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

Leukemia. 2012 May;26(5):985-90. doi: 10.1038/leu.2011.360. Epub 2011 Dec 20.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Bone Marrow Cells / drug effects*
  • Bone Marrow Cells / metabolism
  • Bone Marrow Cells / pathology
  • Cell Adhesion
  • Cell Line, Tumor
  • Cell Proliferation
  • Coculture Techniques
  • Drug Resistance, Neoplasm
  • Flow Cytometry
  • Heterocyclic Compounds / pharmacology
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Mice
  • Pyrimidines / therapeutic use*
  • Receptors, CXCR4 / antagonists & inhibitors*
  • Stromal Cells / drug effects*
  • Stromal Cells / metabolism
  • Stromal Cells / pathology

Substances

  • 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
  • Antineoplastic Agents
  • CXCR4 protein, human
  • Heterocyclic Compounds
  • Pyrimidines
  • Receptors, CXCR4
  • plerixafor