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Minimal Residual Disease

Inhibition of CXCR4 in CML cells disrupts their interaction with the bone marrow microenvironment and sensitizes them to nilotinib

Leukemia volume 26, pages 985–990 (2012)Cite this article

Abstract

Drug resistance is a growing area of concern. It has been shown that a small, residual pool of leukemic CD34+ progenitor cells can survive in the marrow microenvironment of chronic myeloid leukemia (CML) patients after years of kinase inhibitor treatment. Bone marrow (BM) stroma has been implicated in the long-term survival of leukemic cells, and contributes to the expansion and proliferation of both transformed and normal hematopoietic cells. Mechanistically, we found that CML cells expressed CXCR4, and that plerixafor diminished BCR–ABL-positive cell migration and reduced adhesion of these cells to extra cellular-matrix components and to BM stromal cells in vitro. Moreover, plerixafor decreased the drug resistance of CML cells induced by co-culture with BM stromal cells in vitro. Using a functional mouse model of progressive and residual disease, we demonstrated the ability of the CXCR4 inhibitor, plerixafor, to mobilize leukemic cells in vivo, such that a plerixafor–nilotinib combination reduced the leukemia burden in mice significantly below the baseline level suppression exhibited by a moderate-to-high dose of nilotinib as single agent. These results support the idea of using CXCR4 inhibition in conjunction with targeted tyrosine kinase inhibition to override drug resistance in CML and suppress or eradicate residual disease.

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Acknowledgements

JDG is supported by NIH grant CA66996. JDG has a financial interest with Novartis Pharma AG. JDG and ALK have a financial interest with Novartis Pharma AG. PWM is an employee of Novartis.

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Author notes

  1. E Weisberg and A K Azab: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    E Weisberg, A K Azab, I M Ghobrial & J D Griffin

  2. Novartis Pharma AG, Basel, Switzerland

    P W Manley

  3. Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital, Boston, MA, USA

    A L Kung & A L Christie

  4. Department of Pathology, Rodent Histopathology Core, Harvard Medical School, Boston, MA, USA

    R Bronson

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Weisberg, E., Azab, A., Manley, P. et al. Inhibition of CXCR4 in CML cells disrupts their interaction with the bone marrow microenvironment and sensitizes them to nilotinib. Leukemia 26, 985–990 (2012). https://doi.org/10.1038/leu.2011.360

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