TOX Regulates Growth, DNA Repair, and Genomic Instability in T-cell Acute Lymphoblastic Leukemia.
TOX Regulates Growth, DNA Repair, and Genomic Instability in T-cell Acute Lymphoblastic Leukemia.
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DOI：
10.1158/2159-8290.cd-17-0267
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发表时间：
2017-11
期刊：
影响因子：
28.2
通讯作者：
Langenau DM
中科院分区：
文献类型：
--
作者：
Lobbardi R;Pinder J;Martinez-Pastor B;Theodorou M;Blackburn JS;Abraham BJ;Namiki Y;Mansour M;Abdelfattah NS;Molodtsov A;Alexe G;Toiber D;de Waard M;Jain E;Boukhali M;Lion M;Bhere D;Shah K;Gutierrez A;Stegmaier K;Silverman LB;Sadreyev RI;Asara JM;Oettinger MA;Haas W;Look AT;Young RA;Mostoslavsky R;Dellaire G;Langenau DM
T细胞急性淋巴细胞白血病（T-ALL）是一种侵袭性胸腺细胞恶性肿瘤。在斑马鱼中使用转基因筛选，发现胸腺细胞选择相关的高迁移率盒蛋白（TOX）是一种合作的致癌驱动因子，通过扩大转化克隆的起始库和提高基因组不稳定性来加速T-ALL的发作。TOX在大多数人T-ALL中高度表达，并且是小鼠中增殖和持续异种移植物生长所需的。使用广泛的功能分析，我们发现TOX直接与KU 70/80结合，并抑制该复合物对DNA断裂的募集，以抑制非同源末端连接修复（NHEJ）。众所周知，受损的NHEJ会导致基因组不稳定性，包括Ku 70和Ku 80缺陷小鼠中T细胞恶性肿瘤的发展。总的来说，我们的工作揭示了TOX在调节NHEJ中的重要作用，通过提高白血病起始期间的基因组不稳定性和维持转化后的白血病细胞增殖。
T-cell Acute Lymphoblastic Leukemia (T-ALL) is an aggressive malignancy of thymocytes. Using a transgenic screen in zebrafish, thymocyte selection-associated high mobility 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 Non-Homologous End Joining repair (NHEJ). 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.