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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. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: 2004-04-1322v1 106/4/1346    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Dimberg, L. Y Articles by Jernberg Wiklund, H. Search for Related Content PubMed PubMed Citation Articles by Dimberg, L. Y Articles by Jernberg Wiklund, H. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 8, 2004 Accepted April 6, 2005 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 Stromberg, Anders Osterborg, Kenneth Nilsson, Fredrik Oberg, and Helena Jernberg Wiklund* Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden Department of Hematology and Oncology, Karolinska Hospital, Stockholm, Sweden * Corresponding author; email: helena.jernberg_wiklund{at}genpat.uu.se. 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 anti-apoptotic signals. We have previously reported that interferons (IFNs) sensitize MM cells to Fas/CD95-mediated apoptosis 1. In the present study, we explore the mechanism underlying this effect. In a wide screening of apoptosis-related genes, Apo2L/TRAIL 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 down-stream receptor activation. In addition, IFN treatment attenuated the IL-6 dependent activation of 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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