Mpl-Ligand and the Regulation of Megakaryocytopoiesis

Abstract

SummaryAfter 35 years of research, the physiological regulator of platelet production has been isolated and its gene cloned. This discovery originates from studies performed with the myeloproliferative leukaemia virus (MPLV), a murine retrovirus which induces an acute myeloproliferative syndrome in adult mice. MPLV carries the v-mpl oncogene in its genome. This oncogene corresponds to a truncated form of the c-mpl proto-oncogene. c-mpl encodes a cytokine receptor (Mpl-R) belonging to the hematopoietin receptor superfamily. Among the hematopoietic cell lineages, Mpl-R is preferentially expressed on late MK progenitors, megakaryocytes and platelets. The ligand for Mpl-R, called Mpl-L, thrombopoietin (TPO), megakaryocyte growth and development factor (MGDF) or megapoietin, is a gly-cosylated hormone of 322 amino acids in man which comprises two domains; the N-terminus domain shares 50% similarity with erythropoietin and is respon-sible for the biological activity; the C-terminus part is required for secretion. In vitro Mpl-L is capable of directly inducing both the proliferation of MK progenitors and the terminal maturation of megakaryocytes. MK grown in vitro in presence of Mpl-L can shed platelets. Notwithstanding its major action on megakaryocytopoiesis and thrombocytopoiesis, Mpl-L also potentiates the action of other cytokines on early hematopoietic progenitors. The plasma level of Mpl-L inversely correlates with the platelet and MK mass. However, in the two major organs (liver and kidney) which synthesize Mpl-L, there is no regulation at the transcription level of the synthesis of Mpl-L by the platelet demand, suggesting that regulation of the plasma level occurs by uptake and consumption at the level of platelets. A deregulation of Mpl-L synthesis obtained by infecting, murine hematopoietic stem cells by a retrovirus containing the coding sequence for Mpl-L induces a disease which has many common features with idiopathic myelofibrosis in man. Therefore, Mpl-L might be a very useful therapeutical cytokine to treat thrombocytopenia, but these data emphasize that chronic exposure to Mpl-L may lead to a severe disease. Thus, human clinical trials will require well controlled administration protocols.