The physiologic role and therapeutic potential of the Mpl-ligand in thrombopoiesis.

Abstract

The constant and appropriate production of megakaryocytes, and subsequently platelets, is critical for maintenance of hemostasis. Inadequate megakaryopoiesis and/or thrombopoiesis can lead to serious bleeding disorders. The humoral factors regulating these processes have been the subject of study for several decades. Although many cytokines have been shown to influence megakaryocyte development and platelet production, none appeared to do so in a lineage-dominant fashion analogous to the situation with erythrocyte and neutrophil production. More recently, a ligand for the hematopoietic cytokine receptor encoded by the c-mpl gene (Mpl ligand) has been shown to have profound effects on megakaryocyte growth and development. These effects appear to include the expansion of megakaryocyte progenitors (i.e. megakaryocyte-colony stimulating activity), and induction of megakaryocyte maturation to the point of platelet production (i.e. thrombopoietin). Administration of recombinant Mpl-ligand 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 data to date indicate that this new cytokine holds tremendous promise as a therapeutic agent for the treatment of thrombocytopenia associated with cancer therapies.