title: Abnormal growth factor modulation of beta1-integrin-mediated adhesion in chronic myelogenous leukaemia haematopoietic progenitors.
abstract: Abnormal progenitor circulation and extramedullary haematopoiesis are characteristic features of chronic myelogenous leukaemia (CML). Growth factor (GF) and beta1-integrin interactions play an important role in regulation of progenitor trafficking to and from the marrow space. CML progenitors demonstrate abnormal beta1-integrin-mediated adhesion to fibronectin (FN). In the present study we investigated whether GF modulation of beta1-integrin-mediated adhesion and migration was altered in CML progenitors. Culture with low concentrations of GF enhanced normal progenitor adhesion to FN compared with no GF, but failed to enhance CML progenitor adhesion to FN. Similarly, high concentrations of selected GF rapidly enhanced beta1-integrin-mediated adhesion of normal progenitors to FN through a phosphotidylinositol-3 (PI-3) kinase-dependent mechanism, but failed to increase CML progenitor adhesion. Exposure to a BCR-ABL tyrosine kinase inhibitor restored GF modulation of CML progenitor adhesion. CML colony-forming cells (CFC) demonstrated increased migration across FN-coated transwells compared with normal CFC in the absence of GF. The addition of stem cell factor resulted in enhanced migration of CML and normal CFC on FN. In conclusion, GF stimulation failed to enhance integrin-mediated adhesion but enhanced migration in CML progenitors on FN. BCR-ABL induced abnormalities in GF-integrin interactions could contribute to abnormal circulation and microenvironmental localization of CML progenitors.
authors.affiliation: Division of Hematology and Bone Marrow Transplantation, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA. rbhatia@coh.org
authors.forename: R
authors.initials: R
authors.lastname: Bhatia
authors.forename: H A
authors.initials: HA
authors.lastname: Munthe
authors.forename: S J
authors.initials: SJ
authors.lastname: Forman
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D016022:Case-Control Studies; D002448:Cell Adhesion / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D054407:Chemokine CCL4; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005353:Fibronectins / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000494:pharmacology; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology*; D006360:Heat-Shock Proteins / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D019012:Integrin beta1 / Q000502:physiology*; D007377:Interleukin-3 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D053605:Leukemia Inhibitory Factor; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood* / Q000276:immunology; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology; D008565:Membrane Proteins / Q000494:pharmacology; D008840:Microfilament Proteins; D018832:Molecular Chaperones / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011506:Proteins; D029702:Schizosaccharomyces pombe Proteins; D020032:Tyrphostins / Q000494:pharmacology; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D018797:Cell Cycle Proteins; D054407:Chemokine CCL4; D002867:Chromones; D004791:Enzyme Inhibitors; D005353:Fibronectins; D006133:Growth Substances; D006360:Heat-Shock Proteins; D019012:Integrin beta1; D007377:Interleukin-3; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D019402:Macrophage Inflammatory Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D018832:Molecular Chaperones; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011506:Proteins; C099792:Scf1 protein, S pombe; D029702:Schizosaccharomyces pombe Proteins; D020032:Tyrphostins; C115237:actin interacting protein 1; C084881:flt3 ligand protein; C104965:tyrphostin AG957; D016179:Granulocyte Colony-Stimulating Factor; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D016044:Fusion Proteins, bcr-abl; D000077191:Wortmannin