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

Nat Commun. 2021 Jan 4;12(1):51. doi: 10.1038/s41467-020-20259-0.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / drug effects
  • DNA Damage
  • DNA Repair / drug effects
  • Drug Resistance, Neoplasm* / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fusion Proteins, bcr-abl
  • Gene Expression Regulation, Leukemic / drug effects
  • Humans
  • K562 Cells
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
  • Mice
  • Mice, Knockout
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology*
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding / drug effects
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Stability / drug effects
  • Proteolysis / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • STAT5 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Thiophenes / pharmacology
  • Ubiquitin Thiolesterase / metabolism*
  • Ubiquitin-Specific Proteases / metabolism*
  • Xenograft Model Antitumor Assays
  • Y-Box-Binding Protein 1 / metabolism
  • ras Proteins / metabolism

Substances

  • 1-(5-((2,4-difluorophenyl)thio)-4-nitrothiophen-2-yl)ethanone
  • Protein Kinase Inhibitors
  • RNA, Messenger
  • STAT5 Transcription Factor
  • Thiophenes
  • USP47 protein, human
  • Y-Box-Binding Protein 1
  • YBX1 protein, human
  • Fusion Proteins, bcr-abl
  • Extracellular Signal-Regulated MAP Kinases
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Proteases
  • Usp47 protein, mouse
  • Proteasome Endopeptidase Complex
  • ras Proteins