Megakaryocytes are derived from hematopoietic stem cells and give rise to platelets. Polyploidization and apoptosis are hallmarks of terminal megakaryopoiesis. Genome-scale microarray analyses performed in our group have identified a significant up-regulation of the p53 transcriptional network at the stage of terminal megakaryocytic (Mk) differentiation. We proceeded to silence p53 in the human CD34+CD41+ megakaryoblastic cell line CHRF-288-11 via lentiviral vector mediated delivery of miRNA. Silencing of p53 was confirmed on the protein and transcript levels. CHRF-288-11 cells undergo terminal Mk differentiation accompanied by pronounced polyploidization and apoptosis upon phorbol ester stimulation. A substantial increase in the percentage of polyploid cells and in overall viability was evident upon terminal differentiation of p53-silenced cells versus cells transduced with scrambled controls. Expression levels of p53 transcriptional targets assayed via Q-RT-PCR (PUMA, p21, TP53I3, TP53INP1, MDM2 and BAX) were detected at significantly lower levels in the p53-silenced cells versus cells transduced with scrambled controls upon Mk differentiation. Work with primary megakaryocytes derived from culture of bone marrow cells of p53-/- mice is currently in progress to validate these results.