The life history of MPNs. The gain of an MPN-driver mutation in a hematopoietic stem cell (HSPC) progenitor, such as JAK2-p.V617F, may occur as early as during embryogenesis. Over a long period of latency likely measured in decades, clonal hematopoiesis develops. The transition to an MPN ensues in a minority of patients, and subsequent acquisition of deleterious genetic mutations, eg, TP53 during clonal evolution, results in a secondary AML. The ultimate aim of therapy is disease modification, by reducing the clonal burden of disease, ie, using JAK2-p. V617F VAF as a surrogate marker. sAML, secondary acute myeloid leukemia.