Model depicting the development and evolution of MPNs. Monoclonal expansion of HSCs can occur in healthy individuals and often precedes acquisition of mutations that drive the phenotype of MPNs. JAK2, MPL, and CALR mutations and other genetic or patient factors influence the MPN phenotype seen in patients (PV, red-shaded cells; ET, blue-shaded cells). MPNs are clonally heterogeneous, with multiple mutant subclones existing within neoplasms. Subclonal expansion can be associated with acceleration of disease, the phenotype and prognosis of which is determined by the nature of additional somatic mutations or chromosomal aberrations acquired. Transformation to AML can occur from early or late subclones.