The CXCR4 antagonist AMD3100 impairs survival of human AML cells and induces their differentiation
S Tavor1, M Eisenbach, J Jacob-Hirsch
1Institute of Hematology and Bone Marrow Transplantation, Sourasky Medical Center, Tel Aviv, Israel. tavorsigal@yahoo.com
Insights
Stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4, along with elastase, regulate acute myeloblastic leukemia (AML) cell survival and differentiation. Inhibiting this axis promotes AML cell differentiation.
Area of Science:
- Hematology
- Molecular Biology
- Cell Biology
Background:
- The stromal cell-derived factor-1 (SDF-1)/CXCR4 axis is crucial for acute myeloblastic leukemia (AML) cell homing and retention in the bone marrow.
- AML cells express SDF-1-dependent elastase, influencing their migration and proliferation.
- Understanding the molecular mechanisms regulated by SDF-1/CXCR4 and elastase is vital for AML treatment.
Purpose of the Study:
- To investigate the molecular events and gene expression profiles regulated by the SDF-1/CXCR4 axis and elastase in AML cells.
- To explore the potential of targeting this axis for therapeutic intervention in AML.
Main Methods:
- Gene expression profiling of the U937 AML cell line using DNA microarray technology.
- Treatment of cells with a neutralizing anti-CXCR4 antibody or an elastase inhibitor.
- Analysis of gene expression data using unsupervised hierarchical clustering, pathway, and functional analysis.
- Further investigation using the CXCR4 antagonist AMD3100 to assess effects on AML cell growth and differentiation.
Main Results:
- Hierarchical clustering revealed similar gene expression profiles between anti-CXCR4 antibody or elastase inhibitor-treated cells and controls.
- Pathway analysis indicated a tendency toward differentiation in cells treated with either modality.
- AMD3100 treatment arrested proliferation and induced differentiation in AML cell lines, characterized by morphological changes and myeloid antigen expression.
- Elastase inhibition also triggered AML cell differentiation.
Conclusions:
- The SDF-1/CXCR4 axis plays a significant role in regulating leukemic cell survival.
- Inhibition of the SDF-1/CXCR4 axis and elastase promotes AML cell differentiation.
- Targeting the SDF-1/CXCR4 axis represents a potential therapeutic strategy for AML.
Abstract:
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.
