1. The ubiquitin ligase FBXW7 modulates leukemia-initiating cell activity by regulating MYC stability.
- Author
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King B, Trimarchi T, Reavie L, Xu L, Mullenders J, Ntziachristos P, Aranda-Orgilles B, Perez-Garcia A, Shi J, Vakoc C, Sandy P, Shen SS, Ferrando A, and Aifantis I
- Subjects
- Animals, Cell Cycle Proteins genetics, Disease Models, Animal, F-Box Proteins genetics, F-Box-WD Repeat-Containing Protein 7, Hematopoietic Stem Cells metabolism, Humans, Mice, Mice, Knockout, Mutation, Missense, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics, Proto-Oncogene Proteins c-myc antagonists & inhibitors, Receptor, Notch1 metabolism, Tumor Suppressor Protein p53 metabolism, Ubiquitin-Protein Ligases genetics, Ubiquitination, Cell Cycle Proteins metabolism, F-Box Proteins metabolism, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma metabolism, Proto-Oncogene Proteins c-myc metabolism, Ubiquitin-Protein Ligases metabolism
- 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., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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