Evolution of a myeloid neoplasm. The natural history of JAK2^V617F-positive PV, illustrating the evolution of subclones (only 1 is shown) from the founding LT-HSC clone, which first acquires JAK2^V617F and, with time, additional fitness mutations, though the latter are not mandatory for clonal expansion. Importantly, leukemic transformation can occur at several levels. It is JAK2^V617F-negative when arising in the founding LT-HSCs, and JAK2^V617F-positive when arising from an involved LT-HSC daughter clone. The acquisition and phenotypic consequences of these mutations appear to be due to and modified not only by host genetic variation, in particular, age and sex, but also by chemotherapy exposure. Clonal dominance, in which there is suppression of normal LT-HSCs by the malignant clone, is a central feature of PMF and, to a lesser extent and later in its natural history, of PV, usually resulting in leukocytosis and extramedullary hematopoiesis. Clonal dominance is not a function of a particular MPN driver mutation but rather, a function of the MPN driver mutation VAF frequency at the level of the involved LT-HSC; it is usually present when the neutrophil allele burden is ≥70%.⁵⁹  LOH, loss of heterozygosity; UPD, uniparental disomy.