GROWTH-REGULATORY PATHWAYS IN MYELOMA - EVIDENCE FOR AUTOCRINE ONCOSTATIN-M EXPRESSION

Expression of autocrine growth factors by myeloma cells is an importan t mechanism that may contribute to tumor expansion. IL-6 is one of sev eral cytokines that uses the signal transducer gp130 as a receptor com ponent. Of these cytokines, those that have been shown to be paracrine growth factors for some myeloma cells include IL-6, IL-11, ciliary ne urotrophic factor, leukemia inhibitory factor, and oncostatin M (OSM). Only IL-6, however, has been identified as an autocrine growth factor for myeloma cells. In this study we used a panel of three IL-6-respon sive myeloma cell lines to investigate the expression of other autocri ne growth factor loops. Initial studies employing neutralizing mAbs to IL-6 or gp130 revealed that the growth of the DP-6 and KP-6 cell line s was inhibited by both mAbs, whereas the growth of the KAS6/1 cell li ne was inhibited only by the anti-gp130 mAb. Anti-OSM neutralizing mAb also inhibited KAS-6/1 cell growth. Autocrine OSM production by the K AS-6/1 cells was confirmed using a sensitive ELISA;. Although the anti -OSM mAb had no significant effects on KP-6 and DP-6 cell growth, OSM was detected in DP-6 supernatants. These results suggest that OSM prod uction and responsiveness by myeloma cells are distinct phenotypes and not necessarily related in all myeloma cells. Finally, we analyzed th e significance of OSM-mediated myeloma cell growth by assessing the ef fects of OSM on normal, in vitro-generated plasmablasts. OSM markedly enhanced plasmablast Ig secretion but did not affect growth. Thus, the nature of the response elicited by OSM in myeloma cells is distinct f rom its effects on normal B lineage cells. Moreover, because gp130-med iated signaling results in myeloma cell growth, autocrine expression o f any gp130-utilizing cytokine has the potential to significantly augm ent tumor expansion.