THE TSA58 SIMIAN-VIRUS-40 LARGE TUMOR-ANTIGEN DISRUPTS MEGAKARYOCYTE DIFFERENTIATION IN TRANSGENIC MICE

Thrombocytopenia is a condition of multiple etiologies affecting the m egakaryocyte lineage. To perturb this lineage in transgenic mice, the tsA58 mutation of the simian virus 40 large tumor antigen was targeted to megakaryocytes using the platelet factor 4 promoter. Ten of 17 tra nsgenic lines generated exhibited low platelet levels, each line displ aying a distinct, heritable level of thrombocytopenia. Within a line, the degree of the platelet reduction correlated directly with transgen e zygosity. The platelet level could be further reduced by the inactiv ation of one copy of the endogenous retinoblastoma gene. Western blot analysis detected large tumor antigen protein in the most severely aff ected lines; less affected lines were below the level of detection. Pl atelets and megakaryocytes from thrombocytopenic mice exhibited morpho logical abnormalities. Mice with either normal or reduced platelet lev els developed megakaryocytic malignancies with a mean age of onset of about 8 months. There was no correlation between severity of thrombocy topenia and onset of malignancy. These mice provide a defined genetic model for thrombocytopenia, and for megakaryocytic neoplasia, and impl icate the retinoblastoma protein in the process of megakaryocyte diffe rentiation.