Overexpression of the Chemokine Receptor CXCR4 in B Cell Chronic Lymphocytic Leukemia Is Associated With Increased Functional Response to Stromal Cell-Derived factor-1 (SDF-1)

Leukemia. 1999 Dec;13(12):1954-9. doi: 10.1038/sj.leu.2401602.

Abstract

The chemokine receptor CXCR4 and its ligand stromal cell-derived factor-1 (SDF-1) play an important role in trafficking of normal lymphocytes, monocytes, as well as hematopoietic stem- and progenitor cells. SDF-1 constitutively produced by bone marrow stromal cells acts as a chemoattractant supporting the homing of stem cells and may also contribute to the tropism of malignant cells for the bone marrow. Low-grade lymphoproliferative disorders, particularly B cell chronic lymphocytic leukemia (B-CLL), are characterized by the presence of bone marrow infiltration. Therefore, we analyzed expression of the chemokine receptor CXCR4 in B-CLL, and investigated the functional effect of SDF-1 on the malignant cells. By flow cytometry, CXCR4 was consistently expressed on circulating CLL cells at a fluorescence intensity four-fold greater than that of normal B cells, and three-fold greater than that of CD19+/CD5+ cells from the normal bone marrow. CXCR4 was functionally active as demonstrated by a rapid flux of intracellular free calcium in response to SDF-1, which was significantly reduced by the partially blocking CXCR4 antibody 12G5. Moreover, transendothelial migration of B-CLL cells in vitro was stimulated by conditioned medium from bone marrow stromal cells due to its content of SDF-1, as suggested by reduced migration after addition of the CXCR4 antibody 12G5. In accordance with the CXCR4 overexpression, migration of CLL cells was more efficiently stimulated by recombinant SDF-1 compared to migration of normal B cells. We conclude that CXCR4 is overexpressed and functionally active in B-CLL, and may therefore contribute to the tropism of B-CLL cells for the bone marrow stroma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Calcium / metabolism
  • Cell Movement / drug effects
  • Chemokine CXCL12
  • Chemokines, CXC / pharmacology*
  • Endothelium, Vascular / cytology
  • Female
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism*
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology
  • Male
  • Middle Aged
  • Receptors, CXCR4 / analysis*

Substances

  • CXCL12 protein, human
  • Chemokine CXCL12
  • Chemokines, CXC
  • Receptors, CXCR4
  • Calcium