Abstract
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.
Document Type
Article
Publication Date
11-2017
Digital Object Identifier (DOI)
https://doi.org/10.1158/2159-8290.CD-17-0267
Funding Information
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).
Related Content
Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).
Repository Citation
Lobbardi, Riadh; Pinder, Jordan; Martinez-Pastor, Barbara; Theodorou, Marina; Blackburn, Jessica S.; Abraham, Brian J.; Namiki, Yuka; Mansour, Marc; Abdelfattah, Nouran S.; Molodtsov, Aleksey; Alexe, Gabriela; Toiber, Debra; de Waard, Manon; Jain, Esha; Boukhali, Myriam; Lion, Mattia; Bhere, Deepak; Shah, Khalid; Gutierrez, Alejandro; Stegmaier, Kimberly; Silverman, Lewis B.; Sadreyev, Ruslan I.; Asara, John M.; Oettinger, Marjorie A.; Haas, Wilhelm; Look, A. Thomas; Young, Richard A.; Mostoslavsky, Raul; Dellaire, Graham; and Langenau, David M., "TOX Regulates Growth, DNA Repair, and Genomic Instability in T-cell Acute Lymphoblastic Leukemia" (2017). Molecular and Cellular Biochemistry Faculty Publications. 154.
https://uknowledge.uky.edu/biochem_facpub/154
Supplementary Data
180365_2_supp_4223878_ffy411.xlsx (40 kB)
Table S1
180365_2_supp_4223877_66y411.xlsx (34 kB)
Table S2
180365_2_supp_4223874_ggy411.xlsx (62 kB)
Table S3
180365_2_supp_4223875_77y411.xlsx (53 kB)
Table S4
180365_2_supp_4223879_88y411.xlsx (37 kB)
Table S5
180365_2_supp_4223876_tty411.xlsx (51 kB)
Table S6
Included in
Biochemistry, Biophysics, and Structural Biology Commons, Cancer Biology Commons, Genetics and Genomics Commons
Notes/Citation Information
Published in Cancer Discovery, v. 7, issue 11, p. 1336-1353.
© 2017 American Association for Cancer Research
The copyright holder has granted the permission for posting the article here.
The document available for download is the authors' post-peer-review final draft of the article.