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Stem Cells

CXCR4 antagonists mobilize childhood acute lymphoblastic leukemia cells into the peripheral blood and inhibit engraftment

Leukemia volume 21, pages 1249–1257 (2007)Cite this article

Abstract

The role of CXCL12 in the bone marrow (BM) homing and growth of B-cell progenitor acute lymphoblastic leukemia (ALL) has been established. However, the effect of modulating CXCL12/CXCR4 interactions on the retention of ALL cells within the supportive BM microenvironment and the expansion and dissemination of ALL cells in vivo has not been examined. We used mouse models of human childhood and murine leukemia and specific peptide and small molecule CXCR4 antagonists to examine the importance of CXCL12/CXCR4 in the development of leukemia in vivo. CXCR4 antagonists mobilized ALL cells into the peripheral blood (PB). Extended administration of CXCR4 antagonists to mice with leukemia resulted in a reduction in the number of leukemic cells in the PB and spleens of animals compared to control treated animals in three of the five cases tested. There was also a marked reduction in the dissemination of ALL cells to extramedullary sites including liver and kidney in all cases where this occurred. Considering the inhibitory effect of stromal layers on the activity of chemotherapeutic agents and the interactive effect of CXCL12 antagonists with chemotherapeutic agents in vitro, this raises the possibility of using these agents to potentiate the effects of current chemotherapy regimens.

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Acknowledgements

We acknowledge Drs Mitsuko Takenaga and Rie Igarashi in St Marianna University for preparation of 4-fluoro-benzoyl-TE14011-PLA. This work was funded by the Anthony Rothe Memorial Trust, National Health and Medical Research Council of Australia Grant No. 352326, the Cancer Institutes NSW, Westmead Millennium Foundation and a Faculty of Medicine/Medical Foundation Postgraduate Research Scholarship from the University of Sydney (JJ).

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Authors and Affiliations

  1. Westmead Institute for Cancer Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia

    J Juarez, A Dela Pena, R Baraz, J Hewson, A Cisterne & L J Bendall

  2. Department of Pharmacology, University of Sydney, Sydney, Australia

    M Khoo

  3. AnorMed, Langley, British Columbia, Canada,

    S Fricker

  4. Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan

    N Fujii

  5. Department of Haematology, Westmead Hospital, Sydney, Australia

    K F Bradstock

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Correspondence to L J Bendall.

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Juarez, J., Dela Pena, A., Baraz, R. et al. CXCR4 antagonists mobilize childhood acute lymphoblastic leukemia cells into the peripheral blood and inhibit engraftment. Leukemia 21, 1249–1257 (2007). https://doi.org/10.1038/sj.leu.2404684

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