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

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

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Myeloid Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Lipids
src-Family Kinases
Protein-Tyrosine Kinases
bcr-abl Fusion Proteins
Bone Marrow
CXCR4 Receptors
Chemokine CXCL12
Chemokine Receptors
Stromal Cells
Imatinib Mesylate
Cholesterol
Pharmacology

Keywords

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

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Tabe, Y., Jin, L., Iwabuchi, K., Wang, R. Y., Ichikawa, N., Miida, T., ... 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

Role of stromal microenvironment in nonpharmacological resistance of CML to imatinib through Lyn/CXCR4 interactions in lipid rafts. / Tabe, Y.; Jin, L.; Iwabuchi, K.; Wang, R. Y.; Ichikawa, N.; Miida, T.; Cortes, J.; Andreeff, M.; Konopleva, M.

In: Leukemia, Vol. 26, No. 5, 01.05.2012, p. 883-892.

Research output: Contribution to journalArticle

Tabe, Y, Jin, L, Iwabuchi, K, Wang, RY, 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, vol. 26, no. 5, pp. 883-892. https://doi.org/10.1038/leu.2011.291
Tabe, Y. ; Jin, L. ; Iwabuchi, K. ; Wang, R. Y. ; Ichikawa, N. ; Miida, T. ; Cortes, J. ; Andreeff, M. ; Konopleva, M. / Role of stromal microenvironment in nonpharmacological resistance of CML to imatinib through Lyn/CXCR4 interactions in lipid rafts. In: Leukemia. 2012 ; Vol. 26, No. 5. pp. 883-892.
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