{"doi":"10.1158/2159-8290.cd-17-0267","title":"TOX Regulates Growth, DNA Repair, and Genomic Instability in T-cell Acute Lymphoblastic Leukemia","abstract":"<jats:title>Abstract</jats:title>\n                  <jats:p>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.</jats:p>\n                  <jats:p>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.</jats:p>\n                  <jats:p>This article is highlighted in the In This Issue feature, p. 1201</jats:p>","journal":"Cancer Discovery","year":2017,"id":657339,"datarank":2.766423318355857,"base_score":4.248495242049359,"endowment":4.248495242049359,"self_citation_contribution":0.637274286307404,"citation_network_contribution":2.1291490320484527,"self_endowment_contribution":0.637274286307404,"citer_contribution":2.1291490320484527,"corpus_percentile":null,"corpus_rank":null,"citation_count":69,"citer_count":64,"citers_with_citation_signal":56,"citers_with_endowment":56,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1715976,"name":"Jordan Pinder","orcid":null,"position":1,"is_corresponding":false},{"id":1715977,"name":"Barbara Martinez-Pastor","orcid":null,"position":2,"is_corresponding":false},{"id":1270848,"name":"Marina Theodorou","orcid":null,"position":3,"is_corresponding":false},{"id":451605,"name":"Jessica S. 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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.</jats:p>\n                  <jats:p>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.</jats:p>\n                  <jats:p>This article is highlighted in the In This Issue feature, p. 1201</jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"28974511","pmcid":"PMC5683427","openalex_id":null,"authors":[],"funders":[{"funder_name":"NCI NIH HHS","grant_id":"R01 CA193651","title":null},{"funder_name":"NIH HHS","grant_id":"S10 OD010612","title":null},{"funder_name":"NCI NIH HHS","grant_id":"K99 CA181500","title":null},{"funder_name":"NCI NIH HHS","grant_id":"P01 CA120964","title":null},{"funder_name":"NCI NIH HHS","grant_id":"R00 CA181500","title":null},{"funder_name":"NCI NIH HHS","grant_id":"DP2 CA228043","title":null},{"funder_name":"NCI NIH HHS","grant_id":"R01 CA211734","title":null},{"funder_name":"NCI NIH HHS","grant_id":"P01 CA109901","title":null}],"total_grants":8,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"bronze","license":null,"oa_locations":[{"url":"https://cancerdiscovery.aacrjournals.org/content/candisc/7/11/1336.full.pdf","host_type":"publisher"},{"url":"https://aacrjournals.org/cancerdiscovery/article-pdf/7/11/1336/1838320/1336.pdf","host_type":"publisher"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/5683427","host_type":"repository"}],"fields_of_study":[],"mesh_terms":["T-Lymphocytes","Animals","Animals, Genetically Modified","Zebrafish","Humans","Mice","Genomic Instability","HMGB Proteins","Transcription Factors","Xenograft Model Antitumor Assays","Cell Proliferation","Precursor T-Cell Lymphoblastic Leukemia-Lymphoma","DNA End-Joining Repair","Ku Autoantigen"],"keywords":[],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-12T00:43:06.182500Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}