title: SPARC expression in CML is associated to imatinib treatment and to inhibition of leukemia cell proliferation.
abstract: BACKGROUND
  SPARC is a matricellular glycoprotein with growth-inhibitory and antiangiogenic activity in some cell types. The study of this protein in hematopoietic malignancies led to conflicting reports about its role as a tumor suppressor or promoter, depending on its different functions in the tumor microenvironment. In this study we investigated the variations in SPARC production by peripheral blood cells from chronic myeloid leukemia (CML) patients at diagnosis and after treatment and we identified the subpopulation of cells that are the prevalent source of SPARC.
  
  
  METHODS
  We evaluated SPARC expression using real-time PCR and western blotting. SPARC serum levels were detected by ELISA assay. Finally we analyzed the interaction between exogenous SPARC and imatinib (IM), in vitro, using ATP-lite and cell cycle analysis.
  
  
  RESULTS
  Our study shows that the CML cells of patients at diagnosis have a low mRNA and protein expression of SPARC. Low serum levels of this protein are also recorded in CML patients at diagnosis. However, after IM treatment we observed an increase of SPARC mRNA, protein, and serum level in the peripheral blood of these patients that had already started at 3 months and was maintained for at least the 18 months of observation. This SPARC increase was predominantly due to monocyte production. In addition, exogenous SPARC protein reduced the growth of K562 cell line and synergized in vitro with IM by inhibiting cell cycle progression from G1 to S phase.
  
  
  CONCLUSIONS
  Our results suggest that low endogenous SPARC expression is a constant feature of BCR/ABL positive cells and that IM treatment induces SPARC overproduction by normal cells. This exogenous SPARC may inhibit CML cell proliferation and may synergize with IM activity against CML.
authors: Department of Clinical and Molecular Biomedicine, University of Catania, Ospedale Ferrarotto, Italy.
authors: Cesarina
authors: C
authors: Giallongo
authors: Piera
authors: P
authors: La Cava
authors: Daniele
authors: D
authors: Tibullo
authors: Ignazio
authors: I
authors: Barbagallo
authors: Nunziatina
authors: N
authors: Parrinello
authors: Alessandra
authors: A
authors: Cupri
authors: Fabio
authors: F
authors: Stagno
authors: Carla
authors: C
authors: Consoli
authors: Annalisa
authors: A
authors: Chiarenza
authors: Giuseppe A
authors: GA
authors: Palumbo
authors: Francesco
authors: F
authors: Di Raimondo
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides / Q000627:therapeutic use*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D015676:Osteonectin; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013997:Time Factors; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D015676:Osteonectin; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; C577241:SPARC protein, human; D025521:Tumor Suppressor Proteins; D000068877:Imatinib Mesylate
references: J Cell Biochem. 1998 Sep 15;70(4):543-52
references: 9712151
references: Hematol J. 2004;5(2):168-77
references: 15048068
references: Cancer Metastasis Rev. 2008 Dec;27(4):691-705
references: 18542844
references: Exp Hematol. 2009 Apr;37(4):461-8
references: 19302920
references: Nature. 1982 Dec 23;300(5894):765-7
references: 6960256
references: Blood. 2002 Mar 15;99(6):1928-37
references: 11877262
references: Leukemia. 2006 Mar;20(3):426-32
references: 16424866
references: N Engl J Med. 2001 Apr 5;344(14):1038-42
references: 11287973
references: Br J Haematol. 1997 Mar;96(4):876-7
references: 9074438
references: N Engl J Med. 2003 Mar 13;348(11):994-1004
references: 12637609
references: Biochem Biophys Res Commun. 2007 Apr 27;356(1):6-12
references: 17343824
references: Am J Pathol. 2001 Aug;159(2):609-22
references: 11485919
references: J Biol Chem. 1997 Jul 18;272(29):18411-7
references: 9218484
references: Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1281-5
references: 1311092
references: Cancer Res. 2007 Feb 1;67(3):1113-20
references: 17283145
references: Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11406-11
references: 17576924
references: Hematol Oncol. 2012 Mar;30(1):27-33
references: 21544849
references: Blood. 2006 Jun 1;107(11):4532-9
references: 16469872
references: J Biol Chem. 1998 Nov 6;273(45):29635-40
references: 9792673
references: Haematologica. 2008 Jul;93(7):1101-3
references: 18508797
references: Matrix Biol. 2000 Dec;19(7):569-80
references: 11102747
references: Mol Cancer. 2010 Jun 04;9:138
references: 20525313
references: N Engl J Med. 2006 May 11;354(19):2006-13
references: 16687713
references: N Engl J Med. 2006 Dec 7;355(23):2494-5
references: 17151376
references: J Cell Biochem. 2004 Jul 1;92(4):679-90
references: 15211566
references: Leukemia. 2005 Jun;19(6):1034-41
references: 15815728
references: Blood. 2008 Mar 1;111(5):2538-47
references: 18042796
references: Leuk Res. 2008 Jun;32(6):962-71
references: 18190961
references: Cancer Res. 2010 Dec 1;70(23):9659-70
references: 21098700
references: Oncogene. 2000 May 15;19(21):2496-504
references: 10851048
references: Semin Hematol. 2003 Apr;40(2 Suppl 2):11-4
references: 12783369
references: J Clin Invest. 2005 Jun;115(6):1492-502
references: 15902309
references: Cancer Res. 2005 Apr 15;65(8):3264-72
references: 15833859
references: Cell. 1981 Oct;26(1 Pt 1):99-105
references: 7034958
references: Proc Natl Acad Sci U S A. 1991 Apr 1;88(7):2648-52
references: 2011576
references: Cancer Res. 2002 Dec 15;62(24):7357-63
references: 12499280
references: Mol Cell Biol. 2000 Feb;20(4):1179-86
references: 10648603
references: Leukemia. 2004 Feb;18(2):189-218
references: 14737178
references: Cancer Cell. 2002 Jun;1(5):479-92
references: 12124177
references: Exp Cell Res. 2010 May 1;316(8):1390-6
references: 20211165
references: Br J Haematol. 2003 Sep;122(5):728-44
references: 12930383
references: Blood. 2002 Jan 1;99(1):319-25
references: 11756187