Ablation of Fbxw7 eliminates leukemia-initiating cells by preventing quiescence

Cancer Cell. 2013 Mar 18;23(3):347-61. doi: 10.1016/j.ccr.2013.01.026.

Abstract

Imatinib eradicates dividing progenitor cells of chronic myeloid leukemia (CML) but does not effectively target nondividing leukemia-initiating cells (LICs); thus, the disease often relapse after its discontinuation. We now show that Fbxw7 plays a pivotal role in maintenance of quiescence in LICs of CML by reducing the level of c-Myc. Abrogation of quiescence in LICs by Fbxw7 ablation increased their sensitivity to imatinib, and the combination of Fbxw7 ablation with imatinib treatment resulted in a greater depletion of LICs than of normal hematopoietic stem cells in mice. Purging of LICs by targeting Fbxw7 to interrupt their quiescence and subsequent treatment with imatinib may thus provide the basis for a promising therapeutic approach to CML.

MeSH terms

  • Animals
  • Apoptosis
  • Benzamides / therapeutic use*
  • Cell Cycle
  • Down-Regulation
  • F-Box Proteins / antagonists & inhibitors*
  • F-Box Proteins / genetics
  • F-Box Proteins / metabolism*
  • F-Box-WD Repeat-Containing Protein 7
  • Hematopoietic Stem Cells / physiology
  • Imatinib Mesylate
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neoplastic Stem Cells / physiology
  • Piperazines / therapeutic use*
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Pyrimidines / therapeutic use*
  • RNA Interference
  • RNA, Small Interfering
  • Tumor Suppressor Protein p53 / metabolism
  • Ubiquitin-Protein Ligases / antagonists & inhibitors*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Benzamides
  • F-Box Proteins
  • F-Box-WD Repeat-Containing Protein 7
  • Fbxw7 protein, mouse
  • Myc protein, mouse
  • Piperazines
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-myc
  • Pyrimidines
  • RNA, Small Interfering
  • Tumor Suppressor Protein p53
  • Imatinib Mesylate
  • Ubiquitin-Protein Ligases