TOX Regulates Growth, DNA Repair, and Genomic Instability in T-cell Acute Lymphoblastic Leukemia.

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.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.

DOI: 10.1158/2159-8290.CD-17-0267

Cite this paper

@article{Lobbardi2017TOXRG, title={TOX Regulates Growth, DNA Repair, and Genomic Instability in T-cell Acute Lymphoblastic Leukemia.}, author={Riadh Lobbardi and Jordan B. Pinder and B{\'a}rbara Mart{\'i}nez-Pastor and Marina Theodorou and Jessica S. Blackburn and Brian J Abraham and Yuka Namiki and Marc R. Mansour and Nouran S. Abdelfattah and Aleksey Molodtsov and Gabriela Alexe and Debra Toiber and Manon de Waard and Esha Jain and Myriam Boukhali and Mattia Lion and Deepak Bhere and Khalid Shah and Alejandro Gutierrez and Kimberly Stegmaier and Lewis B. Silverman and Ruslan I Sadreyev and John M. Asara and Marjorie A. Oettinger and W. Bas de Haas and A Thomas Look and Richard A. Young and Raul Mostoslavsky and Graham Dellaire and David M Langenau}, journal={Cancer discovery}, year={2017}, volume={7 11}, pages={1336-1353} }