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Blood, 1 February 2005, Vol. 105, No. 3, pp. 1280-1287.
Prepublished online as a Blood First Edition Paper on September 30, 2004; DOI 10.1182/blood-2004-04-1614.
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Submitted April 30, 2004
Accepted September 18, 2004
PML mediates IFN induced apoptosis in myeloma by regulating TRAIL induction
Chun Crowder, Oyvind Dahle, R E Davis, Odd S Gabrielsen, and Stuart Rudikoff*
Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
Department of Molecular Biosciences, University of Oslo, Oslo, Norway
Metabolism Branch, National Cancer Institute, NIH, Bethesda, MD, USA
* Corresponding author; email: rudikoff{at}helix.nih.gov.
Interferon (IFN) induces expression of pro-apoptotic genes and has been used in the clinical treatment of multiple myeloma. The promyelocytic leukaemia (PML) gene is an IFN induced target that encodes a tumor suppressor protein. PML protein is typically localized within discrete speckled nuclear structures termed PML nuclear bodies (NBs). Multiple myeloma cells demonstrate differential responses to IFN treatment, the mechanism of which is largely unknown. Herein, we show that growth inhibition effects of IFN in myeloma cells correlate with PML NBs and TNF-related apoptosis inducing ligand (TRAIL) induction, whereas known IFN targets including STAT1, STAT3, p38 and Daxx cannot account for these differential responses. RNAi silencing of PML blocks IFN induced apoptosis in myeloma cells and correspondingly down regulates TRAIL expression. Similarly, stable expression of a dominant negative TRAIL receptor DR5 partially blocks IFN induced cell death. These results demonstrate that PML and TRAIL play important roles in IFN induced apoptosis and identify TRAIL as a novel downstream transcriptional target of PML. Identification of PML and PML NBs as effectors of IFN responses provides insights into mechanisms by which tumor cells exhibit resistance to this class of agents and may prove useful in assessing treatment regimens.
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