Evidence for somatic mutations in genes other than those activating JAK-STAT signaling in MPN patients. (A) Given that JAK2V617F mutations are common to 3 MPN disorders with distinct phenotypes (PV, ET, and PMF), it has been postulated that additional somatic or germline variants might contribute to the MPNs produced. In addition, mutations in genes outside of JAK2V617F are thought to play a role in transformation of PV and ET to PMF and in the transformation of chronic MPNs to AML. (B) Since the discovery of the JAK2V617F mutation, it was noted that patients with JAK2 mutant chronic MPN may undergo transformation to a JAK2 wild-type AML. This observation suggests that the JAK2V617F mutation may not be required for leukemic transformation or that a clone ancestral to the JAK2V617F mutant cell was subject to leukemic transformation. (C) Finally, it has also been observed that occasional patients with the JAK2V617F mutation in addition to a cytogenetic alteration (illustrated here by deletion 20q) may have the JAK2 mutation in only a portion of the MPN clones, whereas the majority of the MPN cells bear both the cytogenetic alteration and the JAK2 mutation. This finding again suggests that the JAK2V617F mutation may not be the initiating genetic event in MPN pathogenesis.