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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 12 (June 15), 1998:
pp. 4523-4530
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
By
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.
 |
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-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.
| |
INTRODUCTION |
THE CHEMOKINE STROMAL cell-derived
factor-1 (SDF-1) was initially identified as a growth factor for B-cell
progenitors and as a chemotactic factor for T cells and
monocytes.1,2 SDF-1 is a member of the CXC subfamily of
chemokines, which is characterized by an intervening residue (X)
separating the first two cystein residues (C) within a conserved
motif.3 Other CXC chemokines (eg, interleukin [IL]-8) are
also involved in granulocyte migration.4 The chemotactic
effect of SDF-1 is mediated by the chemokine receptor CXCR-4 (fusin,
LESTR), which is expressed on mononuclear leukocytes and shows
structural similarities to the IL-8 receptor.5,6
Expression of CXCR-4 is also found in a variety of nonhematopoietic
cells and organs.7-9 However, the presence of CXCR-4 on the
cell surface is not necessarily related to chemotaxis induced by SDF-1.
For example, astrocytes express CXCR-4, but do not migrate in response
to SDF-1.10 The idea that the chemokine SDF-1 and its
receptor play a functional role in nonhematopoietic tissues is
supported by the the observation that SDF-1  / mice show
impaired heart development.11 Furthermore, CXCR-4 has been
shown to function as a coreceptor for the entry of the human
immunodeficiency virus-1 (HIV-1) into CD4+
lymphocytes.12
Recent data also suggest a role of SDF-1/CXCR-4 in hematopoietic stem
cell migration. In gene knockout experiments, bone marrow hematopoiesis
was virtually absent in mice deficient in SDF-1, while fetal liver
hematopoiesis was not affected.11 Given the fact that SDF-1
is produced by bone marrow stromal cells and may act as a
chemoattractant in the hematopoietic microenvironment, it could play a
role in the migration and homing of circulating hematopoietic
progenitor cells to the bone marrow.13 This concept is
supported by the finding that SDF-1 is chemotactic for
CD34+ hematopoietic progenitor cells from bone marrow and
peripheral blood.14 One might speculate that the capability
of leukemic cells to egress from the bone marrow microenvironment and
circulate in the peripheral blood also depends on the chemotactic
response to SDF-1. Thus, analysis of expression and function of the
SDF-1 receptor in acute leukemia could be useful to further elucidate mechanisms involved in the trafficking of malignant, immature hematopoietic cells.
Antibodies to CXCR-4 have previously been used to analyze expression of
this cell surface molecule, particularly on T
lymphocytes.15 One might expect that hematopoietic
progenitor cells also express CXCR-4, as the chemotactic effect of
SDF-1 on CD34+ cells has clearly been
demonstrated.14 In the context of stem cell homing, we were
particularly interested whether more primitive progenitor cells express
CXCR-4. Initial observations suggest that the chemotactic response of
CD34+ cells to SDF-1 is independent of differentiation and
lineage commitment.14
We analyzed expression of CXCR-4 on hematopoietic progenitors, primary
leukemic cells, and cell lines by flow cytometry and reverse
transcriptase-polymerase chain reaction (RT-PCR). Transendothelial migration in vitro was assessed using confluent layers of the bone
marrow endothelial cell line BMEC-1 grown on a 3-µm microporous membrane.16,17 Spontaneous transendothelial migration was
compared with transmigration supported by a SDF-1 gradient, which was
achieved by addition of conditioned medium from the SDF-1-producing
stromal cell line MS-52,14 underneath the endothelial
monolayer. In addition, the effect of a CXCR-4 blocking antibody and
recombinant SDF-1 was assessed. Our results suggest that expression of
CXCR-4 on circulating normal CD34+ hematopoietic progenitor
cells including more primitive
CD34+/CD38 and
CD34+/Thy-1+ subsets could play a role in the
homing to the bone marrow. Furthermore, the expression level of CXCR-4
in leukemic cells determines the migratory response to SDF-1 and is
therefore likely to be also involved in the trafficking of malignant
hematopoietic cells.
| |
MATERIALS AND METHODS |
Hematopoietic progenitors and leukemic cells.
After informed consent, peripheral blood mononuclear cells (PBMNC) were
obtained from cancer patients during peripheral blood progenitor cell
mobilization in preparation for high-dose chemotherapy in
nonhematologic malignancies. Progenitor cells were mobilized with
chemotherapy plus granulocyte colony-stimulating factor (G-CSF). MNC
were separated by Ficoll density gradient centrifugation. PB
CD34+ cells were isolated with immunomagnetic microbeads
(MACS system, Miltenyi Biotech, Bergisch Gladbach, Germany). Primary
leukemic cells from the peripheral blood of patients with acute
myeloblastic leukemia (AML) were isolated by Ficoll density gradient
centrifugation. The diagnosis of leukemia was based on routine
morphologic evaluation and cytochemical smears using the
French-American-British (FAB) classification, as well as
immunophenotyping. The patient characteristics are shown in
Table 1.
Cell lines.
The CD34+ leukemic cell lines KG1, KG1a, Kasumi-1, MOLM-1,
the CD34 cell line HL60, and B lymphoma cell lines (OCI-Ly8, DOHH-2) were cultivated in Iscove's modified Dulbecco's medium (IMDM) or RPMI
1640 medium (Seromed-Biochrom, Berlin, Germany) supplemented with 10%
to 20% fetal calf serum (FCS). The cells were passaged weekly. For the
migration experiments, logarithmically growing cells were used.
Cell counts.
Cell numbers and concentrations were assessed using a hemocytometer or
automated cell counter. The viability of the cells was assessed by
Trypan Blue dye exclusion. The viability was >90% in all experiments
(before and after transmigration).
Flow cytometry.
A total of 1 to 2 × 105 cells were incubated for 30 minutes at 4°C with the fluorescein isothiocyanate (FITC),
phycoerythrin (PE), or PerCP-conjugated monoclonal antibody (MoAb)
CD11a-FITC, CD34-FITC (clone G-25.2, HPCA2; Becton-Dickinson,
Heidelberg, Germany), CD38-FITC, (clone T16; Dianova-Immunotech,
Hamburg, Germany), CD45-RA-FITC, HLA-DR-FITC (L48, L243;
Becton-Dickinson), Thy-1-FITC, CXCR-4-PE (clone 5E10,
12G515; Pharmingen, Hamburg, Germany), CD34-PerCP (HPCA2,
Becton-Dickinson). Isotype-identical antibodies served as controls
(IgG1 and IgG2, FITC/PE/PerCP-conjugated; Becton-Dickinson). The cells
were analyzed using a FACScalibur flow cytometer
(Becton-Dickinson). For analysis of CXCR-4 expression in
CD34+ subpopulations, isolated CD34+ cells were
stained with CD34-PerCP and the respective FITC/PE-labeled antibodies.
CD34+ cells were gated in a SSC/FL-3 dot plot. A FL-1/FL-2
dot plot was used for further analysis of CD34+
subpopulations. To calculate the percentage of positive cells, a
proportion of 1% false positive events was accepted in the negative control sample. The mean fluorescence intensity was calculated from the
fluorescence histogram and expressed in arbitrary units.
RT-PCR analysis.
Oligonucleotide primers for human CXCR-4 cDNA (genbank M99293,
HUMSTSR18) were synthesized. The sense primer was
5 -CTGAGAAGCATGACGGACAA-3 and the antisense primer was
5-TGGAGTGTGACAGCTTGGAG-3, resulting in a PCR-product of
484 bp for CXCR-4. First strand cDNA was synthesized by reverse
transcription of 200 ng total RNA isolated from the cells and amplified
by Taq DNA polymerase dissolved in PCR buffer (KlenTaq, Clontech,
Heidelberg, Germany) in a 50-µL reaction containing 0.2 mmol/L deoxyribonucleoside triphosphates (dNTPs) and 40 pmol of each primer. As a negative control, RNA without addition of RT
was subjected to PCR analysis. The PCR profile consisted of a 1-minute
initial denaturation at 94°C, followed by 30 cycles of 1 minute
denaturation at 94°C, 1 minute annealing at 60°C, 2 minutes
polymerization at 72°C, and finally 10 minutes extension at
72°C. A total of 20 µL of the PCR products was separated in 2%
wt/vol agarose gels and stained with ethidium bromide.
Transendothelial migration.
Migration across bone marrow endothelium in vitro was analyzed as we
have described previously.17 The BMEC-1 cell line was cultivated in Medium 199 (Seromed-Biochrom) supplemented with 20% FCS.
For the transmigration experiments, 5 × 105 BMEC-1
cells were seeded on 3-µm transwell microporous membranes (Transwell,
Corning-Costar, Bodenheim, Germany). After 3 to 4 days, the monolayers
achieved full confluency and were suitable for transmigration studies.
The transwell inserts with the monolayers were placed in a 6-well
tissue culture plate, thus seperating an upper from a lower chamber in
each well. To assess the effect of SDF-1 on transendothelial migration
in vitro, conditioned medium from the SDF-1-producing cell line MS-5
(0.2 mL medium per cm2 confluent MS-5 layer incubated for 5 days) was added to the lower chamber. MS-5 is a bone marrow stromal
cell line from which the chemotactic factor SDF-1 was initially
isolated.2 Conditioned medium from this cell line has been
shown to stimulate migration as efficient as optimal amounts of
SDF-1.14 A total of 5 × 105
CD34+ progenitor cells or leukemic cells were added to the
upper chamber. After 10 hours, the transmigrated cells were recovered
from the lower chamber and counted.
In additional experiments, recombinant SDF-1 (rhSDF-1, R&D Systems
GmbH, Wiesbaden, Germany) was added to the lower chamber of the
transmigration system at a final concentration of 500 ng/mL. Furthermore, the effect of a partially blocking CXCR-4 antibody (clone
12G5, Pharmingen) on transendothelial migration in response to either
MS-5-conditioned medium or rhSDF-1 was assessed. The antibody was
added to the upper and lower chamber of the transmigration system at a
final concentration of 10 mg/mL.
Statistical analysis.
The percentage of CXCR-4 positive cells was analyzed using the quadrant
statistics of the dot plot (coexpression analysis) and expressed as
mean standard error of the mean (SEM) of at least three experiments. In
the transmigration experiments, spontaneous transendothelial migration
was assessed in parallel with SDF-1-induced migration and also
expressed as mean SEM (n = 3 or 4). Standard linear regression analysis
(CXCR-4 mean fluorescence v % transmigrated cells) was
performed on logarithmized data.
| |
RESULTS |
CXCR-4 is expressed on CD34+ hematopoietic progenitor
cells.
As shown in Fig 1, circulating
CD34+ cells expressed significant amounts of CXCR-4.
Analysis of hematopoietic progenitor cell subpopulations was performed
using CD34+ cells after immunomagnetic cell separation.
Coexpression of CXCR-4 and differentiation-related antigens (CD38,
HLA-DR, CD11a, and CD45RA), which are low or absent on pluripotent
progenitor and stem cells,19-22 was analyzed. In contrast,
the CD34+/Thy-1+ subpopulation is enriched for
more primitive progenitor cells.23 A
representative analysis is shown in Fig 2.
Expression of CXCR-4 was not related to differentiation, as
demonstrated by coexpression analysis of CD38, Thy-1, HLA-DR,
CD11a, and CD45RA. The percentage of CXCR-4+ cells in
subpopulations enriched for primitive progenitors (77.2% ± 21.2% of the CD34+/CD38
cells, 75.7% ± 10.1% of the CD34+/Thy-1+
cells, 62.8% ± 12.4% of the
CD34+/HLA-DR cells, 58.0% ± 15.0%
of the CD34+/CD11a cells, and 60.9% ± 12.8% of the
CD34+/CD45RA cells) was approximately as
great as the percentage of CXCR-4+ cells in the total
CD34+ population (61.2% ± 14.7%, n = 4).
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| Fig 1.
Analysis of CXCR-4 expression by flow cytometry. The
results are shown as fluorescence histograms (solid, CXCR-4 expression; line, respective IgG control). CD34+ hematopoietic
progenitor cells from four patients (CD34+ no. 1 through
4) were positive for CXCR-4, while CD34+ cell lines (KG1,
KG1a, Kasumi-1, MOLM-1) expressed only low levels. In contrast,
variable CXCR-4 expression was found in primary leukemic cells (AML #1
through #12). The cell line HL60, peripheral blood B lymphocytes, and B
lymphoma cell lines (OCI-Ly8, DOHH-2) were brightly positive for
CXCR-4.
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| Fig 2.
Coexpression analysis of CXCR-4 and
differentiation-related antigens on purified, circulating
CD34+ hematopoietic progenitor cells. Results from a
representative three-color flow cytometry analysis are shown. After
immunomagnetic separation and staining with CD34-PerCP and the
respective FITC/PE-labeled antibodies, CD34+ cells were
gated in a FSC/SSC and SSC/FL-3 dot plot. Only low SSC/CD34+ cells were further analyzed. Most of the cells
of the more primitive subsets (CD34+/CD38,
CD34+/Thy-1+,
CD34+/HLA-DR,
CD34+/CD45RA,
CD34+/CD11a) coexpressed CXCR-4, as
indicated by the shaded areas.
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Variable amounts of CXCR-4 are expressed on primary AML blasts.
Primary leukemic blasts from the peripheral blood of patients with AML
expressed variable amounts of CXCR-4 (Fig 1). The mean fluorescence intensity of CXCR-4 was more variable (range, 6 to 601)
compared with normal CD34+ cells (range, 13 to 37), while
the average percentage of CXCR-4 positive cells (66.7% ± 9.7%, n = 12) was comparable (normal CD34+ cells: 61.2% ± 14.7%, n = 4). Unexpectedly, expression of the SDF-1 receptor on the
CD34+ leukemic cell lines KG1 (18.1%), KG1a (0.0%),
Kasumi-1 (7.5%), and MOLM-1 cells (5.7%) was substantially lower than
the average expression on the nonmalignant circulating
CD34+ cells and AML leukemic blasts (Fig 1). In contrast to
the CD34+ leukemic cell lines, there were cases of primary
CD34+ AML cells, which were also brightly positive for
CXCR-4. Interestingly, the CD34 leukemic cell line
HL60 expressed high levels of CXCR-4. As a control, normal
CD19+ lymphocytes were brightly positive for CXCR-4. The
level of CXCR-4 expression was even higher in the B-lymphoma cell lines
OCI-Ly8 and DOHH-2 (Fig 1). Surprisingly, expression of CXCR-4 mRNA was found in CD34+ progenitor cells, in all cell lines, and all
AML blasts by RT-PCR (data not shown), including the cell line KG1a,
which was negative for CXCR-4 by immunofluorecence. These results
indicate that at least basal levels of CXCR-4 were produced by these
cells.
SDF-1 supports transendothelial migration of progenitors and leukemic
cells in vitro.
Transmigrated cells were recovered from the lower chamber of the
transmigration system after 10 hours and enumerated. Circulating CD34+ cells efficiently transmigrated the bone marrow
endothelium in vitro when SDF-1-containing conditioned medium was
added to the lower chamber of the transmigration system
(Fig 3, upper panel). In contrast, no
migration was observed when the CD34+ leukemic cell lines
KG1, KG1a, Kasumi-1, and MOLM-1 were added to the upper chamber of the
transmigration system, independent of addition of SDF-1 containing
conditioned medium to the lower chamber. The CD34 leukemic cell line
HL60 and B-lymphoma cell lines efficiently migrated in response to
SDF-1. The response of primary AML blasts to a transendothelial SDF-1
gradient was more heterogeneous (Fig 3, lower panel). Leukemic cells
from some AML patients rapidly migrated across the bone marrow
endothelial cell layer when SDF-1-containing conditioned medium was
added to the lower chamber, while migration of cells from other samples was only weak. Interestingly, also significant spontaneous migration was observed in the samples with the greatest level of CXCR-4 expression (Fig 3, lower panel).
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| Fig 3.
Transendothelial migration in vitro. A total of 5 × 105 cells (purified PB CD34+ progenitors,
different cell lines, or primary leukemic blasts) were added to the
upper chamber of the transmigration system. After 10 hours,
transmigrated cells recovered from the lower chamber were enumerated.
Due to the detection limit of this assay, migration of >1% could be
quantified reliably. Spontaneous migration (addition of control medium
to the lower chamber) was compared with SDF-1-induced migration
(addition of SDF-1-containing conditioned medium to the lower
chember). CD34+ progenitors, CD34 leukemic
(HL60), and lymphoma (OCI-Ly8, DOHH-2) cell lines showed significant
migration, in contrast to CD34+ leukemic cell lines.
SDF-1-induced migration of primary AML blasts was variable.
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The chemotactic effect of MS-5-conditioned medium on AML blasts is
due to SDF-1.
CXCR-4-positive primary AML blasts migrated across bone marrow
endothelium in response to recombinant SDF-1 nearly as efficient as in
response to the MS-5-conditioned medium
(Fig 4). Addition of the antibody 12G5,
which partially blocks CXCR-4,15 markedly reduced migration
in response to both conditioned medium and recombinant SDF-1. These
results demonstrate that SDF-1 contained in the MS-5-conditioned medium is the predominant chemotactic activity for AML blasts, which
mediates its effects through the chemokine receptor CXCR-4.
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| Fig 4.
Effect of a CXCR-4 blocking antibody on transendothelial
migration of CXCR-4-positive primary AML blasts. Migration was
expressed as relative transendothelial migration compared with
migration in response to MS-5-conditioned medium (CM [MS-5] = 100%). The CXCR-4 antibody (mAb) 12G5 markedly reduced migration of
CXCR-4-positive, primary AML blasts (AML no. 7, 8, 11, and 12) in
response to SDF-1-containing conditioned medium (CM + mAb).
Transendothelial migration induced by 500 ng/mL rhSDF-1 was nearly
as efficient as migration induced by the conditioned medium. The
chemotactic effect of both MS-5-conditioned medium and recombinant
SDF-1 was reduced by the partially blocking CXCR-4 antibody to a
similar extent.
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The expression level of CXCR-4 correlates with transmigration in
response to SDF-1.
A positive correlation (r = 0.97) was found between the expression
density of CXCR-4 on the cell surface (as reflected by the mean
fluorescence intensity) and the percentage of cells transmigrating in
response to SDF-1-containing conditioned medium, indicating that the
chemokine receptor CXCR-4 is functionally active in malignant AML
blasts (Fig 5).
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| Fig 5.
Correlation of CXCR-4 expression and SDF-1-induced
transendothelial migration of primary AML blasts. A positive
correlation (r = 0.97) was found between the expression
level (mean fluorescence intensity) of CXCR-4 and the percentage of AML
blasts (AML no. 1 through AML no. 12) transmigrating in response to
SDF-1 (addition of SDF-1-containing conditioned medium to the lower
chamber of the transmigration system).
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| |
DISCUSSION |
In this study, we show that significant levels of CXCR-4 are expressed
on circulating normal CD34+ hematopoietic progenitor cells.
The vast majority of the CD34+ cells consists of lineage
committed progenitors, which are not capable of establishing long-term
hematopoiesis.24 These progenitors might not even
contribute to marrow recovery after high-dose therapy and progenitor
cell transplantation.25 Therefore, we focused on the
expression of CXCR-4 on more primitive progenitors. Previous studies
have shown that coexpression of CD38, HLA-DR, CD11a, and CD45RA on
CD34+ cells is related to differentiation and lineage
commitment.19-22 Pluripotent progenitors including
hematopoietic stem cells are mainly found in the subpopulations
negative for these markers, while the
CD34+/Thy-1+ subpopulation is enriched for more
primitive progenitor cells.23 Because the proportion of
progenitors coexpressing CXCR-4 was comparable or tended to be even
greater in the more primitive subpopulations, we conclude that the
expression of CXCR-4 on the cell surface is not related to
differentiation and lineage commitment. Also primitive progenitors,
including stem cells capable of long-term hematopoietic reconstitution
after myeloablative therapy, might therefore express the chemokine
receptor CXCR-4 and respond to a transendothelial SDF-1 gradient with
enhanced migration. Dramatically reduced bone marrow hematopoiesis in
SDF-1 / mice further supports the idea that the
interaction of SDF-1 and CXCR-4 is critical for stem cell
homing.11
We have previously shown that only a small proportion of
CD34+ hematopoietic progenitor cells migrates spontaneously
across bone marrow endothelium in vitro.17 However, only
differentiated, CD34+/CD38++ cells are found
among those spontaneously migrating progenitors. Particularly primitive
progenitors may require additional stimulation for efficient migration
across endothelium also in vivo. Given the fact that bone marrow
stromal cells constitutively produce SDF-1, a transendothelial SDF-1
gradient could contribute to migration of more primitive progenitor
cells during the process of stem cell homing in vivo.
In contrast to CD34+ hematopoietic progenitor cells,
primary leukemic blasts from AML patients expressed variable amounts of the SDF-1 receptor. In malignant cells, a chemokine receptor might not
be functionally active, even when expressed in large amounts on the
cell surface. However, a CXCR-4 blocking antibody reduced migration of
AML blasts in response to MS-5-conditioned medium as well as
recombinant SDF-1, demonstrating that CXCR-4 is the functionally active
SDF-1 receptor also in primary AML blasts. In addition, our results
clearly show that the level of CXCR-4 expression is directly related to
the ability of the leukemic cells to migrate across bone marrow
endothelium in response to the ligand SDF-1. CXCR-4 expression was not
related to positivity for CD34. Both, CD34+ AML blasts
coexpressing high levels of CXCR-4 and CD34+ blasts
virtually negative for CXCR-4 were observed.
Interestingly, significant spontaneous transendothelial migration was
found in some primary AML blasts (AML no. 2, no. 7). Similar
spontaneous migration across endothelium has been reported in mature
monocytes.26 However, the mechanisms controlling leukocyte locomotion are only partially understood. The aquisition of spontaneous transendothelial migration might reflect differentiation of the AML
blasts into the monocytic lineage.
Surprisingly, CXCR-4 was low or virtually absent in CD34+
leukemic cell lines. At least basal levels of mRNA were produced by all
cell lines, as suggested by the positive RT-PCR signals. In accordance
with the flow cytometry data, the CD34+ leukemic cell lines
did not transmigrate bone marrow endothelium, when SDF-1-containing
conditioned medium was added to the lower chamber of the transmigration
system. The larger size of the leukemic cell lines could not account
for the absence of migration in vitro, as the cell line HL60, which
consists of cells larger than KG1 or KG1a, showed significant migration
in response to SDF-1. This CD34 cell line was brightly
positive for CXCR-4, which demonstrated that expression of CXCR-4 was
not downmodulated by culturing of the cells in vitro. Similary,
B-lymphoma cell lines overexpressed CXCR-4 compared with normal B
lymphocytes, associated with efficient transendothelial migration in
response to SDF-1. However, a greater level of CXCR-4 expression on the
larger malignant cell lines might be required for significant
SDF-1-induced migration at least in the in vitro model using
endothelium grown on 3-µm microporous membranes.
A recent study showed expression of CXCR-4 in CD34+
hematopoietic progenitor cells by RT-PCR.27 However, as
shown by the results of this report, a positive RT-PCR signal is not
necessarily related to a functionally relevant cell surface expression
of CXCR-4. Furthermore, even a few contaminating cells such as
monocytes or lymphocytes may give rise to a positive PCR signal in
separated CD34+ cells. Our results suggest that migration
in response to SDF-1 is regulated by gradual changes in CXCR-4
expression rather than in an all-or-nothing manner.
It is still an open question whether hematopoietic stem cells can be
infected by HIV-1.28-33 It has previously been reported that hematopoietic progenitor cells express low levels of
CD4.34,35 RT-PCR data have also raised the possibility that
CD34+ cells express both coreceptors required for entry of
HIV-1, CXCR-4, and CKR-5.27 As far as CXCR-4 is concerned,
we have shown that significant levels are expressed on hematopoietic
progenitor cells including more primitive subsets. These results
further confirm the hypothesis that also primitive, pluripotent
hematopoietic progenitor cells can be targets for HIV-1 infection.
In conclusion, CXCR-4 is a cell surface antigen expressed in
significant levels on CD34+ hematopoietic progenitor cells
including primitive, pluripotent CD34+ subsets. Expression
of this receptor is related to efficient SDF-1-induced
transendothelial migration in vitro. It is therefore conceivable that
the SDF-1/CXCR-4-mediated migration is involved in the homing of
hematopoietic stem cells to the bone marrow. In contrast, primary AML
blasts express more variable amounts of functionally active CXCR-4.
Because migration is an important function related to the spreading of
malignant diseases, further studies are required to determine whether
CXCR-4 is a useful marker for the staging of hematopoietic
malignancies, which might also be related to prognosis and treatment
outcome.
| |
FOOTNOTES |
Submitted July 24, 1997;
accepted February 3, 1998.
Supported by grants from Deutsche Forschungsgemeinschaft, Bonn, Germany
(SFB 510) to R.M., F.B., W.B., and L.K.; by National Institutes of
Health Grant NO. KO8-HL-02926, Dorothy Rodbell Cohen Foundation for Sarcoma Research, and The Rich Foundation (to S.R.); by
The Gar Reichman Fund of the Cancer Research Institute and the Rosemary
Breslin Fund (to M.A.S.M.).
Address reprint requests to Robert Möhle, MD, Department of
Medicine II, University of Tübingen, Otfried-Müller-Str.
10, 72076 Tübingen, Germany.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
We thank Alexandra Schüller and Petra Mayer for excellent
technical assistance and Dr I.G. Schmidt-Wolf (University of Berlin, Berlin, Germany) for providing the OCI-Ly8 cell lines.
| |
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J.-J. Lataillade, D. Clay, C. Dupuy, S. Rigal, C. Jasmin, P. Bourin, and M.-C. L. Bousse-Kerdiles
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K. Hodohara, N. Fujii, N. Yamamoto, and K. Kaushansky
Stromal cell-derived factor-1 (SDF-1) acts together with thrombopoietin to enhance the development of megakaryocytic progenitor cells (CFU-MK)
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A. J. Naiyer, D.-Y. Jo, J. Ahn, R. Mohle, M. Peichev, G. Lam, R. L. Silverstein, M. A.S. Moore, and S. Rafii
Stromal Derived Factor-1-Induced Chemokinesis of Cord Blood CD34+ Cells (Long-Term Culture-Initiating Cells) Through Endothelial Cells Is Mediated by E-Selectin
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Abstract
Introduction
Abstract