Differential myeloma cell responsiveness to interferon-α correlates with differential induction of p19(INK4d) and cyclin D2 expression

Interferon-α (IFN-α) has been used as therapy for the treatment of a variety of viral diseases and malignancies including multiple myeloma. The effectiveness of interferon-α in treating multiple myeloma, however, has been somewhat variable, and the mechanism(s) accounting for this is not well understood. As a means to examine the basis for the differential effectiveness of this cytokine, we have analyzed IFN-α-mediated modulation of the cell cycle in two human myeloma cell lines. These two cell lines, ANBL-6 and KAS-6/1, display dramatically different outcomes in response to this cytokine. Although IFN-α inhibited the growth of ANBL-6 cells by blocking cell cycle progression from G₀/G₁ to S phase, IFN-α stimulated cell cycle progression in KAS-6/1 cells. Moreover, the effects of IFN-α on cell cycle progression correlated with the phosphorylation status of the retinoblastoma protein. Of interest, IFN-α increased cyclin D2 expression and cyclin-dependent kinase activity in the KAS-6/1 cells but not in the ANBL-6 cells. To determine whether the differential effects of IFN-α on myeloma cell cycle progression could also result from differences in the expression of cyclin-dependent kinase inhibitors, we examined the effects of IFN-α on the induction of cyclin-dependent kinase inhibitors with broad regulatory function (p21 and p27) and those with specificity for G₁- associated cyclin-cyclin-dependent kinase complexes (p15, p16, p18, and p19). Although we failed to detect an effect of IFN-α on expression levels of p21, p15, p16, or p18, IFN-α treatment of the ANBL-6 cell line resulted in induction of p19 expression, whereas it was without effect on the KAS-6/1 cell line. These results suggest that heterogeneity in IFN-α-mediated growth effects in myeloma cells correlates with differential induction of cyclin D2 and p19(INK4d) expression.