Proposed role of TP53 dysregulation in the evolution of the MPNs. Decreased TP53 activity can result from several genomic alterations in the MPN clone and is hypothesized to be a crucial driver of MPN disease progression. Mutations and deletions (del17p) of the TP53 gene can directly result in decreased TP53 activity. MDM2 and MDM4 are negative regulators of TP53 that decrease transcription and increase degradation of TP53. Upregulation of these regulators ultimately decreases p53 activity. In MPNs, there are increased MDM2 protein levels resulting from increased MDM2 translation stimulated by JAK2V617 through the La autoantigen. In addition, gain of 1q results in upregulation of MDM4 transcript levels.