The tumor suppressor p53 plays an integral role in the regulation of the cell cycle, apoptosis, DNA repair, and senescence. Fifty percent of cancers are found to have inactivating mutations of p53. Although, inactivating mutations of p53 are uncommon in the chronic phases of MPNs, they increase in frequency in the blast phase of MPNs. The p53 pathway can also be down-regulated in MPN cells that express wild-type p53 through alternative pathways. Over-expression of the ubiquitin ligase murine double minute 2 (MDM2; HDM2 in humans) is a regulator of wild type p53 through a variety of different mechanisms. MDM2 1) promotes proteosomal degradation and 2) inhibits p53 transcription, and 3) inhibits transactivation 4) facilitates export from the nucleus. Inhibition of MDM2 is expected to release the negative regulation of p53 and ultimately promote tumor suppressor function. MDM2 overexpression can be a consequence of gene amplification, increased transcription, and increased translation. It has previously been shown that in primary hematopoietic cells from patients with JAK2V617F PV, reduced expression of p53 is a result of increased La autoantigen expression leading to increased translation of MDM2. It would appear that JAK2V617F induces this ribonucleoprotein and furthermore, La protein expression can be down-regulated by in vitro JAK2 inhibitor treatment. Lu et al demonstrated increased MDM2 expression and reduced p53 levels in JAK2V617F-positive PV CD34+ cells. The physical structure and interaction of p53 and MDM2 is known and has allowed for the development of small molecule inhibitors of MDM2-p53 interaction. Nutlin-3, a small molecule antagonist of MDM2, was shown to inhibit the proliferation of PV CD34+ cells through increased p53 mediated apoptosis. Moreover, in vitro combination of low doses of Pegasys with nutlin-3 resulted in selective and significant inhibition of JAK2V67F-positive CD34+ PV colony formation compared to normal colony formation. Thus, MDM2 appears to be a novel therapeutic target in JAK2V617F-positive PV and ultimately may prove to be most effective when used in combination with Pegasys.