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 (June 2013) The Ubiquitin Ligase FBXW7 Modulates Leukemia-Initiating Cell Activity by Regulating MYC Stability. Cell, 153 (7). pp. 1552-1566. ISSN 0092-8674
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.
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