title: The ubiquitin ligase FBXW7 modulates leukemia-initiating cell activity by regulating MYC stability.
abstract: Sequencing efforts led to the identification of somatic mutations that could affect the self-renewal and differentiation of cancer-initiating cells. One such recurrent mutation targets the binding pocket of the ubiquitin ligase Fbxw7. Missense FBXW7 mutations are prevalent in various tumors, including T cell acute lymphoblastic leukemia (T-ALL). To study the effects of such lesions, we generated animals carrying regulatable Fbxw7 mutant alleles. Here, we show that these mutations specifically bolster cancer-initiating cell activity in collaboration with Notch1 oncogenes but spare normal hematopoietic stem cell function. We were also able to show that FBXW7 mutations specifically affect the ubiquitylation and half-life of c-Myc protein, a key T-ALL oncogene. Using animals carrying c-Myc fusion alleles, we connected Fbxw7 function to c-Myc abundance and correlated c-Myc expression to leukemia-initiating activity. Finally, we demonstrated that small-molecule-mediated suppression of MYC activity leads to T-ALL remission, suggesting an effective therapeutic strategy.
authors.affiliation: Howard Hughes Medical Institute and NYU Cancer Institute, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: King
authors.forename: Thomas
authors.initials: T
authors.lastname: Trimarchi
authors.forename: Linsey
authors.initials: L
authors.lastname: Reavie
authors.forename: Luyao
authors.initials: L
authors.lastname: Xu
authors.forename: Jasper
authors.initials: J
authors.lastname: Mullenders
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Ntziachristos
authors.forename: Beatriz
authors.initials: B
authors.lastname: Aranda-Orgilles
authors.forename: Arianne
authors.initials: A
authors.lastname: Perez-Garcia
authors.forename: Junwei
authors.initials: J
authors.lastname: Shi
authors.forename: Christopher
authors.initials: C
authors.lastname: Vakoc
authors.forename: Peter
authors.initials: P
authors.lastname: Sandy
authors.forename: Steven S
authors.initials: SS
authors.lastname: Shen
authors.forename: Adolfo
authors.initials: A
authors.lastname: Ferrando
authors.forename: Iannis
authors.initials: I
authors.lastname: Aifantis
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C513272:Fbxw7 protein, mouse; C489427:MYC protein, human; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D051881:Receptor, Notch1; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases