E2F-1 BLOCKS TERMINAL DIFFERENTIATION AND CAUSES PROLIFERATION IN TRANSGENIC MEGAKARYOCYTES

The transcription factor E2F-1 plays a central role in the cell cycle through its ability to activate genes involved in cell division. E2F-1 activity is regulated by a number of proteins, including the retinobl astoma susceptibility gene product, cyclin-dependent kinases, and thei r inhibitors, proteins that have been implicated in the control of cer tain developmental processes. To investigate a potential role of E2F-1 in differentiation, we assayed the ability of megakaryocytes to form platelets in an in vivo transgenic model. E2F-1 expression in megakary ocytes blocked differentiation during maturation, resulting in severe thrombocytopenia. Ultrastructural analysis of megakaryocytes revealed abnormal development characterized by hyperdemarcation of cytoplasmic membranes and reduced numbers of alpha granules. Administration of meg akaryocyte growth and development factor or interleukin 6 could not ov ercome the differentiation block. Additionally, E2F-1 caused massive m egakaryocyte accumulation in both normal and ectopic sites, first evid ent in E15 embryonic liver. Furthermore, significant apoptosis was obs erved in transgenic megakaryocytes. These data indicate that E2F-1 can prevent terminal differentiation, probably through its cell cycle-sti mulatory activity.