Chronic Lymphocytic Leukemia Cells Are Dependent on Autocrine VEGF and α4β1 Integrin for Chemokine-Induced Motility.

VEGF is a multifunctional cytokine involved in tumourigenesis. 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 α4β1-integrin are involved in the chemokine-dependent motility of CLL cells on and through endothelium - processes important for the invasion of lymphoreticular tissues. In contrast, normal lymphocytes were not dependent on autocrine VEGF or α4β1 for either type of cell movement. Moreover, in contrast to normal B lymphocytes, CLL cells failed to cluster and activate αLβ2 in response to chemokines, unless VEGF receptor(s) and α4β1 were also engaged by their respective ligands. This is the first demonstration that autocrine VEGF is involved in CLL-cell motility and that the αLβ2 on the malignant cells is functionally altered in the disease. Taken together, the results suggest that VEGF and α4 blockade may be therapeutically useful in CLL patients with tissue disease.