The chemokine receptor CXCR4 enhances integrin-mediated in vitro adhesion and facilitates engraftment of leukemic precursor-B cells in the bone marrow

Exp Hematol. 2001 Dec;29(12):1439-47. doi: 10.1016/s0301-472x(01)00741-x.

Abstract

Objective: It has been demonstrated that acute lymphoblastic leukemia (ALL) blasts migrate into layers of bone marrow fibroblasts (BMF) in vitro using the beta1 integrins VLA-4 and VLA-5, and that the chemokine SDF-1 and its receptor CXCR4 influences ALL migration. We investigated whether this effect was due to SDF-1-mediated induction of adhesion through beta1 integrins.

Methods: Adhesion of pre-B ALL cells or the cell line NALM6 to extracellular matrix proteins was examined using short-term in vitro binding assays. The effects of exposure of cells to SDF-1, antibodies to CXCR4, and the G protein inhibitor pertussis toxin (PTX) were assessed. The consequences of down regulation of CXCR4 on the in vivo behavior of pre-B ALL cells after injection into sublethally irradiated NOD/SCID mice was studied.

Results: Treatment with SDF-1 of NALM6 cells or cells from cases of precursor-B ALL resulted in a doubling of adhesion to fibronectin, laminin, and VCAM-1, but had no effect on binding to collagens I or IV. Antibodies to CXCR4 and PTX inhibited SDF-1-induced adhesion on these substrates. NALM6 cells with CXCR4 expression downregulated by SDF-1 exposure demonstrated a reduced capacity to engraft into the bone marrow of NOD/SCID mice, with only 22 +/- 11% of marrow cells being of human origin in mice receiving SDF-1-treated cells compared to 48 +/- 5% in mice receiving untreated cells (p < 0.001). The homing of SDF-1-treated cells to the bone marrow after 24 hours was also reduced by 72 +/- 16% compared to control cells.

Conclusions: These data show that SDF-1 and CXCR4 are involved in regulation of beta1 integrin function, and are important for the localization of pre-B cells to the bone marrow in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • B-Lymphocytes / pathology*
  • Bone Marrow Cells / pathology*
  • Burkitt Lymphoma / pathology
  • Cell Adhesion / drug effects
  • Cell Adhesion / physiology*
  • Cell Movement / drug effects
  • Cell Movement / physiology*
  • Chemokine CXCL12
  • Chemokines, CXC / pharmacology*
  • Chemokines, CXC / physiology
  • Down-Regulation / drug effects*
  • Extracellular Matrix Proteins / metabolism
  • Flow Cytometry
  • Humans
  • Mice
  • Mice, SCID
  • Pertussis Toxin
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Protein Binding
  • Receptors, CXCR4 / drug effects
  • Receptors, CXCR4 / physiology*
  • Transplantation, Heterologous / immunology
  • Tumor Cells, Cultured
  • Vascular Cell Adhesion Molecule-1 / pharmacology
  • Virulence Factors, Bordetella / pharmacology

Substances

  • Antibodies
  • CXCL12 protein, human
  • Chemokine CXCL12
  • Chemokines, CXC
  • Cxcl12 protein, mouse
  • Extracellular Matrix Proteins
  • Receptors, CXCR4
  • Vascular Cell Adhesion Molecule-1
  • Virulence Factors, Bordetella
  • Pertussis Toxin