NPM1c mutations were always preceded by mutations previously considered as possible founders; DNMT3A, IDH2, WT1, TET2, as well as some additional mutations that are less well validated as early events in NPM1c AML including NRAS, ZRSR2 and CBL. FLT3 mutations and FLT3−ITDs were found to occur both before and after the acquisition of NPM1c but were always sub-clonal to putative founder mutations. Here, IDH2 is linked to acute myeloid leukemia.