The progression to AML with the dedifferentiation of leukemic cells in more malignant sub-clones is associated with the acquisition of subsequent cooperating mutations in AML-specific driver genes like NPM1. In many patients, chemotherapy eradicates the aggressively growing leukemic clone (including clones carrying NPM1 mutations) together with their stem cells, while the earlier (and thus more quiescent) pre-leukemic neoplastic clones with their CHIP-like mutations persist [23]. Here, NPM1 is linked to acute myeloid leukemia.