[Biology of thrombopoietin and its receptors]

Megakaryocytopoiesis is regulated by a number of cytokines with either stimulatory or inhibitory effects. Thrombopoietin (TPO), a cytokine with specific megakaryocyte maturational activity recently has been identified as the c-Mpl ligand. The physiological role of TPO and its potential mechanism of regulation has been investigated by generating mice that are missing the gene for TPO receptor (c-Mpl) and therefore deficient in the receptor itself. In homozygous knock-out mice (c-Mpl-/-) blood platelet counts were reduced to about 85% compared to wild-type mice. Several groups have now reported on the genomic structure of the TPO locus and the gene maps to the long arm of human chromosome 3 and mouse chromosome 16. The human cDNA predicts a mature molecule of 332 amino acids with striking homology to erythropoietin throughout the N-terminal half. Recombinant TPO has profound effects on megakaryocyte growth and development. These effects appear to include the expansion of megakaryocyte progenitors and induction of megakaryocyte maturation to the point of platelet production. Administration of recombinant. TPO to rodents or primates treated with myelosuppressive agents abrogates or alleviates the severity and the duration of the resultant thrombocytopenias. The in vitro and in vivo activities of the TPO indicate that this cytokine may hold a promise for prevention and treatment of thrombocytopenia associated with chemotherapy, irradiation and bone marrow transplantation.