Targeting USP47 overcomes tyrosine kinase inhibitor resistance and eradicates leukemia stem/progenitor cells in chronic myelogenous leukemia

Hu Lei, Han-Zhang Xu, Hui-Zhuang Shan, Meng Liu, Ying Lu, Zhi-Xiao Fang, Jin Jin, Bo Jing, Xin-Hua Xiao, Shen-Meng Gao, Feng-Hou Gao, Li Xia, Li Yang, Li-Gen Liu, Wei-Wei Wang, Chuan-Xu Liu, Yin Tong, Yun-Zhao Wu, Jun-Ke Zheng, Guo-Qiang Chen (), Li Zhou () and Ying-Li Wu ()
Additional contact information
Hu Lei: Shanghai Jiao Tong University School of Medicine
Han-Zhang Xu: Shanghai Jiao Tong University School of Medicine
Hui-Zhuang Shan: Shanghai Jiao Tong University School of Medicine
Meng Liu: Shanghai Jiao Tong University School of Medicine
Ying Lu: Shanghai Jiao Tong University School of Medicine
Zhi-Xiao Fang: Shanghai Jiao Tong University School of Medicine
Jin Jin: Shanghai Jiao Tong University School of Medicine
Bo Jing: Shanghai Jiao Tong University School of Medicine
Xin-Hua Xiao: Shanghai Jiao Tong University School of Medicine
Shen-Meng Gao: The First Affiliated Hospital of Wenzhou Medical University
Feng-Hou Gao: Shanghai Jiao Tong University School of Medicine
Li Xia: Shanghai Jiao Tong University School of Medicine
Li Yang: Shanghai Jiao Tong University School of Medicine
Li-Gen Liu: Shanghai Jiao Tong University School of Medicine
Wei-Wei Wang: Shanghai Jiao Tong University School of Medicine
Chuan-Xu Liu: Shanghai Jiao Tong University School of Medicine
Yin Tong: Shanghai Jiao Tong University School of Medicine
Yun-Zhao Wu: Shanghai Jiao Tong University School of Medicine
Jun-Ke Zheng: Shanghai Jiao Tong University School of Medicine
Guo-Qiang Chen: Shanghai Jiao Tong University School of Medicine
Li Zhou: Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine
Ying-Li Wu: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-020-20259-0

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