title: Ablation of Fbxw7 eliminates leukemia-initiating cells by preventing quiescence.
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.
authors.affiliation: Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Fukuoka, Fukuoka 812-8582, Japan.
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Takeishi
authors.forename: Akinobu
authors.initials: A
authors.lastname: Matsumoto
authors.forename: Ichiro
authors.initials: I
authors.lastname: Onoyama
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Naka
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hirao
authors.forename: Keiichi I
authors.initials: KI
authors.lastname: Nakayama
mesh_terms: D000818:Animals; D017209:Apoptosis; D001549:Benzamides / Q000627:therapeutic use*; D002453:Cell Cycle; D015536:Down-Regulation; D044783:F-Box Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D006412:Hematopoietic Stem Cells / Q000502:physiology; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000502:physiology; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011743:Pyrimidines / Q000627:therapeutic use*; D034622:RNA Interference; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
chemical_list: D001549:Benzamides; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513272:Fbxw7 protein, mouse; C489428:Myc protein, mouse; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D011743:Pyrimidines; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D000068877:Imatinib Mesylate; D044767:Ubiquitin-Protein Ligases