Targeting USP47 overcomes tyrosine kinase inhibitor resistance and eradicates leukemia stem/progenitor cells in chronic myelogenous leukemia
Hu Lei, Hanzhang Xu, Huizhuang Shan, Meng Liu, Ying Lu, Zhixiao Fang, Jin Jin, Bo Jing, Xinhua Xiao, Shenmeng Gao, Feng‐Hou Gao, Xia Li, Yang Li, Ligen Liu, Weiwei Wang, Chuanxu Liu, Yin Tong, Yunzhao Wu, Junke Zheng, Guoqiang Chen, Li Zhou, Yingli Wu, Yingli Wu, Yingli Wu
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-ABL T315I -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.