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 |
S0006-4971(20)64564-5
|
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 |
17.794
|
Times Cited |
58
|
WOS Category
|
HEMATOLOGY
|
Resource |
Human and Animal Cells |
Ba/F3(RCB0805) |