An actually accepted model of clonal evolution in humans, also supported by studies at single cell level, suggests that NPM1 mutations may be a secondary later event, acting as a “gatekeeper” in the pathogenesis of NPM1-mutated AML, and occurring in the setting of clonal hematopoiesis, characterized by founder mutations mainly involving DNA methylation pathway-related genes [5,88,115,116,117,118,119,120]. Here, NPM1 is linked to acute myeloid leukemia.