title: 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).
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.
authors.affiliation: Department of Medicine II, University of Tübingen, Tübingen, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Möhle
authors.forename: C
authors.initials: C
authors.lastname: Failenschmid
authors.forename: F
authors.initials: F
authors.lastname: Bautz
authors.forename: L
authors.initials: L
authors.lastname: Kanz
mesh_terms: D000328:Adult; D000368:Aged; D002118:Calcium / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D019718:Receptors, CXCR4 / Q000032:analysis*
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D019718:Receptors, CXCR4; D002118:Calcium