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Blood, 15 June 2005, Vol. 105, No. 12, pp. 4813-4819.
Prepublished online as a Blood First Edition Paper on February 24, 2005; DOI 10.1182/blood-2004-10-4054.
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Submitted October 21, 2004
Accepted February 18, 2005
CLL, but not normal, B cells are dependent on autocrine VEGF and  4 1 integrin for chemokine-induced motility on and through endothelium
Kathleen J Till*, David G Spiller, Robert J Harris, Haijuan Chen, Mirko Zuzel, and John C Cawley
Department of Haematology, University of Liverpool, Liverpool, United Kingdom
Center for Cell Imaging, University of Liverpool, Liverpool, United Kingdom
* Corresponding author; email: k.j.till{at}liv.ac.uk.
Vascular endothelial cell growth factor (VEGF) is a multifunctional cytokine involved in tumour formation. In chronic lymphocytic leukaemia (CLL), it is known that the malignant cells secrete VEGF and possess VEGF receptors. This suggests that an autocrine loop might be important in the pathogenesis of CLL. Here we show that, in patients with lymphadenopathy, autocrine VEGF and  4 1-integrin are involved in the chemokine-dependent motility of CLL cells on and through endothelium - processes important for the invasion of lymphoreticular tissues, a major determinant of disease outcome. In contrast, normal lymphocytes were not dependent on autocrine VEGF or 41 for either type of cell movement. Moreover, in contrast to normal B lymphocytes, CLL cells failed to cluster and activate L2 in response to chemokines, unless VEGF receptor(s) and 41 were also engaged by their respective ligands. This is the first demonstration that autocrine VEGF is involved in CLL-cell motility, and that the L2 on the malignant cells is functionally altered as compared with that of normal B cells in not undergoing activation in response to chemokine alone. Given the importance of cell motility for tissue invasion, the present results provide a rationale for a trail of VEGF and 4 blockade in CLL patients with tissue disease.
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