CXCR4 antagonists for the treatment of CML

Anupriya Agarwal, Thomas O'Hare, Michael Deininger

Research output: Chapter in Book/Report/Conference proceedingChapter

3 Scopus citations

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.

Original languageEnglish (US)
Title of host publicationNovel Developments in Stem Cell Mobilization
Subtitle of host publicationFocus on CXCR4
PublisherSpringer US
Pages351-367
Number of pages17
ISBN (Electronic)9781461419600
ISBN (Print)9781461419594
DOIs
StatePublished - Jan 1 2012

Keywords

  • CML
  • CXCR4
  • Disease persistence
  • Plerixafor (AMD3100)
  • SDF-1

ASJC Scopus subject areas

  • Medicine(all)

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