J Cancer 2020; 11(12):3476-3482. doi:10.7150/jca.29751

Research Paper

Arsenic trioxide induces autophagic degradation of the FLT3-ITD mutated protein in FLT3-ITD acute myeloid leukemia cells

Xiao-Jian Liu1*, Li-Na Wang1*, Zu-Han Zhang2*, Cong Liang1, Yu Li1, Jie-Si Luo1, Chun-Jin Peng1, Xiao-Li Zhang1, Zhi-Yong Ke1, Li-Bin Huang1, Yan-Lai Tang1✉, Xue-Qun Luo1✉

1. Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
2. Department of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou 510623, China
*Equal contribution for the first authorship.

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Citation:
Liu XJ, Wang LN, Zhang ZH, Liang C, Li Y, Luo JS, Peng CJ, Zhang XL, Ke ZY, Huang LB, Tang YL, Luo XQ. Arsenic trioxide induces autophagic degradation of the FLT3-ITD mutated protein in FLT3-ITD acute myeloid leukemia cells. J Cancer 2020; 11(12):3476-3482. doi:10.7150/jca.29751. Available from http://www.jcancer.org/v11p3476.htm

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Abstract

The prognosis of acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations is poor. Some studies, including our previous study, have indicated that arsenic trioxide (ATO) exhibited significant anti-carcinogenic activity in FLT3-ITD AML cells and explored the possibility of targeting the FLT3-ITD protein for degradation as a therapy. Autophagy is a critical mechanism of the anti-leukemic effects of ATO. In this study, we explored the therapeutic efficacy of ATO treatment in a mouse model bearing FLT3-ITD AML and found that ATO significantly reduced the leukemic burden in bone marrow and spleen. We also found that autophagy was responsible for, at least in part, the degradation of the FLT3-ITD protein by ATO. After ATO treatment, MV4-11 cells showed complete autophagic flux. The autophagy inhibitor bafilomycin A or down-regulation of the key autophagy genes Atg5 and Atg7 reversed the FLT3 degradation induced by ATO. We also found that p62/SQSTM1 delivered FLT3-ITD proteins to the lysosome, where they were subsequently degraded. These results indicate that ATO can induce autophagic degradation of the FLT3-ITD mutated protein in FLT3-ITD AML.

Keywords: FLT3-ITD, acute myeloid leukemia, arsenic trioxide, autophagy