Apo2L/TRAIL and Bcl-2-related proteins regulate type I interferon-induced in multiple myeloma

it has been reported that interferons (IFNs) may have antitumor activity in multiple myeloma (MM). The mechanism for their effect on MM, however, rema ins elusive. This study shows that IFN-alpha and -beta, but not -gamma, ind uce apoptosis characterized by Annexin V positivity, nuclear fragmentation and condensation, and loss of clonogenicity in 3 MM cell lines (U266, RPMI- 8266, and NCI-H929), and in plasma cells from 10 patients with MM. Apo2 lig and (Apo2L, also TRAIL) induction was one of the earliest events following IFN administration in U266 cells. Treatment of these cells with TRAIL, but not with Fas agonistic antibodies, induces apoptosis. Cell death induced by IFNs and Apo2L in U266 cells was partially blocked by a dominant-negative Apo2L receptor, DR5, demonstrating the functional significance of Apo2L ind uction. This study shows that IFNs activate caspases and the mitochondrial- dependent apoptotic pathway, possibly mediated by Apo2L production. Thus, I FN-alpha and -beta induce cytochrome c release from mitochondria starting a t 12 hours, with an amplified release seen at 48 hours. Moreover, Bid cleav age precedes the initial cytochrome c release, whereas the late, amplified cytochrome c release coincides with changes in levels of Bcl-2, Bcl-X-L, an d reduction of mitochondrial membrane potential. These results link the Apo 2L induction and modulation of Bcl-2 family proteins to mitochondrial dysfu nction. Furthermore, IFNs and Apo2L induce cell death of CD38(+)/CD45(-/dim ) plasma cells, without significant effect on nonplasma blood cells, in a c aspase and Bcl-2 cleavage-dependent manner. These results warrant further c linical studies with IFNs and Apo2L in MM. (C) 2001 by The American Society of Hematology.