Various routes to leukemic transformation in MPNs. Mutations in epigenetic modifiers (ie, TET2, ASXL1, etc) can be acquired before or after JAK2V617F. Over time, additional somatic genetic and/or epigenetic remodeling events, under influence of various cellular-intrinsic or -extrinsic factors, promote progressive proliferative and self-renewal capacity upon the expanding cell population, ultimately leading to blast-phase transformation. Notably, in many instances, leukemic clones arise from a JAK2V617F wild-type (yellow) cell population suggesting evolution of a separate, coexisting clonal process. In the case of TP53-mutant post-MPN AML (red box), literature suggests a distinct route to leukemic transformation in which “second-hit” loss of heterozygosity (LOH) of TP53 in a preexisting JAK2V617F/TP53 heterozygous-mutant clone results in rapid clonal expansion, chromosomal instability, and blast-phase transformation.