Schematic model showing the action of mechanism of combined FLT3 and HDAC8 inhibition. When FLT3-ITD⁺ AML cells are exposed to FLT3 inhibitors, FOXO1 and FOXO3 are activated following the downregulation of FLT3 signaling and downstream AKT and ERK signaling (left panel). Activated FOXO1 and FOXO3 bind to HDAC8 promoter and induce its transcription, which, in turn, associates with and inhibits the antitumor activity of p53 via deacetylation, thus promoting the maintenance and TKI resistance of FLT3-ITD⁺ AML. Combining HDAC8 inhibitors with FLT3 inhibitors abrogates the inhibitory effect of HDAC8 on p53 and increases p53 acetylation, thus significantly enhancing the elimination of FLT3-ITD⁺ AML (right panel).