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THE CONTROL OF NORMAL AND ABERRANT MEGAKARYOPOIESIS BY THROMBOPOIETIN AND ITS RECEPTRO, c-MPL Radek C. Skoda Introduction Mature blood cells are short-lived and must be constantly replaced. A small number of multipotent hematopoietic stem cells (HSC) are the source of this regenerative process. Hematopoiesis is the best studied stem cell system and constitutes a model for other organs. HSC can either remain multipotent or differentiate into mature cells with very diverse functions and morphologies, as exemplified by lymphocytes, granulocytes, erythrocytes or megakaryocytes. Extracellular signals, such as cytokines and growth factors and their cell surface receptors, act in concert with cell intrinsic factors, e.g. components of the signal transduction machinery and transcription factors, to maintain a balance between production and destruction of blood cells. Given the complex- ity of the known regulatory pathways and the needs for adaptation to changing environmental factors, we should consider it surprising that blood cell disorders are not more common. Here I review the physiolog- ical role of a humoral factor called thrombopoietin and its receptor in the formation of megakaryocytes and platelets and I summarize our current understanding of disorders associated with an overproduction of platelets. Thrombopoietin and its receptor, c-Mpl are the primary regulators of platelet production Thrombopoietin (TPO) was first described as an biological activity in serum that stimulated the production of platelets in vivo (Kelemen et al., 1958). For more than 30 years this activity eluded all attempts of biochemical purification. TPO cDNA was finally cloned in 1994 by virtue of its high affinity receptor, which served as a bait for immuno- 40