A mitophagy inhibitor targeting p62 attenuates the leukemia-initiation potential of acute myeloid leukemia cells. (10th July 2021)

• Record Type: Journal Article
• Authors: Li, Yinghui; Li, Yafang; Yin, Jingjing; Wang, Chaoqun; Yang, Ming; Gu, Jiali; He, Mei; Xu, Hui; Fu, Weichao; Zhang, Wenshan; Ru, Yongxin; Liu, Xiaolei; Li, Ying; Xin, Yue; Gao, Huier; Xie, Xiangqun; Gao, Yingdai
• Is Part Of: Cancer letters. Volume 510(2021)
• Page Start: 24
• Page End: 36
• Publication Date: 2021-07-10
• Subjects: Autophagy -- Small molecular compound -- LICs -- AML; AML Acute myeloid leukemia -- SQSTM1 Sequestosome 1 -- LICs Leukemia initiating cells -- HSCs Hematopoietic stem cells -- UCB Umbilical cord blood -- MNCs Mononuclear cells -- PDX Patient-derived tumor xenograft -- IC50 50% inhibitory Concentration -- ROS Reactive oxygen species -- MMP Mitochondrial membrane potential -- CCLE Cancer cell line encyclopedia -- GEXC Gene expression commons -- TCGA The cancer genome atlas -- KEGG Kyoto encyclopedia of genes and genomes -- GSEA Gene set enrichment analysis -- LDA Limiting dilution assay -- RT-PCR Real-time PCR -- TEM Transmission electron microscopy -- CR Complete remission -- OS Overall survival; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2021.04.003
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: There has been an increasing focus on the tumorigenic potential of leukemia initiating cells (LICs) in acute myeloid leukemia (AML). Despite the important role of selective autophagy in the life-long maintenance of hematopoietic stem cells (HSCs), cancer progression, and chemoresistance, the relationship between LICs and selective autophagy remains to be fully elucidated. Sequestosome 1 (SQSTM1), also known as p62, is a selective autophagy receptor for the degradation of ubiquitinated substrates, and its loss impairs leukemia progression in AML mouse models. In this study, we evaluated the underlying mechanisms of mitophagy in the survival of LICs with XRK3F2, a p62-ZZ inhibitor. We demonstrated that XRK3F2 selectively impaired LICs but spared normal HSCs in both mouse and patient-derived tumor xenograft (PDX) AML models. Mechanistically, we observed that XRK3F2 blocked mitophagy by inhibiting the binding of p62 with defective mitochondria. Our study not only evaluated the effectiveness and safety of XRK3F2 in LICs, but also demonstrated that mitophagy plays an indispensable role in the survival of LICs during AML development and progression, which can be impaired by blocking p62. Highlights: XRK3F2 acts as a mitophagy inhibitor to impair LICs. XRK3F2 selectively impairs LICs but spares normal HSCs. XRK3F2 may serve as a probe to investigate the difference between LICs and HSCs.