The tumor suppressor p53 is thought to play a role in megakaryocyte (MK) 
development. To assess the influence of the p53 regulatory pathway further, we 
studied the effect of RG7112, a small molecule MDM2 antagonist that activates 
p53 by preventing its interaction with MDM2, on normal megakaryocytopoiesis and 
platelet production. This drug has been previously been evaluated in clinical 
trials of cancer patients where thrombocytopenia was one of the major 
dose-limiting toxicities. In this study, we demonstrated that administration of 
RG7112 in vivo in rats and monkeys results in thrombocytopenia. In addition, we 
identified two distinct mechanisms by which RG7112-mediated activation of p53 
affected human megakaryocytopoiesis and platelet production in vitro. RG7112 
promoted apoptosis of MK progenitor cells, resulting in a reduction of their 
numbers and RG7112 affected mature MK by blocking DNA synthesis during 
endomitosis and impairing platelet production. Together, the disruption of these 
events provides an explanation for RG7112-induced thrombocytopenia and insight 
into the role of the p53-MDM2 auto-regulatory loop in normal 
megakaryocytopoiesis.