RRC ID 68726
Author Takeishi S, Matsumoto A, Onoyama I, Naka K, Hirao A, Nakayama KI.
Title Ablation of Fbxw7 eliminates leukemia-initiating cells by preventing quiescence.
Journal Cancer Cell
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.
Volume 23(3)
Pages 347-61
Published 2013-3-18
DOI 10.1016/j.ccr.2013.01.026
PII S1535-6108(13)00045-7
PMID 23518349
MeSH 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*
IF 26.602
Human and Animal Cells OP9(RCB1124)