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Blood, 1 August 2008, Vol. 112, No. 3, pp. 542-550. Prepublished online as a Blood First Edition Paper on June 3, 2008; DOI 10.1182/blood-2007-12-125906. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-12-125906v1 112/3/542    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Yamane, A. Articles by Miyakawa, Y. Search for Related Content PubMed PubMed Citation Articles by Yamane, A. Articles by Miyakawa, Y. Related Collections Hematopoiesis and Stem Cells Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS AND STEM CELLS Interferon-2b–induced thrombocytopenia is caused by inhibition of platelet production but not proliferation and endomitosis in human megakaryocytes Akiko Yamane1,*, Takanori Nakamura1,2,*, Hidenori Suzuki3, Mamoru Ito4, Yasuyuki Ohnishi4, Yasuo Ikeda1, and Yoshitaka Miyakawa1 1 Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo; 2 Biological Research Laboratories, Nissan Chemical Industries, Saitama; 3 Medical Research and Development Center, Tokyo Metropolitan Institute of Medical Science, Tokyo; and 4 Central Institute for Experimental Animals, Kanagawa, Japan Human interferon (IFN)– is the standard therapy for chronic hepatitis C to prevent its progression to liver cirrhosis and hepatocellular carcinoma. Thrombocytopenia is one of the major adverse effects of IFN- and often leads to dose reduction or treatment discontinuation. However, there is little information on how IFN- inhibits human megakaryopoiesis. In this study, we demonstrated that IFN- did not inhibit colony formation of megakaryocytes from human CD34+ hematopoietic stem cells. IFN- did not inhibit endomitosis but did inhibit cytoplasmic maturation of megakaryocytes and platelet production in vitro. IFN- suppressed the expression of transcription factors regulating late-stage megakaryopoiesis, such as GATA-1, p45NF-E2, MafG. IFN- also significantly reduced the number of human platelets but not megakaryocytes, and did not inhibit endomitosis of human megakaryocytes in immunodeficient NOD/Shi-scid/IL-2Rnull (NOG) mice transplanted with human CD34+ cells (hu-NOG). We also demonstrated that a novel thrombopoietin mimetic, NIP-004, was effective for treating IFN-–induced thrombocytopenia in hu-NOG mice. From ultrastructural study, IFN- inhibited the maturation of demarcation membranes in megakaryocytes, although NIP-004 prevented the inhibitory effects of IFN-. These results defined the pathogenesis of IFN-–induced thrombocytopenia and suggested possible future clinical applications for thrombopoietin mimetics. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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