title: Regulation of c-Myc ubiquitination controls chronic myelogenous leukemia initiation and progression.
abstract: The molecular mechanisms regulating leukemia-initiating cell (LIC) function are of important clinical significance. We use chronic myelogenous leukemia (CML) as a model of LIC-dependent malignancy and identify the interaction between the ubiquitin ligase Fbw7 and its substrate c-Myc as a regulator of LIC homeostasis. Deletion of Fbw7 leads to c-Myc overexpression, p53-dependent LIC-specific apoptosis, and the eventual inhibition of tumor progression. A decrease of either c-Myc protein levels or attenuation of the p53 response rescues LIC activity and disease progression. Further experiments showed that Fbw7 expression is required for survival and maintenance of human CML LIC. These studies identify a ubiquitin ligase:substrate pair regulating LIC activity, suggesting that targeting of the Fbw7:c-Myc axis is an attractive therapy target in refractory CML.
authors.affiliation: Howard Hughes Medical Institute and Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Linsey
authors.initials: L
authors.lastname: Reavie
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Buckley
authors.forename: Evangelia
authors.initials: E
authors.lastname: Loizou
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Takeishi
authors.forename: Beatriz
authors.initials: B
authors.lastname: Aranda-Orgilles
authors.forename: Delphine
authors.initials: D
authors.lastname: Ndiaye-Lobry
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.forename: Sherif
authors.initials: S
authors.lastname: Ibrahim
authors.forename: Keiichi I
authors.initials: KI
authors.lastname: Nakayama
authors.forename: Iannis
authors.initials: I
authors.lastname: Aifantis
mesh_terms: D000818:Animals; D017209:Apoptosis; D018450:Disease Progression; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D015972:Gene Expression Regulation, Neoplastic; D006412:Hematopoietic Stem Cells; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513272:Fbxw7 protein, mouse; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases