SUPPRESSION OF ERYTHRO-MEGAKARYOCYTOPOIESIS AND THE INDUCTION OF REVERSIBLE THROMBOCYTOPENIA IN MICE TRANSGENIC FOR THE THYMIDINE KINASE GENE TARGETED BY THE PLATELET GLYCOPROTEIN ALPHA-IIB PROMOTER

The mechanisms that regulate the commitment of a totipotent stem cell to the megakaryocytic lineage are largely unknown. Using a molecular a pproach to the study of megakaryocytopoiesis and platelet production, mice in which thrombocytopoiesis could be controlled were produced by targeting the expression of the herpes simplex virus thymidine kinase toxigene to megakaryocytes using the regulatory region of the gene enc oding the or subunit of the platelet integrin alpha IIb beta 3. The pr ogrammed eradication of the megakaryocytic lineage was induced by trea ting transgenic mice bearing the hybrid construct (alpha IIbtk) with t he antiherpetic drug ganciclovir (GCV). After 10 d of treatment, the p latelet number was reduced by >94.6%. After discontinuing GCV, the bon e marrow was repopulated with megakaryocytes and the platelet count wa s restored within 7 d. Prolonged GCV treatment induced erythropenia in the transgenic mice. Assays of myeloid progenitor cells in vitro demo nstrated that the transgene was expressed in early erythro-megakaryocy tic progenitor cells. The reversibility and facility of this system pr ovides a powerful model to determine both the critical events in megak aryocytic and erythroid lineage development and for evaluating the pre cise role that platelets play in the pathogenesis of a number of vascu lar occlusive disorders.