Role of stromal microenvironment in nonpharmacological resistance of CML to imatinib through Lyn/CXCR4 interactions in lipid rafts

Y. Tabe, L. Jin, K. Iwabuchi, R. Y. Wang, N. Ichikawa, T. Miida, J. Cortes, M. Andreeff, M. Konopleva

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

We and others have previously demonstrated that p210 Bcr-Abl tyrosine kinase inhibits stromal cell-derived factor-1α/CXCR4 chemokine receptor signaling, contributing to the deficient adhesion of chronic myeloid leukemia (CML) cells to bone marrow stroma. Conversely, exposure of CML cells to a tyrosine kinase inhibitor (TKI) enhances migration of CML cells towards stromal cell layers and promotes non-pharmacological resistance to imatinib. Src-related kinase Lyn is known to interact with CXCL12/CXCR4 signaling and is directly activated by p210 Bcr-Abl. In this study, we demonstrate that TKI treatment promoted CXCR4 redistribution into the lipid raft fraction, in which it co-localized with active phosphorylated form of Lyn (LynTyr396) in CML cells. Lyn inhibition or cholesterol depletion abrogated imatinib-induced migration, and dual Src/Abl kinase inhibitor dasatinib induced fewer CML cells to migrate to the stroma. These findings demonstrate the novel mechanism of microenvironment-mediated resistance through lipid raft modulation, which involves compartmental changes of the multivalent CXCR4 and Lyn complex. We propose that pharmacological targeting of lipid rafts may eliminate bone marrow-resident CML cells through interference with microenvironment-mediated resistance.

Original languageEnglish (US)
Pages (from-to)883-892
Number of pages10
JournalLeukemia
Volume26
Issue number5
DOIs
StatePublished - May 1 2012
Externally publishedYes

    Fingerprint

Keywords

  • CXCR4
  • Chronic myeloid leukemia (CML)
  • Lyn
  • dasatinib
  • imatinib
  • lipid raft

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Tabe, Y., Jin, L., Iwabuchi, K., Wang, R. Y., Ichikawa, N., Miida, T., Cortes, J., Andreeff, M., & Konopleva, M. (2012). Role of stromal microenvironment in nonpharmacological resistance of CML to imatinib through Lyn/CXCR4 interactions in lipid rafts. Leukemia, 26(5), 883-892. https://doi.org/10.1038/leu.2011.291