title: Role of CXCR4 in the pathogenesis of acute myeloid leukemia.
abstract: The Chemokine receptor CXCR4 and its ligand stromal derived factor-1 (SDF-1/CXCL12) are important players involved in cross-talk between leukemia cells and the bone marrow (BM) microenvironment. CXCR4 expression is associated with poor prognosis in AML patients with and without the mutated FLT3 gene.CXCL12 which is constrictively secreted from the BM stroma and AML cells is critical for the survival and retention of AML cells within the BM. In vitro, CXCR4 antagonists were shown to inhibit the migration of AML cells in response to CXCL12. In addition, such antagonists were shown to inhibit the survival and colony forming potential of AML cells and abrogate the protective effects of stromal cells on chemotherapy-induced apoptosis in AML cells. In vivo, using immune deficient mouse models, CXCR4 antagonists were found to induce the mobilization of AML cells and progenitor cells into the circulation and enhance anti leukemic effects of chemotherapy. The hypothesis that CXCL12/CXCR4 interactions contribute to the resistance of AML cells to signal transduction inhibitor- and chemotherapy-induced apoptosis is currently being tested in a series of Phase I/II studies in humans.
authors: Goldyne Savad Institute of Gene Therapy, Hebrew University Hospital, P.O.B 12000, Jerusalem 91120, Israel. peled@hadassah.org.il
authors: Amnon
authors: A
authors: Peled
authors: Sigal
authors: S
authors: Tavor
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D060833:Cellular Microenvironment / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000473:pathology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D055153:Stem Cell Niche / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D019718:Receptors, CXCR4
keywords: AML; Bone marrow; CXCL12; CXCR4; Microenvironment.
references: Lancet. 2006 Nov 25;368(9550):1894-907
references: 17126723
references: Blood. 2004 Jul 15;104(2):550-7
references: 15054042
references: Leukemia. 2009 Jan;23(1):43-52
references: 18987663
references: J Exp Med. 2009 Aug 31;206(9):1957-70
references: 19687226
references: Blood. 2009 Jun 11;113(24):6215-24
references: 18955566
references: Blood. 2009 Jun 11;113(24):6206-14
references: 19050309
references: Cancer Res. 2004 Apr 15;64(8):2817-24
references: 15087398
references: Stem Cells. 2004;22(2):188-201
references: 14990858
references: Leukemia. 2002 Sep;16(9):1818-26
references: 12200698
references: Nat Med. 2006 Oct;12(10):1167-74
references: 16998484
references: Blood. 2004 Apr 15;103(8):2981-9
references: 15070674
references: Leuk Res. 2009 Jun;33(6):764-8
references: 19042019
references: Exp Hematol. 2011 Mar;39(3):282-92
references: 21138752
references: Blood. 2007 Jan 15;109(2):786-91
references: 16888090
references: Blood. 2000 Jun 1;95(11):3289-96
references: 10828007
references: Nature. 2005 Jun 16;435(7044):969-73
references: 15959517
references: FASEB J. 2006 Sep;20(11):1913-5
references: 16818471
references: Nat Med. 2003 Sep;9(9):1158-65
references: 12897778
references: Cancer. 2007 Mar 15;109(6):1152-6
references: 17315232
references: Blood. 2010 Dec 9;116(24):5306-15
references: 20810927
references: Leukemia. 2008 Dec;22(12):2151-5158
references: 18769446
references: Leuk Res. 2007 Nov;31(11):1553-63
references: 17403536
references: Cell Death Dis. 2012 Oct 04;3:e396
references: 23034331
references: Br J Haematol. 2000 Sep;110(3):563-72
references: 10997965
references: Blood. 2012 Apr 26;119(17):3917-24
references: 22308295
references: Nat Biotechnol. 2007 Nov;25(11):1315-21
references: 17952057
references: Leukemia. 2002 Apr;16(4):650-7
references: 11960346
references: Blood. 2009 Feb 12;113(7):1504-12
references: 18957686
references: Clin Cancer Res. 2013 Jan 15;19(2):357-66
references: 23213054
references: Blood. 1998 Jun 15;91(12):4523-30
references: 9616148
references: Leukemia. 2011 Mar;25(3):515-26
references: 21116281