The structure, biology and potential therapeutic applications of recombinant thrombopoietin.
Platelets, an integral component of hemostasis, are produced by megakaryocytes derived from the differentiation of pluripotent stem cells in the bone marrow or spleen. After decades of study, the regulation of this process is still not well understood. However, the recent cloning and characterization of thrombopoietin, a ligand for the receptor encoded by the c-mpl proto-oncogene, provides new insights into the humoral regulation of megakaryocytopoiesis and platelet production. Consistent with the proposed role as a major physiological regulator of megakaryocytopoiesis, thrombopoietin has potent effects on megakaryocytopoiesis in vitro and in vivo. In addition to the original supposition that thrombopoietin functions as a late-acting megakaryocyte maturation factor, recombinant thrombopoietin proves also to be a potent stimulator of hematopoietic progenitor cells, inducing them to undergo proliferation and differentiation into megakaryocytic colonies. When administered to mice, thrombopoietin causes an increase in peripheral platelet numbers to previously unattainable levels within a few days. Studies of the efficacy of thrombopoietin are underway. It is envisaged that this new cytokine will have widespread applications as a therapeutic agent for the management of bleeding due to thrombocytopenias, in particular those resulting from cancer chemo- or irradiation therapy.
Lok
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Cytokine Research Center, ZymoGenetics Corporation, Seattle, WA 98102.
Foster
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D000818:Animals; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D016207:Cytokines / Q000627:therapeutic use; D004921:Erythropoietin / Q000235:genetics; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D009363:Neoplasm Proteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology; D011519:Proto-Oncogenes; D018121:Receptors, Cytokine; D011971:Receptors, Immunologic / Q000235:genetics / Q000502:physiology; D053628:Receptors, Thrombopoietin; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use; D013921:Thrombocytopenia / Q000188:drug therapy; D013926:Thrombopoietin / Q000737:chemistry / Q000502:physiology / Q000627:therapeutic use*
D016207:Cytokines; D008024:Ligands; C000715470:MAS1 protein, human; D009363:Neoplasm Proteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D018121:Receptors, Cytokine; D011971:Receptors, Immunologic; D053628:Receptors, Thrombopoietin; D011994:Recombinant Proteins; D004921:Erythropoietin; C082218:MPL protein, human; D013926:Thrombopoietin