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

E Weisberg1, A K Azab, P W Manley

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.

Leukemia
|December 21, 2011
PubMed

Insights

Drug resistance in chronic myeloid leukemia (CML) is a concern. Combining CXCR4 inhibitor plerixafor with kinase inhibitors like nilotinib effectively targets residual CML cells and overcomes drug resistance.

Area of Science:

  • Hematology
  • Oncology
  • Pharmacology

Background:

  • Residual leukemic CD34+ progenitor cells can survive in the bone marrow microenvironment despite kinase inhibitor treatment for chronic myeloid leukemia (CML).
  • Bone marrow stroma contributes to leukemic cell survival, proliferation, and drug resistance in CML.
  • CXCR4 expression on CML cells plays a role in their interaction with the bone marrow microenvironment.

Purpose of the Study:

  • To investigate the role of CXCR4 in CML drug resistance and explore the efficacy of CXCR4 inhibition in combination with tyrosine kinase inhibitors.
  • To evaluate the potential of plerixafor, a CXCR4 inhibitor, to overcome drug resistance and eradicate residual CML disease.

Main Methods:

  • In vitro studies assessed the effect of plerixafor on BCR-ABL-positive cell migration, adhesion to bone marrow stromal cells, and drug resistance.
  • A functional mouse model of CML was used to evaluate the in vivo efficacy of plerixafor alone and in combination with nilotinib.

Main Results:

  • Plerixafor diminished BCR-ABL-positive cell migration and reduced their adhesion to extracellular matrix and bone marrow stromal cells in vitro.
  • Plerixafor decreased drug resistance in CML cells co-cultured with bone marrow stromal cells.
  • Combination therapy with plerixafor and nilotinib significantly reduced leukemia burden in mice, surpassing the efficacy of nilotinib monotherapy.

Conclusions:

  • CXCR4 inhibition, particularly with plerixafor, can overcome drug resistance in CML by disrupting leukemic cell interactions with the bone marrow microenvironment.
  • Combining CXCR4 inhibitors with targeted tyrosine kinase inhibitors offers a promising strategy to suppress or eradicate residual CML disease and improve treatment outcomes.

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