Motility, proliferation, and egress to the circulation of human AML cells are elastase dependent in NOD/SCID chimeric mice

Tavor, Sigal; Petit, Isabelle; Porozov, Svetlana; Goichberg, Polina; Avigdor, Abraham; Sagiv, Sari Prutchi; Nagler, Arnon; Naparstek, Elizabeth; Lapidot, Tsvee

doi:10.1182/blood-2004-12-4969

Cited by 34 publications

(29 citation statements)

References 38 publications

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“…37 CXCR4-dependent engraftment of AML cells in NOD/SCID mice was demonstrated by Tavor and colleagues, 28 and this group also reported that the proteolytic enzyme elastase is involved in regulating SDF-1-dependent migration and proliferation of AML cells in vitro and in vivo. 38 We recently reported that CXCR4, in cooperation with VLA-4 integrins, mediates spontaneous migration of AML cells beneath marrow stromal cells. 26 In addition, we noticed a decreased proliferation of migrated AML cells within the stromal layer, as demonstrated by cell cycle analysis and cell division tracking.…”

Section: Discussionmentioning

confidence: 99%

CXCR4 is a prognostic marker in acute myelogenous leukemia

Spoo

Lübbert

Wierda

et al. 2006

Blood

299

213

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CXCR4 chemokine receptors retain hematopoietic progenitors and leukemia cells within the marrow microenvironment. We prospectively evaluated the prognostic implication of CXCR4 in 90 consecutive patients with acute myelogenous leukemia (AML) by flow cytometry. Patients were divided into groups with low (n ‫؍‬ 32), intermediate (n ‫؍‬ 26), or high (n ‫؍‬ 32) CXCR4 expression, as defined by CXCR4 mean fluorescence intensity ratio thresholds of less than 5, 5 to 10, or more than 10, respectively. We found that low CXCR4 expression on AML cells correlated with a better prognosis, resulting in a longer relapse-free and overall survival of 24.3 ؎ 2.9 months for low CXCR4-expressing patients, compared with 17.4 ؎ 3.4 months for intermediate and 12.8 ؎ 2 months (mean ؎ SEM) for patients with high expression. In univariate analyses, CXCR4 expression, cytogenetics, white blood cell count, and serum lactate dehydrogenase (LDH) predicted for shorter survival. Multivariate analysis revealed CXCR4 expression and unfavorable cytogenetics as independent prognostic factors. We conclude that CXCR4 expression in AML is an independent prognostic predictor for disease relapse and survival that can rapidly and easily be determined at disease presentation. These findings warrant further investigation into the role of CXCR4 in AML and suggest that CXCR4 should be incorporated into the risk assessment of AML patients. IntroductionDespite major improvements in the understanding and treatment of certain leukemias during the past years, the overall survival (OS) of patients with acute myelogenous leukemia (AML) remains poor, and new prognostic markers and therapeutic strategies are urgently needed. Several prognostic markers have been described in AML, including age, performance status, karyotype, white blood cell (WBC) count, serum lactate dehydrogenase (LDH), presence or absence of an antecedent hematologic disorder (eg, myelodysplasia), and the presence of distinct cytogenetic abnormalities. [1][2][3] Cytogenetic abnormalities can be detected in approximately 60% of AML patients and represent the most important predictor for responses to therapy and relapse probability. Depending upon cytogenetic characteristics, patients can be classified into low-risk, intermediate-risk, or high-risk groups. 4,5 However, there is substantial heterogeneity within these groups. About 35% to 50% of AML patients display a normal karyotype, which can further be subdivided using predictive molecular markers, such as mutations in the fetal liver tyrosine kinase-3 (FLT3) gene and the mixed-lineage leukemia (MLL) gene. 6,7 Several studies indicated that adhesion to marrow stromal cells affects the survival and proliferation of AML cells 8,9 and protects AML cells from chemotherapy in vitro 10 and in vivo. 11 Adhesion molecules, particularly the very late antigen-4 (VLA-4) and VLA-5 integrins, are considered essential for AML cell adhesion to respective stromal ligands (fibronectin) 12 and for protection of AML cells from spontaneous or drug-induced apoptosis....

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Section: Discussionmentioning

confidence: 99%

CXCR4 is a prognostic marker in acute myelogenous leukemia

Spoo

Lübbert

Wierda

et al. 2006

Blood

299

213

View full text Add to dashboard Cite

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“…12 Moreover, U937 cells secrete elastase that regulates both their proliferation and SDF-1-dependent migration. 15 To compile a list of elastase and SDF-1-responsive genes, we singled out genes that were either induced or repressed by at least twofolds after both anti-CXCR4 and EI treatments, at all time points, while compared with non-treated U937 cells. Unsupervised hierarchical clustering analysis demonstrated distinct gene expression profiles for all treated samples as compared with control non-treated sample (Figures 1 and 2).…”

Section: Global Gene Expression Of U937 Aml Cells Treated With Ei or mentioning

confidence: 99%

“…[9][10][11][12] In addition to controlling cell motility, SDF-1 regulates cell proliferation, induces cell cycle progression and acts as a survival factor for normal human stem cells and AML cells. [13][14][15][16] CXCR4 blockage in AML cells, using the polypeptide RCP168, enhanced chemotherapy-induced apoptosis in vitro. 17 Most importantly, high CXCR4 expression level in leukemic cells was proved as a predictor of overall survival and relapsefree survival in patients with AML.…”

Section: Introductionmentioning

confidence: 99%

“…Recently, we found that AML cells constitutively secrete and express SDF-1-dependent cell surface elastase, which regulates their migration and proliferation. 15 To elucidate the molecular events and genes regulated by SDF-1/CXCR4 axis and elastase, we compared global gene expression profiles of AML cells treated with neutralizing CXCR4 monoclonal antibody (mAb) or with elastase inhibitor (EI) with untreated cells, using a DNA microarray technology. We further investigated the effect of inhibition of these pathways on the growth and differentiation of AML cells using in vitro assays and found that inhibition of either CXCR4 or elastase pathway led to decreased cell survival and provoked differentiation of AML cells.…”

Section: Introductionmentioning

confidence: 99%

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The CXCR4 antagonist AMD3100 impairs survival of human AML cells and induces their differentiation

et al. 2008

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The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4, participate in the retention of acute myeloblastic leukemia (AML) cells within the bone marrow microenvironment and their release into the circulation. AML cells also constitutively express SDF-1-dependent elastase, which regulates their migration and proliferation. To study the molecular events and genes regulated by the SDF-1/CXCR4 axis and elastase in AML cells, we examined gene expression profiles of the AML cell line, U937, under treatment with a neutralizing anti-CXCR4 antibody or elastase inhibitor, as compared with non-treated cells, using DNA microarray technology. Unsupervised hierarchical clustering analysis demonstrated similar gene expression profiles of anti-CXCR4 antibody or elastase inhibitor-treated cells, as compared with control. Pathway and functional analysis showed a greater tendency toward differentiation in cells under either one of both treatment modalities. Thus given, we further analyzed the effects of CXCR4 inhibition on AML cell growth and differentiation using the antagonist AMD3100. AMD3100 arrested proliferation in AML cell lines and triggered changes that mimicked differentiation, including morphological changes and the expression of myeloid differentiation antigens. Inhibition of elastase also triggered the differentiation of AML cells. Our study defines a new role for the SDF-1/CXCR4 axis in the regulation of leukemic cell survival and differentiation.

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“…Increased concentrations of elastase found in the peripheral blood and bone marrow plasma samples isolated from AML patients belonging to our AML cohort (42) suggest that this enzyme perhaps in cooperation with other proteolytic enzymes, such as MMP abnormally expressed in AML patients (43), may cleave SDF-1. Furthermore, SDF-1 is able to enhance in vitro survival of AML cells, even in minimal concentrations (1 ng/mL; ref.…”

Section: Discussionmentioning

confidence: 87%

Functional CXCR4-Expressing Microparticles and SDF-1 Correlate with Circulating Acute Myelogenous Leukemia Cells

et al. 2006

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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/B2m 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

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Motility, proliferation, and egress to the circulation of human AML cells are elastase dependent in NOD/SCID chimeric mice

Cited by 34 publications

References 38 publications

CXCR4 is a prognostic marker in acute myelogenous leukemia

CXCR4 is a prognostic marker in acute myelogenous leukemia

The CXCR4 antagonist AMD3100 impairs survival of human AML cells and induces their differentiation

Functional CXCR4-Expressing Microparticles and SDF-1 Correlate with Circulating Acute Myelogenous Leukemia Cells

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