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Cell. 2013 Jun 20;153(7):1552-66. doi: 10.1016/j.cell.2013.05.041.

The ubiquitin ligase FBXW7 modulates leukemia-initiating cell activity by regulating MYC stability.

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1
Howard Hughes Medical Institute and NYU Cancer Institute, NYU School of Medicine, New York, NY 10016, USA.

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.

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PMID:
23791182
PMCID:
PMC4146439
DOI:
10.1016/j.cell.2013.05.041
[Indexed for MEDLINE]
Free PMC Article

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