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ACS Combinatorial Science

ACS Combinatorial Science

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

Published:4 January 2021 DOI: 10.1038/s41467-020-20259-0 PMID: 33397955
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,?Ying-Li Wu

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.

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Procduct Name CAS Molecular Formula Supplier Price
AZD6738 1352226-88-0 C20H24N6O2S 160 suppliers $22.00-$5490.00
AZD6738 1352226-88-0 C20H24N6O2S 160 suppliers $22.00-$5490.00
AZD6738 1352226-88-0 C20H24N6O2S 160 suppliers $22.00-$5490.00
AZD6738 1352226-88-0 C20H24N6O2S 160 suppliers $22.00-$5490.00

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