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

Bryan King, Thomas Trimarchi, Linsey Reavie, Luyao Xu, Jasper Mullenders, Panagiotis Ntziachristos, Beatriz Aranda-Orgilles, Arianne Perez-Garcia, Junwei Shi, Christopher Vakoc, Peter Sandy, Steven S. Shen, Adolfo Ferrando, Iannis Aifantis

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176 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1552
Number of pages1
JournalCell
Volume153
Issue number7
DOIs
StatePublished - Jun 20 2013

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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, S. S., Ferrando, A., & Aifantis, I. (2013). XThe ubiquitin ligase FBXW7 modulates leukemia-initiating cell activity by regulating MYC stability. Cell, 153(7), 1552. https://doi.org/10.1016/j.cell.2013.05.041