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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 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 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 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. Related Collections Hematopoiesis and Stem Cells Hemostasis, Thrombosis, and Vascular Biology Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS A novel nonpeptidyl 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 From the Pharmaceutical Research Department, Biological Research Laboratories, Nissan Chemical Industries, Saitama; Department of Internal Medicine, Keio University School of Medicine, Tokyo; Medical Research & Development Center, Tokyo Metropolitan Institute of Medical Science, Tokyo; and Central Institute for Experimental Animals, Kanagawa, Japan. 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 dis-played 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. Because 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 mice that received xenotransplants. In immunodeficient nonobese diabetic (NOD)/Shi-scid, IL-2Rnull (NOG) mice receiving transplants of umbilical cord blood–derived CD34+ cells, NIP-004 increased human megakaryoblasts, mature megakaryocytes, and circulating human platelets 6-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: 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. Tian NMR Structural Studies of Interactions of a Small, Nonpeptidyl Tpo Mimic with the Thrombopoietin Receptor Extracellular Juxtamembrane and Transmembrane Domains J. Biol. Chem., May 11, 2007; 282(19): 14253 - 14261. [Abstract] [Full Text] [PDF] B. Andemariam, B. Psaila, and J. B. Bussel Novel Thrombopoietic Agents Hematology, January 1, 2007; 2007(1): 106 - 113. [Abstract] [Full Text] [PDF]

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