Schematic showing the requirement for biallelic inactivation of Trp53 for leukemic transformation in JAK2V617F-mutant MPNs. Erythroid progenitors appear uniquely vulnerable to Trp53 loss, resulting in upregulation of BMP2/SMAD signaling and aberrant self-renewal and leukemogenic potential. The genomic instability resulting from JAK2V617F plus TP53^−/− caused an increased dependence on DNA repair mechanisms and a therapeutic vulnerability to WEE1 and PARP inhibitors. Illustration by Patrick Lane, ScEYEnce Studios.