The characterization of chemokine production and chemokine receptor expression reveals possible functional cross-talks in AML blasts with monocytic differentiation

Cignetti, Alessandro; Vallario, Antonella; Roato, Ilaria; Circosta, Paola; Strola, Giuliana; Scielzo, Cristina; Allione, Bernardino; Garetto, Lucia; Caligaris-Cappio, Federico; Ghia, Paolo

doi:10.1016/s0301-472x(03)00066-3

Cited by 30 publications

(34 citation statements)

References 28 publications

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“…CXCR4 is functional in AML cells, 25,26,35,36 and surface CXCR4 expression, which generally is low compared with lymphoid cells, appears to correlate with functional responses such as chemotaxis. 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.…”

Section: Discussionmentioning

confidence: 99%

CXCR4 is a prognostic marker in acute myelogenous leukemia

Spoo

Lübbert

Wierda

et al. 2006

Blood

291

208

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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

291

208

View full text Add to dashboard Cite

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“…For instance, the increased expression levels of several CC chemokines observed in our analysis may contribute to the increased motility and invasiveness of the Mef2c ϩ tumors by either autocrine or paracrine mechanism by increasing chemotaxis, stimulating proliferation and/or survival, or altering the stroma environment. [53][54][55] Notably, increased levels of CCR2 and its ligands have been observed in AML with a myelomonocytic or monocytic phenotype, and correlated with increased extramedullary involvement. 54 Furthermore, CCL3, CCL4, CCL6, and CCL9 are all highly expressed in the MLL/ENL-transformed cells and also in activated macrophages, providing an additional link between the leukemic phenotype and the importance of Mef2c during normal macrophage differentiation.…”

Section: How May Mef2c Regulate Homing and Invasiveness?mentioning

confidence: 99%

“…[53][54][55] Notably, increased levels of CCR2 and its ligands have been observed in AML with a myelomonocytic or monocytic phenotype, and correlated with increased extramedullary involvement. 54 Furthermore, CCL3, CCL4, CCL6, and CCL9 are all highly expressed in the MLL/ENL-transformed cells and also in activated macrophages, providing an additional link between the leukemic phenotype and the importance of Mef2c during normal macrophage differentiation. Similarly, our microarray analysis also revealed several MMPs that were up-regulated in Mef2c ϩ cells, which have often been linked to tumor metastasis and leukemic survival rates.…”

Section: How May Mef2c Regulate Homing and Invasiveness?mentioning

confidence: 99%

Homing and invasiveness of MLL/ENL leukemic cells is regulated by MEF2C

Schwieger

Schüler

Förster

et al. 2009

Blood

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“…Previous studies have demonstrated that both lung epithelial cells and leukocytes can secret MCP-1 and express its receptors CCR2 [8][9][10]. Similarly, ATRA has been reported to increase gene expression or secretion of MCP-1 and CCR2 in APL cells, neutrophils and lung epithelial cells [8,10,11]. Therefore, the aim of this study was to investigate the role of MCP-1/ CCR2 axis in the cell-cell interaction essential for the chemotactic transmigration of ATRA-treated NB4 APL cells toward A549 alveolar epithelial cells using a co-culture model.…”

mentioning

confidence: 99%

Monocyte chemotactic protein-1 in the migration of differentiated leukaemic cells toward alveolar epithelial cells

Tsai¹,

Shih²,

Lin

et al. 2008

European Respiratory Journal

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All-trans retinoic acid (ATRA) can induce acute respiratory distress syndrome in patients with acute promyelocytic leukaemia (APL). The current study investigated the role of monocyte chemotactic protein (MCP)-1 in the chemotactic transmigration of ATRA-treated NB4 (ATRA-NB4) APL cells toward A549 alveolar epithelial cells.NB4 and A549 cells were separately cultured with ATRA and/or dexamethasone (DEX). ATRA-NB4 cells were then placed in an upper insert and co-incubated with A549 cells or their conditioned medium (CM) located in a lower plate to test their transmigration activity.ATRA stimulated NB4 cells to transmigrate toward the A549 cells. The secretion of MCP-1 was enhanced by ATRA treatment in both A549 and NB4 cells. The binding assay demonstrated that ATRA-NB4 cells bound MCP-1. Pre-treatment of both CM-A549 cells with antibodies against MCP-1 and of ATRA-NB4 cells with antibodies against MCP-1 receptors reduced ATRA-NB4 cell transmigration. DEX did not suppress MCP-1 secretion and transmigration in ATRA-NB4 cells, although when applied to A549 cells, MCP-1 secretion was suppressed and ATRA-NB4 cell transmigration was attenuated.Monocyte chemotactic protein-1 secreted from alveolar epithelial cells plays an important role in the cell-cell interaction involved in the chemotactic transmigration of all-trans retinoic acidtreated acute promyelocytic leukaemia cells toward alveolar epithelial cells.

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The characterization of chemokine production and chemokine receptor expression reveals possible functional cross-talks in AML blasts with monocytic differentiation

Cited by 30 publications

References 28 publications

CXCR4 is a prognostic marker in acute myelogenous leukemia

CXCR4 is a prognostic marker in acute myelogenous leukemia

Homing and invasiveness of MLL/ENL leukemic cells is regulated by MEF2C

Monocyte chemotactic protein-1 in the migration of differentiated leukaemic cells toward alveolar epithelial cells

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