PML-RARα enhances autophagic activity through inhibiting Akt/mTOR pathway

Autophagy is a highly conserved, closely-regulated homeostatic cellular activity that allows for the bulk degradation of long-lived proteins and cytoplasmic organelles. Its roles in cancer initiation and progression and in determining the response of tumor cells to anticancer therapy are complicated, and the potential significance of autophagy in the pathogenesis and therapeutic response of acute myeloid leukemia has a little investigation. Here, we demonstrate that induction of acute promyelocytic leukemia (APL)-specific PML-RARx but not PLZF-RARx/NPM-RARx fusion protein up-regulates constitutive autophagic activation in leukemic and non-leukemic cells. The significant increase of autophagic activity is also found in the leukemic cells infiltrated bone marrow, spleen and liver from PML-RARx-transgenic APL syngenic transplanted mice. The specific autophagy inhibitor 3-methyladenine significantly abrogates PML-RARx-increased autophagy, while the autophagic flux assay reveals that the fusion protein induces autophagy in the manner of on-rate increase. Furthermore, this autophagy modulation of PML-RARx is possibly mediated by decreased activation of Akt/mTOR pathway. Given the critical role of the PML-RARx oncoprotein in APL pathogenesis, this study would shed new sights for an important role of autophagy in the development and treatment of this disease.