トロンボポエチンのクローニングと臨床応用の可能性

抄録

Recently, we purified rat thrombopoietin (TPO) from the plasma of irradiated rats by using a quantitative in vitro assay and then determined its partial amino acid sequences. Based on the sequence information, we isolated a rat TPO cDNA, a human TPO cDNA and the human TPO gene. The human TPO protein comprises 353 amino acids, including a 21 amino acid residue signal peptide. The protein displays two domains, with an amino-terminal region essential for biological activity and a carboxyl-terminal region containing six potential sites for N-glycosylation. The expression of TPO mRNA is the highest in the liver among various tissues tested, indicating that the liver is the primary organ of TPO production. It is now evident that TPO is a lineage-dominant hematopoietic factor that primarily regulates megakaryocytopoiesis and thrombopoiesis. Data from in vitro studies have shown that TPO exhibits both megakaryocyte colony-stimulating and megakaryocyte maturation activities. In vivo, TPO or PEG-rHuMGDF (a truncated form of TPO, chemically modified with polythyelene glycol) markedly increases platelet production in normal animals. Administration of PEG-rHu-MGDF or TPO is highly effective in improving thrombocytopenia in myelosuppressed animal models, suggesting the therapeutic potential of this molecule.