2. Academic Validation
  3. A mitophagy inhibitor targeting p62 attenuates the leukemia-initiation potential of acute myeloid leukemia cells

A mitophagy inhibitor targeting p62 attenuates the leukemia-initiation potential of acute myeloid leukemia cells

  • Cancer Lett. 2021 Jul 10:510:24-36. doi: 10.1016/j.canlet.2021.04.003.
Yinghui Li 1,  Yafang Li 1,  Jingjing Yin 1,  Chaoqun Wang 1,  Ming Yang 1,  Jiali Gu 1,  Mei He 1,  Hui Xu 1,  Weichao Fu 1,  Wenshan Zhang 1,  Yongxin Ru 1,  Xiaolei Liu 1,  Ying Li 2,  Yue Xin 2,  Huier Gao 3,  Xiangqun Xie 4,  Yingdai Gao 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, PUMC Department of Stem Cell and Regenerative Medicine, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.
  • 2 Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China.
  • 3 Department of Pharmacy, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, 300192, China.
  • 4 Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, NIH National Center of Excellence for Computational Drug Abuse Research, Drug Discovery Institute; Departments of Computational Biology and Structural Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15260, United States. Electronic address: xix15@pitt.edu.
  • 5 State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, PUMC Department of Stem Cell and Regenerative Medicine, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China. Electronic address: ydgao@ihcams.ac.cn.
PMID: 33862150 DOI: 10.1016/j.canlet.2021.04.003
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.

Keywords

AML; Autophagy; LICs; Small molecular compound.

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