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Blood, 1 June 2006, Vol. 107, No. 11, pp. 4300-4307. Prepublished online as a Blood First Edition Paper on February 16, 2006; DOI 10.1182/blood-2005-11-4433. This Article Full Text (PDF) All Versions of this Article: 2005-11-4433v1 107/11/4300    most recent Alert me when this article is cited Alert me if a correction is posted 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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Nakamura, T. Articles by Tsuruzoe, N. Search for Related Content PubMed PubMed Citation Articles by Nakamura, T. Articles by Tsuruzoe, N. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 10, 2005 Accepted January 21, 2006 A novel non-peptidyl human c-Mpl activator stimulates human megakaryopoiesis and thrombopoiesis Takanori Nakamura*, Yoshitaka Miyakawa, Atsushi Miyamura, Akiko Yamane, Hidenori Suzuki, Mamoru Ito, Yasuyuki Ohnishi, Norihisa Ishiwata, Yasuo Ikeda, and Nobutomo Tsuruzoe Pharmaceutical Research Department, Biological Research Laboratories, Nissan Chemical Industries Ltd., Shiraoka, Saitama, Japan; Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Tokyo, Japan Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Tokyo, Japan Pharmaceutical Research Department, Biological Research Laboratories, Nissan Chemical Industries Ltd., Shiraoka, Saitama, Japan Medical Research & Development Center, Tokyo Metropolitan Institute of Medical Science, Honkomagome, Tokyo, Japan Central Institute for Experimental Animals, Nogawa, Kanagawa, Japan * Corresponding author; email: tnakamura{at}nissanchem.co.jp. NIP-004 is a novel synthetic compound developed to display human thrombopoietin (TPO) receptor (c-Mpl) agonist activity. NIP-004 displays species specificity, stimulating proliferation or differentiation of human c-Mpl-expressing cells such as UT-7/TPO and human CD34+ cells, but not murine c-Mpl-expressing cells or cynomolgus monkey cells. To test the mechanism of its action, we constructed mutant forms of c-Mpl; murine c-MplL490H displayed a response to NIP-004, whereas human c-MplH499L lost this response, indicating that histidine in the transmembrane domain of c-Mpl is essential for its activity. As histidine is not present in the c-Mpl transmembrane domain of rats, hamsters, rhesus macaques and cynomolgus monkeys, we examined the in vivo efficacy of NIP-004 using xenotransplanted mice. In immunodeficient NOD/Shi-scid,IL-2Rnull (NOG) mice transplanted with umbilical cord blood-derived CD34+ cells, NIP-004 increased human megakaryoblasts, mature megakaryocytes and circulating human platelets six-fold, the latter being morphologically and functionally indistinguishable from normal human platelets. These observations indicate that NIP-004 is a novel human c-Mpl activator and induces human thrombopoiesis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: I. I. Salles, T. Thijs, C. Brunaud, S. F. De Meyer, J. Thys, K. Vanhoorelbeke, and H. Deckmyn Human platelets produced in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice upon transplantation of human cord blood CD34+ cells are functionally active in an ex vivo flow model of thrombosis Blood, December 3, 2009; 114(24): 5044 - 5051. [Abstract] [Full Text] [PDF] W. Nogami, H. Yoshida, K. Koizumi, H. Yamada, K. Abe, A. Arimura, N. Yamane, K. Takahashi, A. Yamane, A. Oda, et al. The effect of a novel, small non-peptidyl molecule butyzamide on human thrombopoietin receptor and megakaryopoiesis Haematologica, October 1, 2008; 93(10): 1495 - 1504. [Abstract] [Full Text] [PDF] A. Yamane, T. Nakamura, H. Suzuki, M. Ito, Y. Ohnishi, Y. Ikeda, and Y. Miyakawa Interferon-{alpha}2b-induced thrombocytopenia is caused by inhibition of platelet production but not proliferation and endomitosis in human megakaryocytes Blood, August 1, 2008; 112(3): 542 - 550. [Abstract] [Full Text] [PDF] J. M. Jenkins, D. Williams, Y. Deng, J. Uhl, V. Kitchen, D. Collins, and C. L. Erickson-Miller Phase 1 clinical study of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist Blood, June 1, 2007; 109(11): 4739 - 4741. [Abstract] [Full Text] [PDF] M.-J. Kim, S. H. Park, S. J. Opella, T. H. Marsilje, P.-Y. Michellys, H. M. Seidel, and S.-S. 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