Journal
CANCER DISCOVERY
Volume 7, Issue 11, Pages 1336-1353Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-17-0267
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Funding
- American Cancer Society
- Leukemia Research Foundation
- MGH Goodman Fellowship
- Live Like Bella Foundation
- Alex's Lemonade Stand Foundation
- Harvey Graham Cancer Research Fund
- Terry Fox Foundation
- Hope Funds for Cancer Research
- William Lawrence and Blanche Hughes Foundation
- Boston Children's Hospital Translational Research Program
- NIH [1S10OD010612, 5 P01CA120964, 1K99CA181500, CA109901, CA193651, CA211734]
- Natural Science and Engineering Research Council (NSERC) [RGPIN 05616]
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T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes. Using a transgenic screen in zebrafish, thymocyte selection-associated high mobility group box protein (TOX) was uncovered as a collaborating oncogenic driver that accelerated T-ALL onset by expanding the initiating pool of transformed clones and elevating genomic instability. TOX is highly expressed in a majority of human T-ALL and is required for proliferation and continued xenograft growth in mice. Using a wide array of functional analyses, we uncovered that TOX binds directly to KU70/80 and suppresses recruitment of this complex to DNA breaks to inhibit nonhomologous end joining (NHEJ) repair. Impaired NHEJ is well known to cause genomic instability, including development of T-cell malignancies in KU70- and KU80-deficient mice. Collectively, our work has uncovered important roles for TOX in regulating NHEJ by elevating genomic instability during leukemia initiation and sustaining leukemic cell proliferation following transformation. SIGNIFICANCE: TOX is an HMG box-containing protein that has important roles in T-ALL initiation and maintenance. TOX inhibits the recruitment of KU70/KU80 to DNA breaks, thereby inhibiting NHEJ repair. Thus, TOX is likely a dominant oncogenic driver in a large fraction of human T-ALL and enhances genomic instability.
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