Models to explain progression from a JAK2-mutant MPN to a JAK2 wild-type leukemia. In model 1 (i) the 2 phases of disease are phylogenetically related, having arisen from a shared (pre-JAK2) founder clone, whereas in model 2 (ii) the 2 phases of disease are clonally unrelated, reflecting transformation of independent stem cells. HSC indicates hematopoietic stem cell.