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Cancer Discov. 2017 Nov;7(11):1336-1353. doi: 10.1158/2159-8290.CD-17-0267. Epub 2017 Oct 3.

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

Author information

1
Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
2
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
3
Harvard Stem Cell Institute, Cambridge, Massachusetts.
4
Departments of Pathology and Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada.
5
Beatrice Hunter Cancer Research Institute, Halifax, Nova Scotia, Canada.
6
College of Medicine, University of Kentucky, Lexington, Kentucky.
7
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts.
8
Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
9
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
10
Department of Haematology, UCL Cancer Institute, University College London, London, United Kingdom.
11
Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
12
Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.
13
Institute of Biology Leiden, University of Leiden, Leiden, the Netherlands.
14
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts.
15
Center for Stem Cell Therapeutics and Imaging, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
16
Division of Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, Massachusetts.
17
Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
18
Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts. dlangenau@mgh.harvard.edu.

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.

PMID:
28974511
PMCID:
PMC5683427
[Available on 2018-11-01]
DOI:
10.1158/2159-8290.CD-17-0267
[Indexed for MEDLINE]

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