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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.

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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-2R{gamma}null (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.


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