The aim of the present study was to explore hTERT as a target for IFN-induced sensitization to apoptosis in multiple myeloma (MM). IFN-alpha and IFN-gamma downregulated telomerase activity in the IL-6-dependent MM cell line U-266-1970. In MM cells undergoing IFN-induced sensitization to Fas-mediated apoptosis, the repression of telomerase was increased as compared to IFN-alpha treatment alone. Similar to the sensitization effect of IFN, the use of a dominant negative I kappa B alpha vector inhibiting hTERT activity via transcriptional targeting resulted in augmentation of Fas-mediated apoptosis. The mechanism underlying the reduction of telomerase activity by IFN was shown to be transcriptional repression of the hTERT gene. The present study does not support a direct effect of IFN on NF-kappa B binding to the hTERT promoter as underlying the transcriptional repression. We conclude that one potential mechanism whereby IFNs induce apoptosis sensitization is by repressing hTERT transcription and telomerase activity, thereby constituting attractive targets for MM therapy. (c) 2006 Elsevier Inc. All rights reserved.