Impact of the inherited genome on the fate of JAK2 V617F mutant hematopoietic stem cells. (A) After the acquisition of the JAK2 V617F mutation, the fate of HSCs and their progeny is markedly influenced by heritable polymorphisms in the host genome. In many instances, expansion of JAK2 V617F–positive clones (depicted as expanding lines) leads to the development of detectable clonal hematopoiesis, and in some of these, the clones enlarge sufficiently to produce an MPN phenotype. It is also probable that, in many instances, clones remain very small and below the detection limits of conventional approaches. It should be noted that, although many genetic polymorphisms are likely to operate in a cell autonomous manner, others may influence the growth of mutant HSCs through non–cell autonomous effects. Also, the clonal size required to produce a clinical phenotype varies significantly between individuals, and this is also likely to be influenced by genetics. (B) Although most cases of JAK2 V617F–positive MPNs do not harbor any additional identifiable somatic driver mutations, some cases do have such mutations and they most commonly affect the TET2 gene. Hypothetically prior acquisition of a mutation in TET2 may be able to convert an unfavorable genome into a favorable one for JAK2 V617F to drive clonal expansion and MPN development (this is depicted in the fates of 2 distinct HSCs from the same individual). Alternatively, acquisition of TET2 mutations after JAK2 can accelerate clonal growth.