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

• Published in: Cancer discovery Vol. 7; no. 11; pp. 1336 - 1353
• Main Authors: Lobbardi, Riadh, Pinder, Jordan, Martinez-Pastor, Barbara, Theodorou, Marina, Blackburn, Jessica S, Abraham, Brian J, Namiki, Yuka, Mansour, Marc, Abdelfattah, Nouran S, Molodtsov, Aleksey, Alexe, Gabriela, Toiber, Debra, de Waard, Manon, Jain, Esha, Boukhali, Myriam, Lion, Mattia, Bhere, Deepak, Shah, Khalid, Gutierrez, Alejandro, Stegmaier, Kimberly, Silverman, Lewis B, Sadreyev, Ruslan I, Asara, John M, Oettinger, Marjorie A, Haas, Wilhelm, Look, A Thomas, Young, Richard A, Mostoslavsky, Raul, Dellaire, Graham, Langenau, David M
• Format: Journal Article
• Language: English
• Published: United States 01.11.2017
• Subjects: 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
• ISSN: 2159-8274; 2159-8290
• DOI: 10.1158/2159-8290.CD-17-0267

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. 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. .