ORIGINAL PAPER

The biological behavior of SDF-1/CXCR4 in patientswith myelodysplastic syndrome

Rui Yang • Jie Pu • Juan Guo • Feng Xu •

Zheng Zhang • Youshan Zhao • Xi Zhang •

ShuCheng Gu • ChunKang Chang • Xiao Li

Received: 28 March 2011 / Accepted: 1 April 2011 / Published online: 10 May 2011

� Springer Science+Business Media, LLC 2011

Abstract The purpose of this investigation is to evaluate

the biological behavior of stromal cell-derived factor-l

(SDF-1) in migration, adhesion, and apoptosis as well as

the related signaling transduction pathways in patients with

myelodysplastic syndrome (MDS) and acute myeloid leu-

kemia (AML). We chose 22 patients with MDS, 7 patients

with de novo AML, and 8 patients with non-clonal cyto-

penia diseases. We performed flow cytometric analysis of

CD34? cells apoptosis using annexinV-FITC, which binds

to exposed phosphatidylserine on apoptotic cells. The cell

adhesion capability was detected by CCK-8 assay. The

migration ability of the cell was checked by transwell

assay. Furthermore, we measured SDF-1 levels in BM

plasma from patients by enzyme-linked immunosorbent

assay (ELISA). Our results indicated that the apoptosis of

CD34? cell was significantly increased in the Low-grade

MDS (IPSS score B 1.0) patients compared with the high-

grade MDS (IPSS score C 1.5) (21.33% vs. 7.27%,

P \ 0.001) and patients with de novo AML (21.33% vs.

7.53%, P \ 0.001). SDF-1 promoted CXCR4 high

expression cells adhesion to the stroma cells (MSC) and

induced these cells migration. SDF-1 could trigger the

occurrence of polarized morphology of the cells that

expressed CXCR4 high. After addition of wortmannin or

PTX, the ability of adhesion and migration of the cells that

expressed CXCR4 high decreased. But in the patient’s cells

that expressed CXCR4 low, there was no above-mentioned

phenomenon. So we can suppose that the signaling path-

way of SDF-1/CXCR4 axis is PI3K pathway, and we

should do more things about this pathway and may find out

the target treatment of MDS.

Keywords SDF-1 � Migration � Adhesion �Myelodysplastic syndromes

Introduction

Myelodysplastic syndromes (MDS) comprised a hetero-

geneous group of hematopoietic stem cell malignancies

characterized by ineffective bone marrow (BM) hemato-

poiesis, peripheral blood (PB) cytopenias, and substantial

risk for progression to acute myeloid leukemia (AML).

Either bone marrow failure or progression to AML can

cause patients’ death.

Chemokines are a superfamily of small molecule

chemoattractive cytokines that mediate several cellular

functions. Stromal cell-derived factor-1 (SDF-1) is member

of the CXC subfamily of chemokines, is produced by

stromal and other cell types, and interacts with the seven-

transmembrane G-protein-coupled receptor CXCR4 [1].

CXCR4 is expressed constitutively in a wide variety of

normal tissue, including lymphatic tissues, thymus, brain,

spleen, stomach, and small intestine [2]. SDF-1 and its

receptor CXCR4 were involved in the mobilizing and

trafficking of hematopoietic progenitor cells [3]. SDF-1

also enhanced survival/anti-apoptosis of hematopoietic

progenitor cells, in vitro as well as in vivo [4], suggesting

R. Yang � J. Guo � F. Xu � Z. Zhang � Y. Zhao � X. Zhang �S. Gu � C. Chang (&) � X. Li

Department of Hematology, Shanghai Sixth People’s Hospital

Affiliated of Shanghai Jiaotong University, 200233 Shanghai,

China

e-mail: changchunkang7010@yahoo.com.cn

R. Yang � Y. Zhao

Medical college, Su Zhou University, 215123 Suzhou, China

J. Pu

Department of Hematology, Hospital Affiliated of Guilin

Medical College, 541001 Guilin, China

123

Med Oncol (2012) 29:1202–1208

DOI 10.1007/s12032-011-9943-7

that the SDF-1/CXCR4 system played an important role in

hematopoietic cell regulation.

In this study, we detected the expression of SDF-1/

CXCR4 axis, and its role in the migration, adhesion and

apoptosis of patients’ cells with MDS was evaluated either.

We may understand the mechanism of MDS and then find

out new pathways of diagnosis and treatment.

Materials and methods

Study population

After informed consent was given, bone marrow (BM)

mononuclear cells were obtained from 22 patients with

newly diagnosed MDS (15 patients’ IPSS score were not

more than 1 and 7 patients’ were not less than 1.5), from 7

de novo AML patients and from 8 patients with non-clonal

cytopenia diseases.

Material

All the monoclonal antibodies and the flow cytometry were

purchased from Becton–Dickinson. ELISA Kits were

purchased from R&D Systems. MicroplateReader was

Labsystems Dragon Wellscan MK-3. Cell Counting Kit-8

(CCK-8) was purchased from DOJINDO Laboratories.

AMD3100, pertussis toxin (PTX), and wortmannin were

purchased from Sigma. 5 lm membrane diameter of the

Transwell inserts cell culture plates were purchased from

Corning. Cell incubator was purchased from SANYO.

Fluorescence microscope was purchased from Olympus.

Mesenchymal stem cells (MSC) were the gift of hematol-

ogy laboratory of Shanghai sixth people’ hospital.

Flow cytometry assay

Bone marrow aspirates of 22 consecutive patients diag-

nosed with MDS between 2009 and 2010 at Shanghai Sixth

People’s Hospital (Shanghai, China) were obtained after

informed consent at the time of diagnosis and examined for

CXCR4 expression during routine flow cytometry work-up,

generally within 2–4 h after the sample was drawn. The

diagnosis of MDS was established using standard mor-

phology, cytochemistry, immunophenotypic criteria, and

cytogenetic evaluation according to the WHO classifica-

tion. For immunodetection of CXCR4 on MDS cells, a

whole-blood lysis method was used with directly labeled

primary antibodies following the manufacturer’s instruc-

tions (Becton–Dickinson, Franklin Lakes, NJ, USA).

Briefly, mononuclear cells were isolated from 2 mL bone

marrow with heparin sodium as the anticoagulant. After

adjusted to 106/mL by the phosphate buffered solution

(PBS), 100 lL of the cell suspension were incubated for

15 min with appropriately diluted monoclonal antibody

conjugates at room temperature protected from the light.

For CXCR4 detection, 10 lL of APC-conjugated anti-

CXCR4 (12G5) was used in combination with 10 lL of

anti-CD34-PerCP. A control sample was incubated with

the appropriate isotype control antibodies. For apoptosis

detection, 5 lL of FITC-conjugated AnnexinV was used in

combination with 2 lL PI. After incubation, cells were

washed once and analyzed within 2 h on a FACS Calibur

(Becton–Dickinson). All antibodies were purchased from

Becton–Dickinson. Flow cytometry data were analyzed

using the FlowJo software (version 2.7.4; Tree Star,

Ashland, OR).

ELISA assay

Plasma obtained from a heparin sodium-anticoagulated

bone marrow sample was kept at -80�C until required for

ELISA determinations. SDF-1 ELISA was developed with

appropriate pairs of coating and catcher anti-SDF-1 anti-

bodies, as well as with standard recombinant human

SDF-1a (R&D Systems, USA). The ELISA conditions for

antibody coating, blocking, reagent for plasma dilution,

and enzyme-developing reaction were as recommended by

the manufacturer (R&D Systems, USA) with ELISA high-

binding capacity plates (R&D Systems, USA). All deter-

minations were done in duplicate, and in most cases, they

were confirmed in an independent experiment.

CCK-8 assay

MSC were seeded in 96-well cell culture plates at a density

of 1 9 105 cells/well and allowed to grow overnight, and

then we planted patients’ bone marrow mononuclear cell

into the plates for 5 9 105 cells/well. The inhibitor groups’

bone marrow mononuclear cells were pretreated with the

corresponding drugs for 2 h. The final concentration of

each drug was as follows: 100 ng/mL of SDF-1, 1 lg/mL

of AMD3100, 200 ng/mL of PTX, 400 ng/mL of wort-

mannin. SDF-1 was added to each well, either. The control

group used PBS instead of SDF-1. Then incubated them

under the environment of 37�C, 5% CO2 for 6 h. 10 lL of

CCK-8 was added into each well, then incubated them

under the environment of 37�C, 5% CO2 for 4 h. Detected

the OD at 450 nm within 30 min.

Transwell assay

A concentration of 5 9 105/mL bone marrow mononuclear

cell was incubated with 10 lL CXCR4-APC protected

from light for 15 min. After washed twice using PBS, cells

were suspended by 100 lL DMEM. The inhibitor groups’

Med Oncol (2012) 29:1202–1208 1203

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bone marrow mononuclear cell were pretreated with the

corresponding drugs for 2 h. The final concentration of

each drug was as follows: 100 ng/mL of SDF-1, 1 lg/mL

of AMD3100, 200 ng/mL of PTX, and 400 ng/mL of

wortmannin. Then we added 600 lL DMEM (contained

60 ng SDF-1) into the bottom room, the control group

using 600 lL DMEM not contained SDF-1. Then we

planted cells into the upper room. Then incubated them

under the environment of 37�C, 5% CO2 for 4 h.

Results

Apoptosis assay

As shown in the representative set of experiments (Figs. 1,

2; Table 1), within the CD34? cell compartment, apoptosis

was significantly increased in Low-grade MDS group

(median 21.33% (range 9.12–35.13%))(n = 15) compared

to High-grade MDS group (median 7.27% (range

0.46–17.75%), P = 0.014) (n = 7), patients with de novo

AML (median 7.53% (range 0.86–13.13%), P \ 0.001)

(n = 7) and the control group. High-grade MDS and

AML group also had no significant difference. There was

no correlation between apoptosis and patient’ age or

gender.

CXCR4 protein expression on CD34? cell surface

As shown in Figs. 1 and 3, CD34? cells of patients with

Low-grade MDS expressed a significantly lower CXCR4

protein (median 10.42 (range 4.17–23.47), n = 15), than in

patients with High-grade MDS (median 16.97 (range

9.85–24.4), n = 7, P = 0.014) and AML (median 20.26

(range 11.96–32.19), n = 7, P \ 0.001). But it did not

Fig. 1 The expression of CXCR4 and the apoptosis of CD34? cells.

The CXCR4 expression of CD34? cells was lower in the Low-grade

MDS group compared to the High-grade MDS group (P = 0.014) and

AML group (P \ 0.001). The apoptosis of CD34? cells was

significantly increased in Low-grade MDS group compared to

High-grade MDS group (P = 0.014), patients with de novo AML

(P \ 0.001)

Fig. 2 Apoptosis of CD34? cells in AML/MDS/normal cases.

Apoptosis was significantly increased in Low-grade MDS group

compared to High-grade MDS group, patients with de novo AML and

the control group. There was no significant difference between

High-grade MDS group and AML group

1204 Med Oncol (2012) 29:1202–1208

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reach statistical significance between Low-grade MDS and

the control group (P = 0.496). We were also unable to

find significant difference between High-grade MDS and

AML.

SDF-1 levels in BM plasma

Furthermore, we measured SDF-1 levels in BM plasma

from patients by enzyme-linked immunosorbent assay

(ELISA) using Quantikines, human SDF-1a immunoassay

(R&D systems, Minneapolis, MN, USA). But there were

no significant difference among the four groups as shown

in Fig. 4.

The adhesion rate of bone marrow mononuclear cells

with MSC

In the high-grade MDS group, the adhesion rate of SDF-1

group was increased significantly compared with other

groups (P \ 0.001, Table 2). And this increase could be

blocked by drugs. But in the low-grade MDS group, there

was no significant difference among groups.

The migration rate of bone marrow mononuclear cells

In the high-grade MDS group, the migration rate of SDF-1

group was increased significantly compared with other

groups (P \ 0.001, Table 2). And this increase could be

blocked by drugs. But in the low-grade MDS group, there

was no significant difference among groups.

Polarized morphology of the cells

After the migration, cells showed a polarized morphology

in the SDF-1 group of the high-grade MDS group.

This phenomenon did not appear in other groups (Fig. 5).

Discussion

SDF-1 is a CXC chemokine, secreted constitutively from

several cell types. There are 2 isoforms of SDF-1, a and b,

which are generated by differential splicing from a single

gene. CXCR4 is a 7-transmembrane surface structure

linked to G proteins. The chemotactic effect of SDF-1 on

hematopoietic progenitor cells has been shown to be

mediated by the CXCR4 receptor. CXCR4 plays a central

role in both progenitor cell homing and mobilization

[5–10].

Phosphoinositide 3-kinase family members are proto-

oncogenes. Generation of 3-phosphoinositides has been

documented to influence diverse cellular pathways and

hence alter a spectrum of fundamental cellular activities. It

can generate 4 forms of the phosphoinositide: PI(3)PI,

PI(3,4)P2, PI(3,5)P2, PI(3,4,5)P3. The upregulation of PI3K

can cause Akt decrease by phosphorylation [11, 12]. Liang

et al. [13] had shown that CXCR4 upregulates the phos-

phorylation of Akt and increases VEGF expression at both

mRNA and protein levels. CXCL12 increases phosphory-

lation of Akt in a dose-dependent manner, indicating a

Fig. 3 CXCR4 expression of CD34? cells in AML/MDS/normal

cases. CD34? cells of patients with Low-grade MDS expressed a

significantly lower CXCR4 protein than in patients with High-grade

MDS and AML. High-grade MDS group expressed a significantly

higher CXCR4 protein than the control group. There were no

significant difference between Low-grade MDS and the control group

Fig. 4 SDF-1 concentration in AML/MDS/normal cases. There were

no significant difference among the four groups about SDF-1 level in

bone marrow

Table 1 CXCR4/SDF-1 concentration related with percentage of

CD34? cells’ apoptosis

CXCR4 MFI CD34?

apoptosis (%)

SDF-1

(ng/mL)

Low-grade MDS 10.42 ± 5.34 21.33 ± 7.51 6.01 ± 2.62

High-grade MDS 16.97 ± 5.59 7.27 ± 5.80 6.46 ± 1.86

AML 20.26 ± 8.19 7.53 ± 4.92 5.38 ± 2.95

Control 8.75 ± 1.55 8.69 ± 3.56 5.79 ± 1.83

Med Oncol (2012) 29:1202–1208 1205

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direct relationship between CXCR4/CXCL12 axis and Akt.

Inversely, blocking the activation of Akt signaling led to a

decrease in VEGF protein levels; blocking CXCR4/

CXCL12 interaction with a CXCR4 antagonist suppressed

tumor angiogenesis and growth in vivo.

There was significant difference on the development and

termination between Low-grade MDS and High-grade

MDS. In our study, we divided MDS patients into two

groups according to the International Prognostic Scoring

System (IPSS) [14]: Low-grade MDS (IPSS score B 1.0)

and High-grade MDS (IPSS score C 1.5).

There was no significant difference on CXCR4 expres-

sion between Low-grade MDS and the control group. But

the apoptosis of CD34? cells was higher in the Low-grade

MDS than it in controls. Considering that SDF-1 was the

only ligand for CXCR4, we furthermore detected the SDF-

1 level in the BM plasma by using ELISA assays. But there

was no significant difference between two groups (Fig. 3).

Our results were different from Matsuda’s report [15].

Broxmeyer et al. [4, 16, 17] reported that in the study of

SDF-1 transgene mice, SDF-1 played anti-apoptisis role on

the hemopoietic progenitor cells. Yin et al. [18] verified

that SDF-1 inhibited hypoxia/serum deprivation induced

bone marrow-derived mesenchymal stem cells apoptosis

through PI3K/Akt signaling pathways. We supposed that in

the Low-grade MDS, the SDF-1/CXCR4 signal pathway

might be injured. Liang [13] reported that SDF-1/CXCR4

signaling axis react though the activation of PI3K/Akt

pathway. Fuhler [19, 20] found that PI3K pathway was

abnormal in MDS patients.

In the High-grade MDS group, the CXCR4 expression

and apoptosis of CD34? cells was similar to AML group.

Clinically, High-grade MDS patients had higher risk for

progression to acute myeloid leukemia compared with

Low-grade MDS. CXCR4 expression is higher in High-

grade group than the control group (P = 0.007) (Fig. 2),

while the apoptosis between two groups being no signifi-

cant difference. It needed higher CXCR4 level to remain

low apoptosis compared with controls. This also can

demonstrate that the SDF-1/CXCR4 signal pathway was

injured.

In the adhesion assays, because of the SDF-1, cells of

high-expression CXCR4 can adhere to MSC, but there was

no this phenomenon on cells of low-expression CXCR4.

Furthermore, we found that this phenomenon can be

blocked by AMD3100, PTX, and wortmannin. The

malignant cells can avoid the cytotoxicity of drugs by

adhering to the stroma cells. So, our study indicated that

SDF-1/CXCR4 axis can promote tumor cells adhering to

MSC. Zhang et al. [21] found that the adhesion capability

of AML cells was enhanced through changing the

expression of the adhesion molecules (ICAM-1 and

LFA-1). So, we thought that SDF-1/CXCR4 axis played an

important role in the adhesion of the MDS clone cells.

Table 2 The adhesion rate and migration rate in each group

Groups The adhesion rate (%) The migration rate (%)

Low grade-MDS High-grade MDS Low grade-MDS High-grade MDS

Control 19.78 ± 2.35 27.00 ± 4.58 16.71 ± 3.49 14.07 ± 2.87

SDF-1 23.24 ± 1.72 52.33 ± 7.51* 22.59 ± 2.41 70.18 ± 3.09**

SDF-1 ? AMD3100 17.48 ± 2.84 21.97 ± 5.01 18.35 ± 3.20 11.38 ± 2.37

SDF-1 ? PTX 20.33 ± 3.75 22.33 ± 2.52 16.27 ± 3.13 13.72 ± 2.61

SDF-1 ? wortmannin 22.59 ± 4.11 20.86 ± 4.04 17.94 ± 2.74 13.29 ± 4.56

* The adhesion rate of SDF-1 group was increased significantly compared with other groups (P \ 0.001)

** The migration rate of SDF-1 group was increased significantly compared with other groups (P \ 0.001)

Fig. 5 Polarized morphology of the migrated cells. The SDF-1

group, the number of cells migrated from upper-room to lower-room

was higher than others. And we can found a polarized morphology on

the migrated cells in the SDF-1 group. But in the other groups, there

was no this phenomenon

1206 Med Oncol (2012) 29:1202–1208

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Furthermore, we found that in High-grade MDS group,

the number of cells that migrate from upper-room to lower-

room in the SDF-1 group increased significantly compared

with in other groups. And, it can be neutralized by

AMD3100, PTX, and wortmannin. In the High-grade MDS

group, morphous polarization was detected in the migrated

cells. Kimura et al. [22] reported that SDF-1/CXCR4 axis

can enhance the migration of bone marrow CD34? cells. Li

et al. [23] demonstrated that the PI3K/Akt signaling path-

way activated enhanced migration of neural-like cells

toward SDF-1. Some researchers reported that chemotaxis

of SDF-1 can be intercepted by PTX [24–26]. In the

AMD3100 group, the number of migrated cells decreased

significantly compared with the SDF-1 group. So, SDF-1

produced a marked effect through binding CXCR4. After

adding PTX and wortmannin, the migration disappeared.

This demonstrated that SDF-1/CXCR4 axis delivered

signals through PI3K pathways. In the High-grade MDS

group, cells were high-expression CXCR4; so, they had

high capability of adhesion and migration; So, High-grade

MDS patients usually developed into AML. In the Low-

grade MDS group, cells were low-expression CXCR4; so,

they had low capability of adhesion and migration; So,

Low-grade MDS patients usually developed into marrow

failure.

Totally, SDF-1/CXCR4 axis can promote the ability of

survival, adhesion to MSC and migration of high-expres-

sion CXCR4 cells. And, this promotion can be disrupted by

AMD3100, PTX, and wortmannin. The faculty for adhe-

sion and migration of tumor cells plays an important role in

the development of disease. We presume that SDF-1/

CXCR4 axis plays an important role in the mechanism of

MDS. Detecting the expression of SDF-1/CXCR4 and the

PI3K pathways can be the new target of diagnosis and

therapy of MDS.

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