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Acute Leukemias

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

Leukemia volume 22, pages 2151–2158 (2008)Cite this article

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.

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Acknowledgements

This work was supported, in part, by grants from the joint program, Weizmann Institute & Tel-Aviv Sourasky Medical Center (ST), the Israel Cancer Association through the Ber-Lehmsdorf Memorial Fund (ST) and the Biodisc program of the German Federal Ministry of Education and Science (BMBF) (VD). We thank the Kahn Family Foundation for their support. G Rechavi holds the Djerassi Chair in Oncology at the Sackler Faculty of Medicine, Tel-Aviv University (Tel-Aviv, Israel).

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Authors and Affiliations

  1. Institute of Hematology and Bone Marrow Transplantation, Sourasky Medical Center, Tel Aviv, Israel

    S Tavor, M Eisenbach, T Golan, I Petit, K BenZion, S Kay, S Baron, V Deutsch & E Naparstek

  2. Cancer Research Center, Sheba Medical Center, Tel-Hashomer, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    J Jacob-Hirsch, N Amariglio & G Rechavi

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  1. S Tavor
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Correspondence to S Tavor.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Tavor, S., Eisenbach, M., Jacob-Hirsch, J. et al. The CXCR4 antagonist AMD3100 impairs survival of human AML cells and induces their differentiation. Leukemia 22, 2151–2158 (2008). https://doi.org/10.1038/leu.2008.238

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