dec 16;15(24):7026-35
references.pmid: 9003778
references.citation: Leukemia. 2008 Feb;22(2):330-8
references.pmid: 17989717
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12481-6
references.pmid: 16885212
references.citation: Science. 1986 Jul 18;233(4761):347-51
references.pmid: 3014652
references.citation: Cancer Res. 2008 Dec 15;68(24):10105-12
references.pmid: 19074876
references.citation: Curr Opin Hematol. 2008 Jul;15(4):352-8
references.pmid: 18536574
references.citation: J Exp Med. 2008 Mar 17;205(3):585-94
references.pmid: 18299402