POSITIVE AND NEGATIVE REGULATION OF MEGAKARYOCYTOPOIESIS

The recently cloned physiological regulator of megakaryocytopoiesis, k nown as Mpl ligand, thrombopoietin (TPO), megakaryocyte growth and dev elopment factor (MGDF) or megapoietin, is undergoing preclinical and c linical trials, This factor is an extremely potent thrombocytopoietic agent in vivo in normal animals, and accelerates platelet recovery in some but not all models of myelosuppression. Together with its apparen t lack of adverse effects, the preclinical data suggest that TPO might permit the use of higher doses of chemotherapy in dose-intensive regi mens and be useful in patients with ineffective platelet production or production abnormalities. The direct effects of TPO on primitive and various myeloid committed haematopoietic progenitor cells predict that TPO may be used in combination with other cytokines in a variety of c linical disorders, Along with the progress made in the understanding o f the positive regulation of megakaryocytopoiesis, accumulating data d emonstrate that platelet production is also controlled by negative reg ulators with potential clinical applications, Some of these regulators are effective in the treatment of essential thrombocythaemia and myel oproliferative disorders, while others seem capable of protecting prog enitor cells from the cytotoxicity of chemotherapeutic drugs.