Role of Autophagy in Resistance of FLT3–ITD AML Stem Cells to FLT3 TKI Treatment

The FLT3-ITD mutation occurs in 25-30% of AML patients, and is associated with increased relapse rate and poor survival. FLT3 tyrosine kinase inhibitors (TKI) have shown encouraging results, but responses are not sustained. Therefore, there is considerable interest in understanding mechanisms of resistance of FLT3-ITD AML stem cells after TKI treatment. Autophagy is an important cellular response that maintains cell survival under stress. Here we investigated the regulation of autophagy in resistance of FLT3-ITD+ AML stem cells to FLT3 TKI treatment. MV4-11 and Molm13 FLT3-ITD AML cells were transduced with GFP-LC3-RFP-LC3 ΔG constructs to measure autophagic flux. Autophagyhigh AML cells showed slower growth(p We tested the effect of Lys05 in vivo by treating NSG mice engrafted with primary FLT3-ITD AML cells with vehicle, AC220 (10mg/kg), Lys05 (20mg/kg) or combination for 3 weeks. Lys05 treatment reduced human CD45+ cell engraftment (8.7% vs 17%, p=0.03), and reduced CD45+CD33+ myeloid cells in BM and spleen (BM: 42% vs 81%, p We conclude that autophagy inhibition enhances sensitivity of FLT3-ITD+ AML stem cells to TKI treatment both in vitro and in vivo. We demonstrate important roles for autophagy in regulating p53 levels and cell cycle in FL3-ITD AML cells. These studies support further development of strategies to target autophagy and related pathways to enhance efficacy of TKI in eliminating AML stem cells. Disclosures No relevant conflicts of interest to declare.