title: Migration of acute lymphoblastic leukemia cells into human bone marrow stroma.
abstract: Most cases of acute lymphoblastic leukemia (ALL) arise from malignant transformation of B-cell precursors in the bone marrow. Recent studies have shown that normal and leukemic B-cell precursors bind to bone marrow stromal cells through the beta-1 integrins VLA-4 and VLA-5, thereby exposing early lymphoid cells to regulatory cytokines. It has been recently reported that the pre-B cell line NALM-6 is capable of migrating under layers of murine stromal cells in vitro (Miyake et al. J Cell Biol 1992;119:653-662). We have further analyzed leukemic cell motility using human bone marrow fibroblasts (BMF) as a stromal layer. The precursor-B ALL cell line NALM-6 rapidly adhered to BMF, and underwent migration or tunneling into BMF layers within 5 h, as demonstrated by light and electron microscopy, and confirmed by a chromium-labeling assay. Migration was also observed with the precursor-B ALL lines Reh and KM-3, with a T leukemia line RPMI-8402, the monocytic line U937, and the mature B line Daudi. In contrast, mature B (Raji), myeloid (K562, HL-60), and T lines (CCRF-CEM, MOLT-4) did not migrate. When cases of leukemia were analyzed, BMF migration was largely confined to precursor-B ALL, occurring in eight of 13 cases tested. Of other types of leukemia, migration was observed in one of four cases of T-ALL, but no evidence was seen in six acute myeloid leukemias and two patients with chronic lymphocytic leukemia. Only minimal migration into BMF was observed with purified sorted CD10+ CD19+ early B cells from normal adult marrow, while normal mature B lymphocytes from peripheral blood did not migrate. ALL migration was inhibited by monoclonal antibodies to the beta sub-unit of the VLA integrin family, and by a combination of antibodies to VLA-4 and VLA-5. Partial inhibition was also observed when leukemic cells were incubated with antibodies to VLA-4, VLA-5, or VLA-6 alone. In contrast, treatment of stromal cells with antibodies to vascular cell adhesion molecule or fibronectin (ligands of VLA-4 and VLA-5) did not prevent leukemic cell migration. These results indicate that ALL cells are highly motile and capable of rapid migration within marrow stroma, an effect largely mediated by VLA-4 and VLA-5. In the case of precursor-B ALL, this process may reflect a homing mechanism to areas of selective growth advantage within the bone marrow microenvironment.
authors.affiliation: Department of Haematology, Westmead Hospital, Sydney, New South Wales, Australia.
authors.forename: V
authors.initials: V
authors.lastname: Makrynikola
authors.forename: A
authors.initials: A
authors.lastname: Bianchi
authors.forename: K
authors.initials: K
authors.lastname: Bradstock
authors.forename: D
authors.initials: D
authors.lastname: Gottlieb
authors.forename: J
authors.initials: J
authors.lastname: Hewson
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D001854:Bone Marrow Cells; D002465:Cell Movement / Q000502:physiology; D002469:Cell Separation; D005347:Fibroblasts / Q000166:cytology; D005434:Flow Cytometry; D006801:Humans; D019012:Integrin beta1; D016023:Integrins / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology / Q000473:pathology*; D017469:Receptors, Fibronectin / Q000378:metabolism; D016029:Receptors, Very Late Antigen / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000473:pathology
chemical_list: D015703:Antigens, CD; D019012:Integrin beta1; D016023:Integrins; D017469:Receptors, Fibronectin; D016029:Receptors, Very Late Antigen