1. Targeting USP47 overcomes tyrosine kinase inhibitor resistance and eradicates leukemia stem/progenitor cells in chronic myelogenous leukemia
- Author
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Li Yang, Feng-Hou Gao, Guo-Qiang Chen, Hu Lei, Li Xia, Yin Tong, Zhixiao Fang, Xinhua Xiao, Bo Jing, Huizhuang Shan, Ying-Li Wu, Ligen Liu, Junke Zheng, Jin Jin, Li Zhou, Ying Lu, Chuan-Xu Liu, Meng Liu, Shen-Meng Gao, Weiwei Wang, Hanzhang Xu, and Yunzhao Wu
- Subjects
0301 basic medicine ,DNA Repair ,Fusion Proteins, bcr-abl ,General Physics and Astronomy ,Tyrosine-kinase inhibitor ,0302 clinical medicine ,hemic and lymphatic diseases ,STAT5 Transcription Factor ,Extracellular Signal-Regulated MAP Kinases ,Mice, Knockout ,Multidisciplinary ,Chemistry ,Cancer stem cells ,Gene Expression Regulation, Leukemic ,Protein Stability ,Leukemia ,Cancer therapeutic resistance ,030220 oncology & carcinogenesis ,Neoplastic Stem Cells ,Ubiquitin-Specific Proteases ,Tyrosine kinase ,Ubiquitin Thiolesterase ,medicine.drug ,Protein Binding ,Signal Transduction ,Proteasome Endopeptidase Complex ,medicine.drug_class ,Science ,Thiophenes ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Myelogenous ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,medicine ,Animals ,Humans ,RNA, Messenger ,Progenitor cell ,neoplasms ,Protein Kinase Inhibitors ,Chronic myeloid leukaemia ,Cell Proliferation ,Imatinib ,General Chemistry ,medicine.disease ,Xenograft Model Antitumor Assays ,respiratory tract diseases ,030104 developmental biology ,Drug Resistance, Neoplasm ,Proteolysis ,Cancer research ,ras Proteins ,Y-Box-Binding Protein 1 ,K562 Cells ,Chronic myelogenous leukemia ,K562 cells ,DNA Damage - Abstract
Identifying novel drug targets to overcome resistance to tyrosine kinase inhibitors (TKIs) and eradicating leukemia stem/progenitor cells are required for the treatment of chronic myelogenous leukemia (CML). Here, we show that ubiquitin-specific peptidase 47 (USP47) is a potential target to overcome TKI resistance. Functional analysis shows that USP47 knockdown represses proliferation of CML cells sensitive or resistant to imatinib in vitro and in vivo. The knockout of Usp47 significantly inhibits BCR-ABL and BCR-ABLT315I-induced CML in mice with the reduction of Lin−Sca1+c-Kit+ CML stem/progenitor cells. Mechanistic studies show that stabilizing Y-box binding protein 1 contributes to USP47-mediated DNA damage repair in CML cells. Inhibiting USP47 by P22077 exerts cytotoxicity to CML cells with or without TKI resistance in vitro and in vivo. Moreover, P22077 eliminates leukemia stem/progenitor cells in CML mice. Together, targeting USP47 is a promising strategy to overcome TKI resistance and eradicate leukemia stem/progenitor cells in CML., Resistance to tyrosine kinase inhibitors (TKI) is a limitation to their use in treating chronic myelogenous leukemia (CML). Here, the authors show that targeting the ubiquitin peptidase USP47 overcomes TKI resistance and eliminates leukaemia stem/progenitor cells in primary and xenograft CML murine models.
- Published
- 2021