RRC ID 42560
Author Nakamura T, Miyakawa Y, Miyamura A, Yamane A, Suzuki H, Ito M, Ohnishi Y, Ishiwata N, Ikeda Y, Tsuruzoe N.
Title A novel nonpeptidyl human c-Mpl activator stimulates human megakaryopoiesis and thrombopoiesis.
Journal Blood
Abstract 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-Mpl(L490H) dis-played a response to NIP-004, whereas human c-Mpl(H499L) 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-2Rgamma(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.
Volume 107(11)
Pages 4300-7
Published 2006-6-1
DOI 10.1182/blood-2005-11-4433
PII 2005-11-4433
PMID 16484588
MeSH Animals Blood Platelets / cytology Cell Count Cell Line, Tumor Cord Blood Stem Cell Transplantation Graft Survival Histidine Humans Megakaryocytes / cytology Mice Mice, SCID Mutation Proto-Oncogene Proteins / agonists* Proto-Oncogene Proteins / genetics Receptors, Cytokine / agonists* Receptors, Cytokine / genetics Receptors, Thrombopoietin Thrombopoiesis / drug effects* Transplantation, Heterologous
IF 16.601
Times Cited 58
Human and Animal Cells