RT Journal Article SR Electronic T1 TOX Regulates Growth, DNA Repair, and Genomic Instability in T-cell Acute Lymphoblastic Leukemia JF Cancer Discovery JO Cancer Discov FD American Association for Cancer Research SP 1336 OP 1353 DO 10.1158/2159-8290.CD-17-0267 VO 7 IS 11 A1 Lobbardi, Riadh A1 Pinder, Jordan A1 Martinez-Pastor, Barbara A1 Theodorou, Marina A1 Blackburn, Jessica S. A1 Abraham, Brian J. A1 Namiki, Yuka A1 Mansour, Marc A1 Abdelfattah, Nouran S. A1 Molodtsov, Aleksey A1 Alexe, Gabriela A1 Toiber, Debra A1 de Waard, Manon A1 Jain, Esha A1 Boukhali, Myriam A1 Lion, Mattia A1 Bhere, Deepak A1 Shah, Khalid A1 Gutierrez, Alejandro A1 Stegmaier, Kimberly A1 Silverman, Lewis B. A1 Sadreyev, Ruslan I. A1 Asara, John M. A1 Oettinger, Marjorie A. A1 Haas, Wilhelm A1 Look, A. Thomas A1 Young, Richard A. A1 Mostoslavsky, Raul A1 Dellaire, Graham A1 Langenau, David M. YR 2017 UL http://cancerdiscovery.aacrjournals.org/content/7/11/1336.abstract AB 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. Cancer Discov; 7(11); 1336–53. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1201