This lower efficacy of differentiation therapy based on IDH, LSD1, and Menin inhibitors compared to ATRA + ATO in APL is seemingly related to a higher genetic complexity and heterogeneity of IDH-mutant, KMT2A-rearranged, and NPM1-mutant AMLs compared to APL cells, in which all the pathogenic events are driven by PML-RARA fusion protein. This evidence concerns the gene NPM1 and acute promyelocytic leukemia.