IFN-ALPHA IS A SURVIVAL FACTOR FOR HUMAN MYELOMA CELLS AND REDUCES DEXAMETHASONE-INDUCED APOPTOSIS

IFN-alpha is used as a maintenance therapy in patients with multiple m yeloma, but its benefit is a matter of controversy. In vitro studies s how that IFN-alpha can both stimulate and inhibit myeloma cell prolife ration, We have tested the effect of IFN-alpha on the survival of myel oma cell lines and primary plasma cells. IFN-alpha significantly reduc ed the apoptosis induced by removal of IL-6 in four IL-6-dependent mye loma cell lines. It also reduced the level of apoptosis induced by dex amethasone in these cell lines as well as in purified primary myeloma cells from seven patients. IFN-alpha promoted the survival of myeloma cells, which, following removal of IL-6, were blocked in G1 and died. However, unlike IL-6, IFN-alpha-treated cells remained mainly blocked in the G1 phase of the cycle. While the effects of IL-6 are mediated t hrough stimulation of its gp130 receptor subunit, the IFN-alpha-induce d survival of myeloma cells was independent of gp130 transducer activa tion las demonstrated using a neutralizing anti-gp130 Ab), However, th e signal transduction cascades activated by these two cytokines share at least some common elements, since stimulation with either IFN-alpha or IL-6 resulted in STAT3 phosphorylation. These results indicate tha t IFN-alpha promotes the survival, but not the proliferation, of myelo ma cells, preventing the apoptosis induced by removal of IL-6 or addit ion of dexamethasone. This survival factor activity may explain the co nflicting reports on the effects of IFN-alpha on myeloma cell prolifer ation.