Etiology of the myeloproliferative disorders: The role of thrombopoietin

Until recently, little was known about the molecular basis for thrombopoiesis. With the cloning and characterization of thrombopoietin (TPO) our understanding of the generation of megakaryocytes and platelets has advanced steadily. One of the unexpected properties of TPO is its effect on hematopoietic stem cells: genetic elimination of the cytokine or its receptor reduces stem cell numbers by seven- to eightfold. A corollary of this finding is that TPO or the c-Mpl receptor is a candidate for involvement in the genesis of chronic myeloproliferative diseases (MPD), disorders of hematopoietic stem cells. Evidence has accumulated that dysregulation of growth factors such as TPO and/or impaired expression of its receptor may be leukemogenic and myelofibrogenic, and will be reviewed. Moreover, the expression of c-Mpl in multiple pathologic states is under investigation as potential means of improving the diagnosis of chronic MPDs. Thus, TPO and Mpl may prove to be effective targets for both diagnosis and therapeutic management of MPD.