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