期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE RESEARCH
DOI: 10.1038/s41467-020-20259-0
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资金
- National Key Research and Development Program of China [2017YFA0505202]
- National Basic Research Program of China (973 Program) [2015CB910403]
- National Natural Science Foundation of China [81570118, 81700475, 81570112, 81670139]
- CAMS Innovation Fund for Medical Sciences (CIFMS) [2019-I2M-5-051]
- Natural Science Foundation of Shanghai [19ZR1428700]
This study reveals that targeting the ubiquitin peptidase USP47 can overcome TKI resistance and eliminate leukemia stem/progenitor cells in CML.
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. 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.
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