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CXCR4 Antagonists for the Treatment of CML

  • Anupriya Agarwal
  • Thomas O’Hare
  • Michael Deininger
Chapter

Abstract

Tyrosine kinase inhibitor (TKI)-based targeted therapy has improved clinical outcomes in chronic myeloid leukemia (CML) to an extent unrivaled in other hematologic malignancies. Targeted therapy elicits durable remissions but does not eradicate leukemic stem cells (LSCs), the reservoir of CML. Recurrence of active leukemia is the predictable result upon cessation of therapy, even in the best responders. Interactions between LSCs and the bone marrow microenvironment are thought to mediate disease persistence in vivo, despite effective inhibition of BCR-ABL tyrosine kinase, the molecular driver of CML. Homing and engraftment of CML LSCs in the absence of therapy is characterized by an exaggerated dependence on the CD44 homing receptor and reduced dependence on C-X-C chemokine receptor 4 (CXCR4) compared to normal hematopoietic stem cells (HSCs). In fact, high-level BCR-ABL expression leads to downregulation of CXCR4. Recent evidence suggests that successful TKI-based targeting of BCR-ABL restores reliance on CXCR4 and its ligand, stromal cell-derived factor 1 (SDF-1), for trafficking and homing of CML LSCs to the bone marrow. Perturbation of the CXCR4/SDF-1 interaction with CXCR4 antagonists can promote egress of CML LSCs and progenitor cells from the bone marrow niche, potentially increasing their susceptibility to targeted and conventional purging strategies. Targeting of CXCR4/SDF-1 interactions represents a promising therapeutic avenue and is currently being evaluated in clinical trials. Here, we explore the role of CXCR4/SDF-1 signaling in the ­navigation of CML LSCs within the bone marrow microenvironment and summarize pre-clinical and clinical development of CXCR4 antagonists for use in extending the practical limit of targeted therapy to disease eradication, the ultimate goal in the treatment of CML.

Keywords

CML CXCR4 SDF-1 Plerixafor (AMD3100) Disease persistence 

Notes

Acknowledgments

We thank Sarah Bowden and Suzanne Wickens for administrative support. This study was supported by NIH grants HL082978-01 (M.W.D.) and CA04963920A2 (M.W.D.), Leukemia and Lymphoma Society grant 7036–01 (M.W.D.), and a grant from Genzyme Pharmaceuticals (M.W.D.). M.W.D. is a Leukemia and Lymphoma Society Scholar in Clinical Research. A.A. is a recipient of Lady Tata Memorial Trust and OHSU Knight Cancer Institute Cancer Research Development Awards.

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Anupriya Agarwal
    • 1
  • Thomas O’Hare
    • 2
  • Michael Deininger
    • 2
  1. 1.Division of Hematology and Medical OncologyOregon Health & Science University, Knight Cancer InstitutePortlandUSA
  2. 2.Division of Hematology and Hematologic Malignancies, Huntsman Cancer InstituteUniversity of UtahSalt Lake CityUSA

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