Dasatinib inhibits CXCR4 signaling in chronic lymphocytic leukaemia cells and impairs migration towards CXCL12

McCaig, A. M., Cosimo, E., Leach, M. T. and Michie, A. M. (2012) Dasatinib inhibits CXCR4 signaling in chronic lymphocytic leukaemia cells and impairs migration towards CXCL12. PLoS ONE, 7(11), e48929. (doi: 10.1371/journal.pone.0048929) (PMID:23133664) (PMCID:PMC3487834)

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Publisher's URL: http://dx.doi.org/10.1371/journal.pone.0048929

Abstract

Chemokines and their ligands play a critical role in enabling chronic lymphocytic leukaemia (CLL) cells access to protective microenvironmental niches within tissues, ultimately resulting in chemoresistance and relapse: disruption of these signaling pathways has become a novel therapeutic approach in CLL. The tyrosine kinase inhibitor dasatinib inhibits migration of several cell lines from solid-organ tumours, but effects on CLL cells have not been reported. We studied the effect of clinically achievable concentrations of dasatinib on signaling induced by the chemokine CXCL12 through its' receptor CXCR4, which is highly expressed on CLL cells. Dasatinib pre-treatment inhibited Akt and ERK phosphorylation in CLL cells upon stimulation with CXCL12. Dasatinib also significantly diminished the rapid increase in actin polymerisation observed in CLL cells following CXCL12 stimulation. Moreover, the drug significantly inhibited chemotaxis in a transwell assay, and reduced the percentage of cells able to migrate beneath a CXCL12-expressing murine stromal cell line. Dasatinib also abrogated the anti-apoptotic effect of prolonged CXCL12 stimulation on cultured CLL cells. These data suggest that dasatinib, akin to other small molecule kinase inhibitors targeting the B-cell receptor signaling pathway, may redistribute CLL cells from protective tissue niches to the peripheral blood, and support the investigation of dasatinib in combination strategies.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Michie, Dr Alison and Mccaig, Dr Alison and Cosimo, Dr Emilio
Authors: McCaig, A. M., Cosimo, E., Leach, M. T., and Michie, A. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:PLoS ONE
Publisher:Public Library of Science
ISSN:1932-6203
Published Online:02 November 2012
Copyright Holders:Copyright © 2012 The Authors
First Published:First published in PLoS ONE 7(11):e48929
Publisher Policy:Reproduced under a Creative Commons License
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
444831Defining the cellular origin of chronic lymphocytic leukaemiaAlison MichieMedical Research Council (MRC)G0601099RI CANCER SCIENCES