title: Human acute myeloid leukemia cells bind to bone marrow stroma via a combination of beta-1 and beta-2 integrin mechanisms.
abstract: Acute myeloid leukemia (AML) cells respond to exogenous stimulation from myeloid growth factors that may be secreted by cells of the bone marrow (BM) stroma and retained by glycosaminoglycans in the extracellular matrix. We have analyzed the capacity of malignant cells from patients with AML to maintain close proximity to sites of growth factor production and retention by binding to BM stromal elements, including fibroblasts and extracellular matrix proteins. Leukemic cells from all cases of AML adhered to BM fibroblast (BMF) monolayers (mean +/- standard error [SE] percentage binding, 30.9% +/- 2.5%; n = 23) and to fibronectin and laminin (mean +/- SE percentage binding, 28.0% +/- 4.1% [n = 11] and 21.5% +/- 2.3% [n = 8], respectively). Binding to bovine and human collagen type 1, vitronectin, hyaluronic acid, and albumin was minimal. Analysis of binding mechanisms indicated that very late antigen-4 (VLA-4) and VLA-5 were responsible for AML cell binding to fibronectin. Binding to laminin could be inhibited by antibody to the alpha chain of VLA-6. In contrast, AML cell adhesion to BMF monolayers was not impaired by blocking antibodies to either beta 1 or beta 2 integrins used alone, although the combination of anti-CD11/CD18 and anti-VLA-4 inhibited binding in more than 50% of cases. When anti-VLA-5 was added in these cases, mean +/- SE inhibition of binding of 45.5% +/- 9.1% (P < .001) was observed. Binding of AML cells to extracellular matrix proteins fibronectin and laminin is predominantly beta 1-integrin-dependent, but AML cell adhesion to BMF relies on the simultaneous involvement of beta 1 and beta 2 integrins as well as other currently unrecognized ligands.
authors.affiliation: Department of Haematology, Westmead Hospital, Westmead New South Wales, Sydney, Australia.
authors.forename: L J
authors.initials: LJ
authors.lastname: Bendall
authors.forename: K
authors.initials: K
authors.lastname: Kortlepel
authors.forename: D J
authors.initials: DJ
authors.lastname: Gottlieb
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000276:immunology; D001853:Bone Marrow / Q000473:pathology*; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000502:physiology; D002675:Child, Preschool; D005260:Female; D005353:Fibronectins / Q000502:physiology; D006801:Humans; D007223:Infant; D019012:Integrin beta1; D016023:Integrins / Q000502:physiology*; D007797:Laminin / Q000502:physiology; D015470:Leukemia, Myeloid, Acute / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D017154:Stromal Cells / Q000473:pathology; D019010:Vascular Cell Adhesion Molecule-1
chemical_list: D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D005353:Fibronectins; D019012:Integrin beta1; D016023:Integrins; D007797:Laminin; D019010:Vascular Cell Adhesion Molecule-1