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

E. Weisberg, A. K. Azab, P. W. Manley, A. L. Kung, A. L. Christie, R. Bronson, I. M. Ghobrial, J. D. Griffin

Research output: Contribution to journalArticlepeer-review

89 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)985-990
Number of pages6
JournalLeukemia
Volume26
Issue number5
DOIs
StatePublished - May 2012
Externally publishedYes

Keywords

  • bone marrow microenvironment
  • chronic myeloid leukemia
  • nilotinib
  • Plerixafor
  • stem cell mobilization
  • stromal-mediated chemoresistance

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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