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Prepublished online as a Blood First Edition Paper on November 21, 2002; DOI 10.1182/blood-2002-05-1521.
Submitted May 30, 2002
Accepted November 12, 2002
Type I interferon differential therapy for erythroleukemia: specificity of STAT activation
Vanessa S Cull, Peta A Tilbrook, Emmalene J Bartlett, Natalie L Brekalo, and Cassandra M James*
Division of Veterinary and Biomedical Sciences, Western Australian Biomedical Research Institute, Murdoch University, Perth, WA, Australia
Centre for Medical Research, Royal Perth Hospital, Western Australian Institute for Medical Research, Laboratory for Cancer Medicine, University of Western Australia, Perth, WA, Australia
* Corresponding author; email: casjames{at}central.murdoch.edu.au.
Type I interferons (IFNs), pleiotropic cytokines with antiviral, antiproliferative, apoptotic and immuno-regulatory functions, are efficacious in the treatment of malignancies, viral infections and autoimmune diseases. Binding of these cytokines to their cognate receptor leads to activation of the Jak-STAT signaling pathway and altered gene expression. This signal pathway has been intensely studied using human IFN- 2 and IFN- . However, there are over 14 human IFN- subtypes and over 10 murine IFN- subtypes, with a single IFN- subtype in both species. J2E cells are immortalized at the proerythroblast stage of development and produce a rapid and fatal erythroleukemia in vivo. These cells retain the ability to respond to erythropoietin in vitro by proliferating, differentiating, and remaining viable in the absence of serum. Here, we show that J2E cells are also functionally regulated differentially by IFN subtype treatment in vitro. A novel finding was the selective activation of STAT and MAPK molecules by different subtypes binding the IFN receptor. These findings indicate distinct effects for individual type I IFN subtypes, which are able to differentially activate members of the STAT and MAPK family. Finally, we investigated the efficacy of IFN naked DNA therapy in treating J2E-induced erythroleukemia in athymic nude mice. IFN subtypes differentially regulated the onset of erythroleukemia with delayed onset and increased survival possibly via a reduction in cell viability, and enhanced anti-proliferative/apoptotic effects observed for IFNA6 and IFNA9 treatment, respectively. Moreover, this data highlights the necessity for best choice of IFN subtype in disease treatment.
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