ZFIN ID: ZDB-PUB-171005-9
TOX regulates growth, DNA repair, and genomic instability in T-cell Acute Lymphoblastic Leukemia
Lobbardi, R., Pinder, J., Martinez-Pastor, B., Theodorou, M., Blackburn, J.S., Abraham, B.J., Namiki, Y., Mansour, M., Abdelfattah, N.S., Molodtsov, A., Alexe, G., Toiber, D., de Waard, M., Jain, E., Boukhali, M., Lion, M., Bhere, D., Shah, K., Gutierrez, A., Stegmaier, K., Silverman, L.B., Sadreyev, R.I., Asara, J.M., Oettinger, M.A., Haas, W., Look, A.T., Young, R.A., Mostoslavsky, R., Dellaire, G., Langenau, D.M.
Date: 2017
Source: Cancer discovery   7(11): 1336-1353 (Journal)
Registered Authors: Gutierrez, Alejandro, Langenau, David, Look, A. Thomas, Mansour, Marc
Keywords: none
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Cell Proliferation/genetics
  • DNA End-Joining Repair/genetics*
  • Genomic Instability/genetics*
  • HMGB Proteins/genetics*
  • Humans
  • Ku Autoantigen/genetics
  • Mice
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology
  • T-Lymphocytes/pathology
  • Transcription Factors/genetics*
  • Xenograft Model Antitumor Assays
  • Zebrafish/genetics
PubMed: 28974511 Full text @ Cancer Discov
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.
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