From origins to outcomes. Different evolutionary paths to MPN and disease progression in 4 patients, each with a unique genetic background (green, gray, red, blue). In the first patient (green), a phenotypic driver mutation acquired in an HSC results in clonal expansion and the emergence of an MPN phenotype as a consequence of favorable cell-intrinsic and/or environmental factors. The MPN in this context has no additional oncogenic driver mutations, as is common for patients in chronic phase. Additional driver mutations, such as those that perturb polycomb repressor 2 function (EZH2, ASXL1 mutations), spliceosome components (SRSF2, SF3B1, U2AF1), or DNA damage repair (TP53), can lead to cells gaining a further clonal advantage and disease progression. In the second patient (gray), the cell-intrinsic and/or environmental context is not favorable, and a cell acquiring a phenotypic driver mutation does not have a clonal advantage relative to competing normal cells. In some circumstances, a phenotypic driver mutation may be insufficient to result in abnormal blood counts and an overt MPN but can instead result in a clonal expansion. Additional mutations or cell-extrinsic changes may be required to result in emergence of disease (patient in red). Finally, in some patients, phenotypic driver mutations may not be the first event. Clonal hematopoiesis as a result of mutations in, for example, TET2, DNMT3A, ASXL1 may be the required backdrop for a phenotypic driver mutation to result in an overt MPN (patient in blue).