原创力文档dasatinib inhibits cxcr4 signaling in chronic lymphocytic leukaemia cells and impairs migration towards cxcl12达沙替尼抑制趋化因子受体cxcr4信号在慢性淋巴细胞白血病细胞向cxcl12和损害迁移.pdfVIP
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dasatinib inhibits cxcr4 signaling in chronic lymphocytic leukaemia cells and impairs migration towards cxcl12达沙替尼抑制趋化因子受体cxcr4信号在慢性淋巴细胞白血病细胞向cxcl12和损害迁移
Dasatinib Inhibits CXCR4 Signaling in Chronic
Lymphocytic Leukaemia Cells and Impairs Migration
Towards CXCL12
1,3 1 2 1
Alison M. McCaig *, Emilio Cosimo , Michael T. Leach , Alison M. Michie
1 Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom, 2 Department of Haematology, West of
Scotland Cancer Centre, Gartnavel General Hospital, Glasgow, United Kingdom, 3 Department of Haematology, Royal Alexandra Hospital, Paisley, United Kingdom
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 sugges
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