Role of PLZF in regulating the Interferon response

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The Interferon (IFN) pathway is essential for immune defense against pathogens in vertebrates. IFNs both protect and alert cells about viral, bacterial, and other immune assaults and promote a cellular antiviral state, reduce proliferation, or induce apoptosis depending on the cell type and environment. Based on these properties, IFNs have been used clinically against a variety of diseases including viral infections, immunomodulatory disorders and hematologic and solid tumors including renal cell carcinoma. However, the factors determining outcome of IFN treatment, remain to be determined. We have identified a subset of interferon stimulated genes whose sustained expression was found to correlate with heightened antiviral sensitivity of renal cell carcinoma cell lines to IFN. Many of these genes were found to have binding sites for the transcriptional repressor promyleocytic zinc finger protein (PLZF). PLZF was first identified in a subset of Acute Promyelocytic Leukemia patients and is involved in maintenance of erythroid lineage stem cells and spermatogonial stem cells in male mice. PLZF has not previously been implicated in the IFN response. Accordingly, we investigated the expression of interferon stimulated genes and showed that increased expression of immune related genes depends on PLZF expression. PLZF was also found to directly associate with binding sites in promoters of interferon stimulated genes and that this requires histone deacetylation. Thus, we uncovered a novel function for PLZF in enhancement of IFN associated gene expression. We propose to test the hypothesis that PLZF is an essential component of the IFN response. As a corollary, we will also test whether PLZF expression can be linked to IFN responsiveness in renal cell carcinoma. These studies will establish the role of PLZF in the IFN response and define its utility in predicting IFN responsiveness in therapeutic applications.