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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
Robert Möhle,
Frank Bautz,
Shahin Rafii,
Malcolm A.S. Moore,
Wolfram Brugger, and
Lothar Kanz
From the Department of Medicine II, University of Tübingen,
Tübingen, Germany; New York Hospital Cornell Medical Center,
Division of Hematology and Oncology, New York, NY; and the Laboratory
of Developmental Hematopoiesis, Sloan-Kettering Institute, New York,
NY.
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-1 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.
Blood, Vol. 91 No. 12 (June 15), 1998:
pp. 4523-4530
© 1998 by The American Society of Hematology.
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