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 Blood, 15 August 2005, Vol. 106, No. 4, pp. 1346-1354.
Prepublished online as a Blood First Edition Paper on April 28, 2005; DOI 10.1182/blood-2004-04-1322.

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NEOPLASIA

Ectopic and IFN-induced expression of Fas overcomes resistance to Fas-mediated apoptosis in multiple myeloma cells

Lina Y. Dimberg, Anna I. Dimberg, Karolina Ivarsson, Thomas Strömberg, Anders Österborg, Kenneth Nilsson, Fredrik Öberg, and Helena Jernberg Wiklund

From the Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden; and Department of Hematology and Oncology, Karolinska Hospital, Stockholm, Sweden.

Multiple myeloma (MM) is an as-yet incurable B-cell malignancy. Increased survival in vitro is a hallmark of MM cells, implying that a therapeutic potential may lie in circumventing antiapoptotic signals. We have previously reported that interferons (IFNs) sensitize MM cells to Fas/CD95-mediated apoptosis. In the present study, we explore the mechanism underlying this effect. In a wide screening of apoptosis-related genes, Apo2L/TRAIL (tumor necrosis factor [TNF]-related apoptosis inducing ligand) and Fas were identified as IFN targets. Sensitization to Fas-mediated apoptosis by IFNs was not affected by blocking Apo2L/TRAIL, suggesting that Apo2L/TRAIL is not a key mediator in this process. In contrast, we found that an elevated Fas expression was functionally linked to increased susceptibility to Fas-mediated apoptosis. This was further supported by the finding that IFN treatment enhanced Fas-mediated caspase-8 activation, one of the earliest signaling events downstream receptor activation. In addition, IFN treatment attenuated the interleukin 6 (IL-6)-dependent activation of signal transducer and activator of transcription 3 (Stat3), interfering with a known survival pathway in MM that has previously been linked with resistance to Fas-mediated apoptosis. Taken together, our results show that IFN-induced up-regulation of Fas sensitizes MM cells to Fas-mediated apoptosis and suggest that attenuation of Stat3 activation may be a potentially important event in this process. (Blood. 2005;106:1346-1354)


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