Iancu-Rubin et al have investigated the biological effect of RG7112 (first generation MDM2 inhibitor) induced p53-MDM2 disruption on megakaryopoiesis and platelet production in order to better elucidate the mechanism of treatment associated thrombocytopenia (ASH 2012). Bone marrow derived CD34+ cells exposed to RG7112 for 7 days generated fewer viable cells, fewer CFU-MK colonies as compared to untreated cells. Based on these findings, it would appear that RG7112 impacts megakaryopoiesis by two potential mechanisms: 1) Impairing the ability of CD34+ cells to generate MK precursors due to increased apoptosis; 2) Limiting DNA synthesis and polyploidization during the late stages of MK development due to pharmacological activation of p53. A combination of these two effects may provide an explanation for thrombocytopenia observed in patients receiving this drug and suggests that p53 plays an important role in normal human thrombocytopoiesis.