The Ubiquitin Ligase FBXW7 Modulates Leukemia-Initiating Cell Activity by Regulating MYC Stability

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, includi...

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Bibliographic Details
Published in:Cell 2013-06, Vol.153 (7), p.1552-1566
Main Authors: King, Bryan, Trimarchi, Thomas, Reavie, Linsey, Xu, Luyao, Mullenders, Jasper, Ntziachristos, Panagiotis, Aranda-Orgilles, Beatriz, Perez-Garcia, Arianne, Shi, Junwei, Vakoc, Christopher, Sandy, Peter, Shen, Steven S., Ferrando, Adolfo, Aifantis, Iannis
Format: Article
Language:English
Subjects:
alleles
Animals
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
cells
Disease Models, Animal
F-Box Proteins - genetics
F-Box Proteins - metabolism
F-Box-WD Repeat-Containing Protein 7
half life
Hematopoietic Stem Cells - metabolism
Humans
lymphocytic leukemia
Mice
Mice, Knockout
mutants
Mutation, Missense
oncogenes
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism
Proto-Oncogene Proteins c-myc - antagonists & inhibitors
Proto-Oncogene Proteins c-myc - metabolism
Receptor, Notch1 - metabolism
remission
somatic mutation
stem cells
T-lymphocytes
Tumor Suppressor Protein p53 - metabolism
ubiquitin-protein ligase
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
Ubiquitination
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Summary: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. [Display omitted] •Fbxw7 mutations cooperate with Notch1 to drive aggressive T cell leukemia (T-ALL)•The stabilization of c-Myc protein defines leukemia-initiating cells (LICs)•Inhibition of c-Myc via depletion or BET inhibitors impedes leukemic progression•Notch, Myc, and Brd4 bind cooperatively to induce LIC gene expression Missense mutations in the ubiquitin ligase FBXW7 specifically augment the function of leukemia-initiating cells without disrupting the function of normal hematopoietic stem cells by increasing the stability of the c-Myc oncogene.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2013.05.041