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Blood, 1 January 2006, Vol. 107, No. 1, pp. 73-78.
Prepublished online as a Blood First Edition Paper on September 20, 2005; DOI 10.1182/blood-2005-05-1784.
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Submitted May 2, 2005
Accepted August 29, 2005
Role of erythropoietin receptor signaling in Friend virus-induced erythroblastosis and polycythemia
Ji Zhang, Mindy S Randall, Melanie R Loyd, Weimin Li, Rachel L Schweers, Derek A Persons, Jerold E Rehg, Constance T Noguchi, James N Ihle, and Paul A Ney*
Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, TN, USA; Integrated Program in Biomedical Science, University of Tennessee Health Science Center, Memphis, TN, USA
Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, TN, USA
Department of Experimental Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA
Laboratory of Chemical Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
* Corresponding author; email: paul.ney{at}stjude.org.
Friend virus is an acutely oncogenic retrovirus that causes erythroblastosis and polycythemia in mice. Previous studies suggested that the Friend virus oncoprotein, gp55, constitutively activates the erythropoietin receptor (EPOR), causing uncontrolled erythroid proliferation. Those studies showed that gp55 confers growth factor independence on an IL-3 dependent cell line (Ba/F3), when the EPOR is coexpressed. Subsequently, we showed that a truncated form of the stem cell kinase receptor (sf-STK) is required for susceptibility to Friend disease. Given the requirement for sf-STK, we sought to establish the in vivo significance of gp55-mediated activation of the EPOR. We found that the cytoplasmic tyrosine residues of the EPOR, and signal transducer and activator of transcription 5 (STAT5), which acts through these sites, are not required for Friend virus-induced erythroblastosis. The EPOR itself was required for the development of erythroblastosis, but not for gp55-mediated erythroid proliferation. Interestingly, the murine EPOR, which is required for gp55-mediated Ba/F3 cell proliferation, was dispensable for erythroblastosis in vivo. Finally, gp55-mediated activation of the EPOR, and STAT5, are required for Friend virus-induced polycythemia. These results suggest that Friend virus activates both sf-STK and the EPOR to cause deregulated erythroid proliferation and differentiation.
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