PUBLICATION
TOX regulates growth, DNA repair, and genomic instability in T-cell Acute Lymphoblastic Leukemia
- Authors
- 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.
- ID
- ZDB-PUB-171005-9
- 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, Genetically Modified
- HMGB Proteins/genetics*
- Zebrafish/genetics
- T-Lymphocytes/pathology
- Mice
- Animals
- Ku Autoantigen/genetics
- Xenograft Model Antitumor Assays
- Transcription Factors/genetics*
- Cell Proliferation/genetics
- DNA End-Joining Repair/genetics*
- Genomic Instability/genetics*
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics*
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology
- Humans
- PubMed
- 28974511 Full text @ Cancer Discov
Citation
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. (2017) TOX regulates growth, DNA repair, and genomic instability in T-cell Acute Lymphoblastic Leukemia. Cancer discovery. 7(11):1336-1353.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping