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.
Highlights
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)
To screen the potential deubiquitinating enzymes (DUBs) involved in the pathogenesis of CML, we compared the expression of DUBs in primary CML cells and normal bone marrow (BM) CD34+ cells (n = 3)
TKI resistance and CML leukemia stem cells remain the major challenges in the treatment of BCR-ABL+ CML
Summary
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). The knockout of Usp[47] significantly inhibits BCR-ABL and BCR-ABLT315I-induced CML in mice with the reduction of Lin−Sca1+c-Kit+ CML stem/progenitor cells. Together, targeting USP47 is a promising strategy to overcome TKI resistance and eradicate leukemia stem/progenitor cells in CML. TKI resistance, including BCR-ABL-dependent and -independent resistance, is a major problem in IM-based CML treatment. It has been reported that the leukemia stem cells (LSCs) in CML are insensitive to TKI in a BCR-ABL-independent manner, thereby leading to relapse and minimal residual disease (MRD)[11]. Identifying promising drug targets that overcome TKI resistance via both mechanisms is urgently required to provide new possibilities for CML treatment.
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