The Chemokine Receptor CXCR-4 Is Expressed on CD34+Hematopoietic Progenitors and Leukemic Cells and Mediates Transendothelial Migration Induced by Stromal Cell-Derived Factor-1

Abstract

The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR-4 (fusin, LESTR) are likely to be involved in the trafficking of hematopoietic progenitor and stem cells, as suggested by the reduced bone marrow hematopoiesis in SDF-1–deficient mice and the chemotactic effect of SDF-1 on CD34+ progenitor cells. Migration of leukemic cells might also depend on the expression of chemokine receptors. Therefore, we analyzed expression of CXCR-4 on mobilized normal CD34+ progenitors and leukemic cells. In addition, SDF-1–induced transendothelial migration across a bone marrow endothelial cell layer was assessed in vitro. By flow cytometry, CXCR-4 was found to be expressed in significant amounts on circulating CD34+ hematopoietic progenitor cells, including more primitive subsets (CD34+/CD38− and CD34+/Thy-1+ cells). In accordance with the immunofluorescence data, CD34+ progenitors efficiently migrated across endothelium in response to SDF-1 containing conditioned medium from the stromal cell line MS-5. Leukemic blasts (mostly CD34+) from patients with acute myeloblastic leukemia (AML) expressed variable amounts of CXCR-4, which was functionally active, as demonstrated by a positive correlation between the SDF-1–induced transendothelial migration and the cell surface density of CXCR-4 (r = 0.97). Also recombinant SDF-1β induced migration of CXCR-4–positive leukemic blasts. The effect of both conditioned medium and recombinant SDF-1 was inhibited by a CXCR-4 blocking antibody. In contrast, CD34+ leukemic cell lines (KG1, KG1a, Kasumi-1, MOLM-1) expressed low levels or were negative for CXCR-4, and did not migrate. By reverse transcriptase-polymerase chain reaction (RT-PCR), however, basal levels of CXCR-4 mRNA were also detected in all leukemic cell lines. We conclude that CXCR-4 is expressed on CD34+cells including more primitive, pluripotent progenitors, and may therefore play a role in the homing of hematopoietic stem cells. CXCR-4 expressed in variable amounts on primary AML leukemic cells is functionally active and may be involved in the trafficking of malignant hematopoietic cells.

Incidence and risk factors of poor mobilization in adult autologous peripheral blood stem cell transplantation: a single‐centre experience

“…Plerixafor directly inhibits the interaction between stromal cell‐derived factor‐1 produced by BM stromal cells and CXCR4 expressed on CD34+ cells. It induces disruption of the interaction between myeloma cells and BM microenvironment and enhances sensitivity to therapy . Mobilization failure rate in patients using G‐CSF combined with plerixafor was lower than those in patients remobilized with G‐CSF alone or combination of chemotherapy .…”

Immunologic Profiles of Effector Cells and Peripheral Blood Stem Cells Mobilized with Different Hematopoietic Growth Factors

“…CXCR4 is the receptor for the stromal cell‐derived factor 1 (SDF‐1) and is coexpressed on CD34 + cells [83‐86] and these cells migrate across a gradient of SDF‐1 concentration, in vitro and in vivo [87, 88]. Also, the expression of CXCR4 was implicated in the process of CD34 + stem cell migration and engraftment, in vitro and in vivo, in a mouse model [87].…”

“…Therefore, one must assume that increased expression of VLA‐4, L‐selectin, and SDF‐1 receptor occurs in vivo, following infusion of the PBSC product. Indeed, recent studies suggest that in vitro culturing of PBSC with a variety of hematopoietic growth factors upregulates the expression of VLA‐4 and L‐selectin [72], and that SDF‐1 alone or in combination with other growth factors such as G‐CSF or GM‐CSF upregulates the expression of CXCR4 [83, 86, 87]. These recent findings begin to explain the molecular mechanisms of stem cell release from the bone marrow to the peripheral blood.…”

Increased transmigration of G–CSF‐mobilized peripheral blood CD34+ cells after overnight storage at 37°C

“…Cells capable of engrafting in nonobese severe combined immunodeficient mice (NOD‐SCID) are primarily located within the CD34+ cell population migrating toward SDF‐1, 4,6 and greater SDF‐1‐directed in vitro migration positively correlates with the degree of human chimerism and enhanced NOD‐SCID engraftment 7 . The correlation of CXCR4 expression with SDF‐1‐induced in vitro transmigration has not been consistently observed, 5,8‐10 but CXCR4‐blocked CD34+ cells have reduced homing and engraftment in NOD‐SCID mice 4,11 …”