The role of hyaluronan and interleukin 8 in the migration of chronic lymphocytic leukemia cells within lymphoreticular tissues

Malignant lymphocyte migration into and within lymphoreticular tissue is an important aspect of chronic lymphocytic leukemia (CLL), Set little is know n about the processes involved, Our previous studies of integrin expression and function in CLL have shown that the abnormal cells are relatively nona dhesive and nonmotile on the protein ligands of these receptors, Here we sh ow that CLL cells adhere to a non-protein ligand, hyaluronan (HA), and beco me motile las assessed by both Boyden chamber migration and time-lapse vide o microscopy) on this ligand when stimulated with interleukin (IL) 8. The c ombined presence of HA and IL-8 was essential for this motility because IL- 8 did not stimulate movement on other surfaces, Blacking antibodies showed that this motility is mediated by the receptor for HA-mediated motility (RH AMM), without the involvement of CD44. Moreover, confocal microscopy showed a polarized distribution of RHAMM and F-actin, but not CD44, in cells whic h had become motile on HA in the presence of IL-8. Immunohistochemical stud ies of nodes and spleen demonstrated an abundant reticular network of HA-co ntaining fibers throughout diseased nodes and in splenic white pulp, The sp lenic red pulp and the luminal surface of high endothelial venules lacked H A. IL-8 was ubiquitously present in these tissues, CLL cells were shown to move spontaneously on fibroblast monolayers derived from lymphoid tissue; t his movement was largely blocked by hyaluronidase or anti-RHAMM or anti-IL- 8 antibodies. These studies indicate that IL-8-induced motility on HA is li kely to be important for CLL cell migration through lymphoid tissue.