NEOPLASIA Apo2L/TRAIL and Bcl-2–related proteins regulate type I interferon–induced apoptosis 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, remains elusive. This study shows that IFN-a and-b, but not-g, induce apoptosis characterized by Annexin V positivity, nuclear fragmenta-tion and condensation, and loss of clono-genicity in 3 MM cell lines (U266, RPMI-8266, and NCI-H929), and in plasma cells from 10 patients with MM. Apo2 ligand (Apo2L, also TRAIL) induction was one of the earliest events following IFN adminis-tration in U266 cells. Treatment of these cells with TRAIL, but not with Fas agonis-tic antibodies, induces apoptosis. Cell death induced by IFNs and Apo2L in U266 cells was partially blocked by a dominant-negative Apo2L receptor, DR5, demon-strating the functional significance of Apo2L induction. This study shows that IFNs activate caspases and the mitochon-drial-dependent apoptotic pathway, possi-bly mediated by Apo2L production. Thus, IFN-a and-b induce cytochrome c release from mitochondria starting at 12 hours, with an amplified release seen at 48 hours. Moreover, Bid cleavage precedes the ini-tial cytochrome c release, whereas the late, amplified cytochrome c release coin-cides with changes in levels of Bcl-2, Bcl-XL, and reduction of mitochondrial membrane potential. These results link the Apo2L induction and modulation of Bcl-2 family proteins to mitochondrial dys-function. Furthermore, IFNs and Apo2L induce cell death of CD381/CD452/dim plasma cells, without significant effect on nonplasma blood cells, in a caspase and Bcl-2 cleavage-dependent manner. These results warrant further clinical studies with IFNs and Apo2L in MM. (Blood. 2001