CXCR4 regulates migration and development of human acute myelogenous leukemia stem cells in transplanted NOD/SCID mice

The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 participate in the retention of normal hematopoietic stem cells within the bone marrow (BM) and their release into the circulation. Homing and engraftment of human stem cells in immunodeficient mice are dependent on cell surface CXCR4 expression and the production of BM SDF-1, which acts also as a survival factor for both human and murine stem cells. However, the role of SDF-1/CXCR4 interactions in the control of human acute myelogenous leukemia (AML) cell trafficking and disease progression is poorly understood. In this study, we report that although some AML cells do not express surface CXCR4, all AML cells tested express internal CXCR4 and SDF-1. Culture of AML cells with SDF-1 promoted their survival, whereas addition of neutralizing CXCR4 antibodies, SDF-1 antibodies, or AMD3100 significantly decreased it. Pretreatment of primary human AML cells with neutralizing CXCR4 antibodies blocked their homing into the BM and spleen of transplanted NOD/SCID/B2m(null) mice. Furthermore, weekly administrations of antihuman CXCR4 to mice previously engrafted with primary AML cells led to a dramatic decrease in the levels of human AML cells in the BM, blood, and spleen in a dose- and time-dependent manner. Interestingly, the same treatment did not affect significantly the levels of normal human progenitors engrafted into NOD/SCID mice. Taken together, our findings demonstrated the importance of the SDF-1/CXCR4 axis in the regulation of in vivo motility and development of human AML stem cells and identified CXCR4 neutralization as a potential treatment for AML.     

Cells enriched in markers of neural tissue-committed stem cells reside in the bone marrow and are mobilized into the peripheral blood following stroke.

The concept that bone marrow (BM)-derived cells participate in neural regeneration remains highly controversial and the identity of the specific cell type(s) involved remains unknown. We recently reported that the BM contains a highly mobile population of CXCR4+ cells that express mRNA for various markers of early tissue-committed stem cells (TCSCs), including neural TCSCs. Here, we report that these cells not only express neural lineage markers (beta-III-tubulin, Nestin, NeuN, and GFAP), but more importantly form neurospheres in vitro. These neural TCSCs are present in significant amounts in BM harvested from young mice but their abundance and responsiveness to gradients of motomorphogens, such as SDF-1, HGF, and LIF, decreases with age. FACS analysis, combined with analysis of neural markers at the mRNA and protein levels, revealed that these cells reside in the nonhematopoietic CXCR4+/Sca-1+/lin-/CD45 BM mononuclear cell fraction. Neural TCSCs are mobilized into the peripheral-blood following stroke and chemoattracted to the damaged neural tissue in an SDF-1-CXCR4-, HGF-c-Met-, and LIF-LIF-R-dependent manner. Based on these data, we hypothesize that the postnatal BM harbors a nonhematopoietic population of cells that express markers of neural TCSCs that may account for the beneficial effects of BM-derived cells in neural regeneration.     

Migratory behavior of leukemic cells from acute myeloid leukemia patients.

The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR-4 contribute to stem cell homing and may play a role in the trafficking of leukemic cells. Therefore, we analyzed migration across Transwell filters of cells derived from bone marrow (BM) or peripheral blood (PB) from 26 acute myeloid leukemia (AML) patients. The presence of the extracellular matrix protein fibronectin (FN) strongly enhanced the spontaneous and SDF-1-induced migration of leukemic PB and BM cells. No differences in spontaneous, SDF-1-induced migration or CXCR-4 expression were observed between the different AML subtypes. Subsequently, it was determined whether SDF-1 preferentially promoted migration of subsets of leukemic cells. Leukemic cells expressing CD34, CD38 and HLA-DR were preferentially migrating, whereas cells expressing CD14 and CD36 showed diminished migration. Analysis of paired PB and BM samples indicated that significantly higher SDF-1-induced migration was observed in AML for CD34(+) BM-derived cells compared to CD34(+) PB-derived cells, suggesting a role for SDF-1 in the anchoring of leukemic cells in the BM or other organs. The lower percentage of circulating leukemic blasts in patients with a relatively high level of SDF-1-induced migration also supports this hypothesis. In conclusion, we have shown that primary AML cells are migrating towards SDF-1 independent of the AML subtypes.     

Bone marrow as a home of heterogenous populations of nonhematopoietic stem cells.

Evidence is presented that bone marrow (BM) in addition to CD45(positive) hematopoietic stem cells contains a rare population of heterogenous CD45(negative) nonhematopoietic tissue committed stem cells (TCSC). These nonhematopoietic TCSC (i) are enriched in population of CXCR4(+) CD34(+) AC133(+) lin(-) CD45(-) and CXCR4(+) Sca-1(+) lin(-) CD45(-) in humans and mice, respectively, (ii) display several markers of pluripotent stem cells (PSC) and (iii) as we envision are deposited in BM early in development. Thus, since BM contains versatile nonhematopoietic stem cells, previous studies on plasticity trans-dedifferentiation of BM-derived hematopoietic stem cells (HSC) that did not include proper controls to exclude this possibility could lead to wrong interpretations. Therefore, in this spotlight review we present this alternative explanation of 'plasticity' of BM-derived stem cells based on the assumption that BM stem cells are heterogenous. We also discuss a potential relationship of TCSC/PSC identified by us with other BM-derived CD45(negative) nonhematopoietic stem cells that were recently identified by other investigators (eg MSC, MAPC, USSC and MIAMI cells). Finally, we discuss perspectives and pitfalls in potential application of these cells in regenerative medicine.     

The regulation of hematopoietic stem cell and progenitor mobilization by chemokine SDF-1

The chemokine, stromal derived factor-1 (SDF1) has been shown to modulate the homing of stem cells to its site by mediating chemotaxis. We demontrated overexpression of SDF-1 induced mobilization of cells with stem cell potential (CFU-S, long-term reconstituting cells). Moreover, SDF-1 activated matrix metalloproteinase-9 induced in bone marrow (BM) cells, causing the release soluble Kit-ligand and permitting the transfer of hematopoietic stem cells (HSCs) from a quiescent to a proliferative niche. The role of SDF-1 in the process of HSC migration and the mechanism underlying this HSCs migration will be reviewed. These studies lay the foundation for using SDF-1 to induce mobilization of progenitor cells in a BM transplantation setting.     

The bone marrow-expressed antimicrobial cationic peptide LL-37 enhances the responsiveness of hematopoietic stem progenitor cells to an SDF-1 gradient and accelerates their engraftment after transplantation

We report that the bone marrow (BM) stroma-released LL-37, a member of the cathelicidin family of antimicrobial peptides, primes/increases the responsiveness of murine and human hematopoietic stem/progenitor cells (HSPCs) to an α-chemokine stromal-derived factor-1 (SDF-1) gradient. Accordingly, LL-37 is upregulated in irradiated BM cells and enhances the chemotactic responsiveness of hematopoietic progenitors from all lineages to a low physiological SDF-1 gradient as well as increasing their (i) adhesiveness, (ii) SDF-1-mediated actin polymerization and (iii) MAPK(p42/44) phosphorylation. Mice transplanted with BM cells ex vivo primed by LL-37 showed accelerated recovery of platelet and neutrophil counts by ～3-5 days compared with mice transplanted with unprimed control cells. These priming effects were not mediated by LL-37 binding to its receptor and depended instead on the incorporation of the CXCR4 receptor into membrane lipid rafts. We propose that LL-37, which has primarily antimicrobial functions and is harmless to mammalian cells, could be clinically applied to accelerate engraftment as an ex vivo priming agent for transplanted human HSPCs. This novel approach would be particularly important in cord blood transplantations, where the number of HSCs available is usually limited.     

A population of very small embryonic-like (VSEL) CXCR4(+)SSEA-1(+)Oct-4+ stem cells identified in adult bone marrow.

By employing multiparameter sorting, we identified in murine bone marrow (BM) a homogenous population of rare (approximately 0.02% of BMMNC) Sca-1(+)lin(-)CD45- cells that express by RQ-PCR and immunohistochemistry markers of pluripotent stem cells (PSC) such as SSEA-1, Oct-4, Nanog and Rex-1. The direct electronmicroscopical analysis revealed that these cells are small (approximately 2-4 microm), posses large nuclei surrounded by a narrow rim of cytoplasm, and contain open-type chromatin (euchromatin) that is typical for embryonic stem cells. In vitro cultures these cells are able to differentiate into all three germ-layer lineages. The number of these cells is highest in BM from young (approximately 1-month-old) mice and decreases with age. It is also significantly diminished in short living DBA/2J mice as compared to long living B6 animals. These cells in vitro respond strongly to SDF-1, HGF/SF and LIF and express CXCR4, c-met and LIF-R, respectively, and since they adhere to fibroblasts they may be coisolated with BM adherent cells. We hypothesize that this population of Sca-1(+)lin(-)CD45- very small embryonic-like (VSEL) stem cells is deposited early during development in BM and could be a source of pluripotent stem cells for tissue/organ regeneration.     

Biological significance of the expression of HIV-related chemokine coreceptors (CCR5 and CXCR4) and their ligands by human hematopoietic cell lines.

The aim of this study was to learn more about the role of the HIV-related chemokine-chemokine receptor axes in human hematopoiesis. To address this issue we phenotyped 35 selected hematopoietic cell lines for the expression of CD4, CXCR4 and CCR5. We next evaluated the functionality of these chemokine receptors by calcium flux and chemotaxis assays, and by the ability of SDF-1, MIP-1alpha, MIP-1beta and RANTES to influence the growth of the cells expressing CXCR4 and/or CCR5. Lastly, we examined whether human hematopoietic cell lines may secrete some HIV-related chemokines, and whether endogenously secreted chemokines might interfere with the infectability. of hematopoietic cells by X4 and R5 HIV strains. These results demonstrate that: (1) HIV-related receptors are widely expressed on human hematopoietic cell lines; (2) stimulation of CXCR4 by SDF-1 induces calcium flux and chemotaxis in several hematopoietic cell lines more efficiently than stimulation of CCR5 by receptor-specific beta-chemokines; (3) chemokines do not regulate proliferation of the hematopoietic cells; and finally (4) infectability of the hematopoietic cells by HIV-1 may be auto-modulated by endogenously secreted chemokines. These data shed more light on the role of HIV-related chemokine-chemokine receptors axes in human hematopoiesis and interaction of hematopoietic cells with HIV.     

Telomere length in haemopoietic stem cells can be determined from that of mononuclear blood cells or whole blood

Telomere length can be used to predict the replicative capacity of haematological progenitor cells and may be an important prognostic factor for the onset of cellular immune dysfunction. However, such measurements require invasive bone marrow (BM) biopsies and laborious stem cell isolations that are impractical in a clinical setting. Previous studies have used peripheral blood (PB) cells as an indicator of stem cell telomere length without demonstrating a correlation. In this study, we examined the telomere length in PB, isolated mononuclear cells (MNC) and BM aspirates from each of 19 patients ranging in age from 45 to 81 years. Correlation analysis confirmed that mean telomere length of BM aspirates was equivalent to that of PB (r = 0.85, P < 0.001), or MNC (r = 0.94, P < 0.001). Since BM is a heterogeneous population of cells, we have also shown in 13 separate patients that the mean telomere length in isolated peripheral blood stem cell (PBSC) harvests was equivalent to that of isolated CD34+ stem cells (r = 0.83, P < 0.001). Thus, telomere length in haemopoietic stem cells can be determined from that of whole or fractionated PB in future studies of haematological disorders.     

Functional CXCR4-expressing microparticles and SDF-1 correlate with circulating acute myelogenous leukemia cells

Stromal cell-derived factor-1 (SDF-1/CXCL12) and its receptor CXCR4 are implicated in the pathogenesis and prognosis of acute myelogenous leukemia (AML). Cellular microparticles, submicron vesicles shed from the plasma membrane of various cells, are also associated with human pathology. In the present study, we investigated the putative relationships between the SDF-1/CXCR4 axis and microparticles in AML. We detected CXCR4-expressing microparticles (CXCR4(+) microparticles) in the peripheral blood and bone marrow plasma samples of normal donors and newly diagnosed adult AML patients. In samples from AML patients, levels of CXCR4(+) microparticles and total SDF-1 were elevated compared with normal individuals. The majority of CXCR4(+) microparticles in AML patients were CD45(+), whereas in normal individuals, they were mostly CD41(+). Importantly, we found a strong correlation between the levels of CXCR4(+) microparticle and WBC count in the peripheral blood and bone marrow plasma obtained from the AML patients. Of interest, levels of functional, noncleaved SDF-1 were reduced in these patients compared with normal individuals and also strongly correlated with the WBC count. Furthermore, our data indicate NH(2)-terminal truncation of the CXCR4 molecule in the microparticles of AML patients. However, such microparticles were capable of transferring the CXCR4 molecule to AML-derived HL-60 cells, enhancing their migration to SDF-1 in vitro and increasing their homing to the bone marrow of irradiated NOD/SCID/beta2m(null) mice. The CXCR4 antagonist AMD3100 reduced these effects. Our findings suggest that functional CXCR4(+) microparticles and SDF-1 are involved in the progression of AML. We propose that their levels are potentially valuable as an additional diagnostic AML variable.     

Stromal cell-derived factor-1 stimulates vasculogenesis and enhances Ewing's sarcoma tumor growth in the absence of vascular endothelial growth factor

Stromal cell-derived Factor-1alpha (SDF-1alpha) stimulates the migration of bone marrow (BM) cells, similar to vascular endothelial growth factor (VEGF). We previously demonstrated that inhibition of VEGF(165) by small interfering RNA inhibited Ewing's sarcoma tumor growth, tumor vessel formation and recruitment of BM cells to the tumor. To determine the importance of BM cells in tumor vessel development, we investigated the effects of SDF-1alpha on VEGF-inhibited TC/siVEGF(7-1) Ewing's tumor neovasculature formation and growth. The effect of SDF-1alpha on CD34(+) progenitor cell chemotaxis was determined in vivo. Using a BM transplantation model with GFP(+) transgenic mice as BM donors and nude mice as recipients, we evaluated the effect of SDF-1alpha on the recruitment of BM-derived cells to VEGF(165)-inhibited TC/siVEGF(7-1) tumors, as well as its effect on neovasculature development, vessel morphology and tumor growth. SDF-1alpha stimulated the migration of CD34(+) progenitor cells to Matrigel plugs in vivo and promoted the retainment of BM-derived pericytes in close association with perfused, functional tumor vessels. Intratumor inoculation of Ad-SDF-1alpha into TC/siVEGF(7-1) tumors resulted in increased SDF-1 and PDGF-BB expression, augmented tumor growth, an increase in the number of large, lumen-bearing vascular structures, and enhanced vessel pericyte coverage, with no change in VEGF(165). SDF-1alpha stimulates BM cell chemotaxis and the association of these cells with functional tumor vessels. Furthermore, SDF-1alpha enhances tumor neovascularization and growth with no alteration in VEGF(165). Our work suggests that SDF-1-mediated vasculogenesis may represent an alternate pathway that could potentially be utilized by tumors to sustain growth and neovasculature expansion after anti-VEGF therapy.     

POL5551, a novel and potent CXCR4 antagonist,enhances sensitivity to chemotherapy in pediatric ALL

The importance of the cell surface receptor CXCR4 and the chemokine stromal cell-derived factor-1 (SDF-1/CXCL12) is well-established in normal and malignant hematopoiesis. The Protein Epitope Mimetic POL5551 is a novel and potent antagonist of CXCR4. POL5551 efficiently mobilizes hematopoietic stem and progenitor cells, but its effects in acute lymphoblastic leukemia (ALL) have not been reported. Here, we demonstrate that POL5551 is a potent antagonist of CXCR4 in pre-B and T cell ALL cell lines and pediatric ALL primary samples. POL5551 has activity at nanomolar concentrations in decreasing CXCR4 antibody binding, blocking SDF-1α-mediated phosphorylation of ERK1/2, inhibiting SDF-1α-induced chemotaxis, and reversing stromal-mediated protection from chemotherapy. POL5551 is significantly more effective at inhibiting CXCR4 antibody binding than the FDA-approved CXCR4 inhibitor plerixafor in ALL cell lines and primary samples. We also show that treatment with POL5551 in vitro and cytarabine +/− POL5551 in vivo modulates surface expression of adhesion molecules, findings that may guide the optimal clinical use of POL5551. Finally, we demonstrate that POL5551 increases sensitivity to cytarabine in a xenograft model of a high-risk pediatric ALL, infant MLL-rearranged (MLL-R) ALL. Therefore, disruption of the CXCR4/SDF-1 axis with POL5551 may improve outcomes in children with high-risk ALL.     

骨髓增生异常综合征中CD34+细胞CXCR4的表达及其与细胞迁移的相关性

  目的  探讨不同危险度骨髓增生异常综合征（myelodysplasticsymdromes,MDS）中骨髓CD34+细胞CXCR4的表达情况及其与细胞迁移率的相关性。   方法  收集40例骨髓增生异常综合征患者的骨髓标本,根据IPSS积分系统进行危险度分组。低危组20例:IPSS积分0~1.5分;高危组20例:IPSS积分≥1.5分;同时采集10例健康者的骨髓标本作为对照。分离纯化骨髓CD34+细胞,通过流式细胞术检测CXCR4膜蛋白的表达;研究SDF-1α趋化作用下CD34+细胞的迁移率及CD34+细胞对骨髓基质细胞的迁移率。   结果  高危组MDS患者CD34+细胞CXCR4的表达率明显高于低危组和正常对照组（P < 0.000 1）;低危组和正常对照组之间CXCR4的表达率无显著性差异（P>0.05）。高危组CD34+细胞对SDF-1α及骨髓基质细胞的迁移率显著高于低危组及正常组（均P < 0.000 1）,且其对骨髓基质细胞的迁移率与CXCR4的表达呈正相关（P=0.000 1）。   结论  高危组MDS患者CD34+细胞CXCR4的表达量及其对骨髓基质细胞的迁移率均明显高于低危组患者,且其迁移率随CXCR4表达量的增加而升高,不同风险组的MDS患者存在SDF-1及其受体CXCR4表达和功能上的差异,SDF-1及其受体CXCR4在MDS发病中具有重要作用。      

CXCR4 signaling regulates metastasis of chemoresistant melanoma cells by a lymphatic metastatic niche

Highly metastatic and chemotherapy-resistant properties of malignant melanomas stand as challenging barriers to successful treatment; yet, the mechanisms responsible for their aggressive characteristics are not fully defined. We show that a distinct population expressing CD133 (Prominin-1), which is highly enriched after administration of a chemotherapeutic drug, dacarbazine, has enhanced metastatic potential in vivo. CD133(+) tumor cells are located close to tumor-associated lymphatic vessels in metastatic organs such as the regional lymph nodes and lung. Lymphatic endothelial cells promote the migratory activity of a CD133(+) subset to target organs and regulation of lymphatic growth efficiently modulates the metastasis of CD133(+) tumor cells. We found that lymphatic vessels in metastatic tissues stimulate chemokine receptor 4 (CXCR4)(+)/CD133(+) cell metastasis to target organs by secretion of stromal cell-derived factor-1 (SDF-1). The CXCR4(+)/CD133(+) cells exhibited higher metastatic activity compared with CXCR4(-)/CD133(+) cells and, importantly, blockade of CXCR4 coupled with dacarbazine efficiently inhibited both tumor growth and metastasis; dacarbazine alone could not attenuate tumor metastasis. The current study demonstrates a previously unidentified role of the lymphatic microenvironment in facilitating metastasis of chemoresistant melanoma cells via a specific chemotactic axis, SDF-1/CXCR4. Our findings suggest that targeting the SDF-1/CXCR4 axis in addition to dacarbazine treatment could therapeutically block chemoresistant CD133(+) cell metastasis toward a lymphatic metastatic niche.     

Biological effects of stroma-derived factor-1 alpha on normal and CML CD34+ haemopoietic cells.

We compared the biological effects of the CXC chemokine SDF-1alpha on immunomagnetically purified CD34+ cells isolated from human normal bone marrow (NBM), leukapheresis products (LP) and patients with chronic myeloid leukaemia (CML). LP CD34+ cells showed a significantly stronger migration response to SDF-1alpha (100 ng/ml) than CD34+ cells isolated from the peripheral blood (PB) of CML patients (P < 0.05). The chemotactic response to SDF-1alpha was also reduced in CML BM CD34+ cells in comparison to NBM CD34+ cells but the observed differences were not statistically significant. In analogy to normal CD34+ cells circulating CML PB CD34+ cells were less responsive to SDF-1alpha than their BM counterparts (P < 0.05). Furthermore, SDF-1alpha elicited similar concentration-dependent growth suppressive effects on normal and CML CD34+ cells (P > 0.05) in colony-forming cell assays. We then demonstrated that SDF-1alpha triggers intracellular calcium increases in CD34+ cells and there were no differences in the time course and dose response characteristics of normal and CML CD34+ cells. The reduced migration response to SDF-1alpha in CML CD34+ cells was not due to a down-regulation of the SDF-1alpha receptor CXCR-4 as flow cytometric analysis revealed similar CXCR-4 expression levels on NBM, LP, CML PB and CML BM CD34+ cells (P > 0.05). Finally, no differences in the modulation of CXCR-4 levels in response to SDF-1alpha and serum were observed in CML and normal CD34+ cells. Our data suggest that the impaired chemotactic response of CML CD34+ cells to SDF-1alpha is not caused by a lack or complete uncoupling of CXCR-4, but may be due to an intracellular signalling defect downstream of the receptor.     

Silencing of CXCR4 inhibits the proliferation, adhesion, chemotaxis and invasion of salivary gland mucoepidermoid carcinoma Mc3 cells in vitro

Mucoepidermoid carcinoma is the most common malignant tumor in salivary glands and high-grade mucoepidermoid carcinoma is often accompanied with poor prognosis. Many recent research works demonstrated that stromal cell-derived factor-1 (SDF-1) and its receptor CXC chemokine receptor-4 (CXCR4) interaction was critical for metastasis of various cancers. In this study, the immunoexpression of CXCR4 in human salivary gland mucoepidermoid carcinoma in different grades was detected by immunohistochemical analysis and the expression of CXCR4 and its ligand SDF-1 in mucoepidermoid carcinoma MEC-1 cell line and its highly metastatic clone Mc3 was examined by RT-PCR, flow cytometry and immunocytochemical analysis. It was found that CXCR4 was over-expressed in Mc3 cell line and SDF-1 was expressed in both cell lines at a nearly equal level. We further constructed CXCR4-shRNA expression vector to stably transfect Mc3 cells. We found that silencing of endogenous CXCR4 gene expression in Mc3 cells resulted in inhibition of the proliferation, adhesion, chemotaxis and invasion of Mc3 cells in vitro. This study implies that CXCR4 molecule is a potential factor controlling the proliferation and metastasis of Mc3 cells.     

Proteoglycans on bone marrow endothelial cells bind and present SDF-1 towards hematopoietic progenitor cells.

Recognition events between hematopoietic progenitor cells (HPC) and bone marrow endothelial cells (BMEC) initiate homing of HPC to the bone marrow. The chemokine SDF-1 is present on BMEC and plays a crucial role in bone marrow engraftment. We studied the role of proteoglycans (PGs) on BMEC in binding and presentation of SDF-1. SDF-1 mRNA was present in three human BMEC cell lines. Competition experiments showed that 125I-SDF-1 alpha binding to the BMEC cell line 4LHBMEC was inhibited by heparins, heparan sulfate (HS) intestinal mucosa, chondroitin and dermatan sulfate (CS/DS), but not by HS bovine kidney. Pretreatment of 4LHBMEC with glycosaminoglycan (GAG)-degrading enzymes or sodium chlorate demonstrated that SDF-1 bound to both HSPGs and CS/DSPGs in a sulfation-dependent manner, as determined with an SDF-1 antibody recognizing the CXCR4-binding site. 4LHBMEC bound four-fold more SDF-1 than HUVEC. Isolated endothelial PGs did not bind SDF-1 in a filter or microplate-binding assay, suggesting the necessity of membrane association. In flow adhesion experiments, endothelial arrest of CXCR4+ KG-1 and not of CXCR4- KG-1a cells increased significantly when SDF-1 was presented on 4LHBMEC. In conclusion, SDF-1 is produced by BMEC and binds to the BMEC cell surface via HS and CS/DS-GAGs, thereby presenting its CXCR4 binding site to HPC contributing to their arrest.     

Can inhibition of the SDF-1/CXCR4 axis eradicate acute leukemia?

Poor prognosis of acute leukemia with current treatments is mainly due to the relapse of the disease following chemotherapy. In the last decade, an emerging concept has proposed that the leukemia stem cells (LSCs) and their interactions with the BM microenvironment are the major cause of the acute leukemia relapse. Adhesion to the stromal niche is crucial for LSCs as it directly supports self-renewal, proliferation, arrest of differentiation and protects from damaging chemo-agents. One of the key players in this crosstalk between leukemic cells and the BM stroma niche is the chemokine SDF-1. SDF-1 regulates the process of homing and engraftment of LSCs into the BM and inhibition of its receptor CXCR4 induces leukemic cell mobilization into the circulation. However, besides its chemotactic and adhesive functions, SDF-1 is also a pleiotropic cytokine that regulates leukemic cell proliferation as well as their program of differentiation. CXCR4 antagonists are used in combination with chemotherapy in preclinical and clinical studies, which demonstrate that blocking CXCR4 is a novel promising approach of therapy. In this review, we focus on the multifaceted SDF-1/CXCR4 axis in acute leukemia and discuss how targeting this pathway could provide potential interest to eradicate the LSCs.