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.

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Published in Cancer Discovery, v. 7, issue 11, p. 1336-1353.

© 2017 American Association for Cancer Research

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The document available for download is the authors' post-peer-review final draft of the article.

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This work was supported through funding provided to D.M. Langenau from the American Cancer Society, the Leukemia Research Foundation, the MGH Goodman Fellowship, the Live Like Bella Foundation, and the Alex's Lemonade Stand Foundation. Funding support was also garnered from the Harvey Graham Cancer Research Fund and The Terry Fox Foundation (J. Pinder), the Hope Funds for Cancer Research (B.J. Abraham), the William Lawrence and Blanche Hughes Foundation (A.T. Look), and the Boston Children's Hospital Translational Research Program (A. Gutierrez). We also acknowledge NIH grants 1S10OD010612 (J.M. Asara), 5 P01CA120964 (J.M. Asara), 1K99CA181500 (J.S. Blackburn), CA109901 (A.T. Look and R.A. Young), CA193651 (A. Gutierrez), and CA211734 (D.M. Langenau). G. Dellaire is funded by a Discovery Grant (RGPIN 05616) from the Natural Science and Engineering Research Council (NSERC).

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Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).