Journal
CELL
Volume 153, Issue 7, Pages 1552-1566Publisher
CELL PRESS
DOI: 10.1016/j.cell.2013.05.041
Keywords
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Funding
- NIH/NCI [P30 CA016087-30]
- NYU Cancer Institute Center [5P30CA16087-31]
- NIH [1RO1CA133379, 1RO1CA105129, 1RO1CA149655, 5RO1CA173636, 1RO1GM088847]
- William Lawrence and Blanche Hughes Foundation
- Leukemia & Lymphoma Society [6340-11, 6373-13]
- Chemotherapy Foundation
- V Foundation for Cancer Research
- St. Baldrick's Foundation
- NYU CMB Training Program
- Ruth L. Kirschstein F31 Award
- Marie Curie Actions Fellowship
- NWO Rubicon
- Dutch Cancer Society
- Jose Carreras Leukemia Foundation [FIJC-12/EDTHOMAS]
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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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