{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:58:27Z","timestamp":1791928707934,"version":"4.3.4"},"reference-count":39,"publisher":"Rockefeller University Press","issue":"10","license":[{"start":{"date-parts":[[2019,9,19]],"date-time":"2019-09-19T00:00:00Z","timestamp":1568851200000},"content-version":"vor","delay-in-days":759,"URL":"http:\/\/www.rupress.org\/terms\/"},{"start":{"date-parts":[[2018,4,2]],"date-time":"2018-04-02T00:00:00Z","timestamp":1522627200000},"content-version":"vor","delay-in-days":224,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","award":["15H02544"],"award-info":[{"award-number":["15H02544"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","award":["25115002"],"award-info":[{"award-number":["25115002"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008732","name":"Uehara Memorial Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008732","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008673","name":"Yasuda Memorial Medical Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008673","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011313","name":"Tokyo Biochemical Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011313","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2017,10,2]]},"abstract":"<jats:p>Recurrent inactivating mutations have been identified in various hematological malignancies in the X-linked BCOR gene encoding BCL6 corepressor (BCOR); however, its tumor suppressor function remains largely uncharacterized. We generated mice missing Bcor exon 4, expressing a variant BCOR lacking the BCL6-binding domain. Although the deletion of exon 4 in male mice (Bcor\u0394E4\/y) compromised the repopulating capacity of hematopoietic stem cells, Bcor\u0394E4\/y thymocytes had augmented proliferative capacity in culture and showed a strong propensity to induce acute T-cell lymphoblastic leukemia (T-ALL), mostly in a Notch-dependent manner. Myc, one of the critical NOTCH1 targets in T-ALL, was highly up-regulated in Bcor\u0394E4\/y T-ALL cells. Chromatin immunoprecipitation\/DNA sequencing analysis revealed that BCOR was recruited to the Myc promoter and restrained its activation in thymocytes. BCOR also targeted other NOTCH1 targets and potentially antagonized their transcriptional activation. Bcl6-deficient thymocytes behaved in a manner similar to Bcor\u0394E4\/y thymocytes. Our results provide the first evidence of a tumor suppressor role for BCOR in the pathogenesis of T lymphocyte malignancies.<\/jats:p>","DOI":"10.1084\/jem.20170167","type":"journal-article","created":{"date-parts":[[2017,8,21]],"date-time":"2017-08-21T10:10:11Z","timestamp":1503310211000},"page":"2901-2913","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":51,"title":["Internal deletion of BCOR reveals a tumor suppressor function for BCOR in T lymphocyte malignancies"],"prefix":"10.1084","volume":"214","author":[{"given":"Tomoyuki","family":"Tanaka","sequence":"first","affiliation":[{"name":"Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan 1"},{"name":"Department of Hematology, Endocrinology and Metabolism, Niigata University, Niigata, Japan 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaeko","family":"Nakajima-Takagi","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2136-4562","authenticated-orcid":true,"given":"Kazumasa","family":"Aoyama","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiro","family":"Tara","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan 1"},{"name":"Department of Hematology, Kumamoto University, Kumamoto, Japan 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3963-0013","authenticated-orcid":true,"given":"Motohiko","family":"Oshima","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsunori","family":"Saraya","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuhei","family":"Koide","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sha","family":"Si","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ichiro","family":"Manabe","sequence":"additional","affiliation":[{"name":"Department of Disease Biology and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masashi","family":"Sanada","sequence":"additional","affiliation":[{"name":"Department of Advanced Diagnosis, Clinical Research Center, Nagoya Medical Center, Nagoya, Japan 6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manabu","family":"Nakayama","sequence":"additional","affiliation":[{"name":"Chromosome Engineering Team, Department of Technology Development, Kazusa DNA Research Institute, Chiba, Japan 7"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayoshi","family":"Masuko","sequence":"additional","affiliation":[{"name":"Division of Stem Cell Transplantation, Niigata University Medical and Dental Hospital, Niigata, Japan 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirohito","family":"Sone","sequence":"additional","affiliation":[{"name":"Department of Hematology, Endocrinology and Metabolism, Niigata University, Niigata, Japan 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8424-5854","authenticated-orcid":true,"given":"Haruhiko","family":"Koseki","sequence":"additional","affiliation":[{"name":"Laboratory for Developmental Genetics, RIKEN Research Center for Integrative Medical Sciences, Yokohama, Japan 8"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9410-8992","authenticated-orcid":true,"given":"Atsushi","family":"Iwama","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2017,8,21]]},"reference":[{"key":"2023072603285550100_bib1","doi-asserted-by":"publisher","first-page":"5455","DOI":"10.1182\/blood-2010-05-286328","article-title":"Deletion-based mechanisms of Notch1 activation in T-ALL: Key roles for RAG recombinase and a conserved internal translational start site in Notch1","volume":"116","author":"Ashworth","year":"2010","journal-title":"Blood."},{"key":"2023072603285550100_bib2","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/j.ccell.2016.07.006","article-title":"EZH2 and BCL6 cooperate to assemble CBX8-BCOR complex to repress bivalent promoters, mediate germinal center formation and lymphomagenesis","volume":"30","author":"B\u00e9guelin","year":"2016","journal-title":"Cancer Cell."},{"key":"2023072603285550100_bib3","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1038\/nrc.2016.63","article-title":"The genetics and mechanisms of T cell acute lymphoblastic leukaemia","volume":"16","author":"Belver","year":"2016","journal-title":"Nat. Rev. Cancer."},{"key":"2023072603285550100_bib4","doi-asserted-by":"publisher","first-page":"1155","DOI":"10.1038\/leu.2016.2","article-title":"BCOR regulates myeloid cell proliferation and differentiation","volume":"30","author":"Cao","year":"2016","journal-title":"Leukemia."},{"key":"2023072603285550100_bib5","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1016\/S0092-8674(03)00567-1","article-title":"H2AX haploinsufficiency modifies genomic stability and tumor susceptibility","volume":"114","author":"Celeste","year":"2003","journal-title":"Cell."},{"key":"2023072603285550100_bib6","doi-asserted-by":"publisher","first-page":"3169","DOI":"10.1182\/blood-2012-11-469619","article-title":"BCOR and BCORL1 mutations in myelodysplastic syndromes and related disorders","volume":"122","author":"Damm","year":"2013","journal-title":"Blood."},{"key":"2023072603285550100_bib7","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1002\/gcc.22348","article-title":"Frequent BCOR aberrations in extranodal NK\/T-cell lymphoma, nasal type","volume":"55","author":"Dobashi","year":"2016","journal-title":"Genes Chromosomes Cancer."},{"key":"2023072603285550100_bib8","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1038\/356215a0","article-title":"Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours","volume":"356","author":"Donehower","year":"1992","journal-title":"Nature."},{"key":"2023072603285550100_bib9","doi-asserted-by":"publisher","first-page":"1002","DOI":"10.1038\/ncb1913","article-title":"BCOR regulates mesenchymal stem cell function by epigenetic mechanisms","volume":"11","author":"Fan","year":"2009","journal-title":"Nat. Cell Biol."},{"key":"2023072603285550100_bib10","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1016\/j.molcel.2012.01.002","article-title":"PCGF homologs, CBX proteins, and RYBP define functionally distinct PRC1 family complexes","volume":"45","author":"Gao","year":"2012","journal-title":"Mol. Cell."},{"key":"2023072603285550100_bib11","doi-asserted-by":"publisher","first-page":"6880","DOI":"10.1128\/MCB.00630-06","article-title":"Polycomb group and SCF ubiquitin ligases are found in a novel BCOR complex that is recruited to BCL6 targets","volume":"26","author":"Gearhart","year":"2006","journal-title":"Mol. Cell. Biol."},{"key":"2023072603285550100_bib12","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1016\/j.molcel.2007.12.026","article-title":"Structure of a BCOR corepressor peptide in complex with the BCL6 BTB domain dimer","volume":"29","author":"Ghetu","year":"2008","journal-title":"Mol. Cell."},{"key":"2023072603285550100_bib13","doi-asserted-by":"publisher","first-page":"6153","DOI":"10.1182\/blood-2011-07-365320","article-title":"Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype","volume":"118","author":"Grossmann","year":"2011","journal-title":"Blood."},{"key":"2023072603285550100_bib14","doi-asserted-by":"publisher","first-page":"1182","DOI":"10.1038\/nm.3955","article-title":"Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in T cell acute lymphoblastic leukemia","volume":"21","author":"Herranz","year":"2015","journal-title":"Nat. Med."},{"key":"2023072603285550100_bib15","doi-asserted-by":"crossref","first-page":"1810","DOI":"10.1101\/gad.14.14.1810","article-title":"BCoR, a novel corepressor involved in BCL-6 repression","volume":"14","author":"Huynh","year":"2000","journal-title":"Genes Dev."},{"key":"2023072603285550100_bib16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0960-9822(00)00002-6","article-title":"Tumor spectrum analysis in p53-mutant mice","volume":"4","author":"Jacks","year":"1994","journal-title":"Curr. Biol."},{"key":"2023072603285550100_bib17","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1038\/ng747","article-title":"Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer","volume":"29","author":"Jonkers","year":"2001","journal-title":"Nat. Genet."},{"key":"2023072603285550100_bib18","doi-asserted-by":"publisher","first-page":"2079","DOI":"10.1084\/jem.20120127","article-title":"Distinct cellular pathways select germline-encoded and somatically mutated antibodies into immunological memory","volume":"209","author":"Kaji","year":"2012","journal-title":"J. Exp. Med."},{"key":"2023072603285550100_bib19","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1038\/nrurol.2015.160","article-title":"Kidney cancer: BCOR mutations that might help in diagnosis of CCSK","volume":"12","author":"Kelsey","year":"2015","journal-title":"Nat. Rev. Urol."},{"key":"2023072603285550100_bib20","doi-asserted-by":"publisher","first-page":"1460","DOI":"10.1182\/blood-2014-03-559542","article-title":"Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia","volume":"124","author":"Kiel","year":"2014","journal-title":"Blood."},{"key":"2023072603285550100_bib21","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1038\/nri2217","article-title":"Germinal centres: Role in B-cell physiology and malignancy","volume":"8","author":"Klein","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"2023072603285550100_bib22","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1038\/nature15395","article-title":"Mutations driving CLL and their evolution in progression and relapse","volume":"526","author":"Landau","year":"2015","journal-title":"Nature."},{"key":"2023072603285550100_bib23","doi-asserted-by":"publisher","first-page":"17764","DOI":"10.18632\/oncotarget.3776","article-title":"Genetic alterations of JAK\/STAT cascade and histone modification in extranodal NK\/T-cell lymphoma nasal type","volume":"6","author":"Lee","year":"2015","journal-title":"Oncotarget."},{"key":"2023072603285550100_bib24","doi-asserted-by":"publisher","first-page":"14581","DOI":"10.1038\/ncomms14581","article-title":"Genomic characterisation of E\u03bc-Myc mouse lymphomas identifies Bcor as a Myc co-operative tumour-suppressor gene","volume":"8","author":"Lefebure","year":"2017","journal-title":"Nat. Commun."},{"key":"2023072603285550100_bib25","doi-asserted-by":"publisher","first-page":"5914","DOI":"10.1182\/blood-2011-05-356204","article-title":"Somatic mutations in the transcriptional corepressor gene BCORL1 in adult acute myelogenous leukemia","volume":"118","author":"Li","year":"2011","journal-title":"Blood."},{"key":"2023072603285550100_bib26","doi-asserted-by":"publisher","first-page":"1367","DOI":"10.1182\/blood-2014-11-610543","article-title":"Acute myeloid leukemia ontogeny is defined by distinct somatic mutations","volume":"125","author":"Lindsley","year":"2015","journal-title":"Blood."},{"key":"2023072603285550100_bib27","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1182\/blood-2014-08-594648","article-title":"Dnmt3a loss predisposes murine hematopoietic stem cells to malignant transformation","volume":"125","author":"Mayle","year":"2015","journal-title":"Blood."},{"key":"2023072603285550100_bib28","doi-asserted-by":"publisher","first-page":"4174","DOI":"10.1182\/blood-2011-01-331181","article-title":"Pre-B cell receptor-mediated activation of BCL6 induces pre-B cell quiescence through transcriptional repression of MYC","volume":"118","author":"Nahar","year":"2011","journal-title":"Blood."},{"key":"2023072603285550100_bib29","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1038\/ng1321","article-title":"Oculofaciocardiodental and Lenz microphthalmia syndromes result from distinct classes of mutations in BCOR","volume":"36","author":"Ng","year":"2004","journal-title":"Nat. Genet."},{"key":"2023072603285550100_bib30","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1038\/nm.2651","article-title":"Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia","volume":"18","author":"Ntziachristos","year":"2012","journal-title":"Nat. Med."},{"key":"2023072603285550100_bib31","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1038\/ng.1107","article-title":"A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion","volume":"44","author":"Pierron","year":"2012","journal-title":"Nat. Genet."},{"key":"2023072603285550100_bib32","doi-asserted-by":"publisher","first-page":"820","DOI":"10.1074\/mcp.M600275-MCP200","article-title":"Proteomics analysis of Ring1B\/Rnf2 interactors identifies a novel complex with the Fbxl10\/Jhdm1B histone demethylase and the Bcl6 interacting corepressor","volume":"6","author":"S\u00e1nchez","year":"2007","journal-title":"Mol. Cell. Proteomics."},{"key":"2023072603285550100_bib33","doi-asserted-by":"publisher","first-page":"1274","DOI":"10.1038\/ng.3900","article-title":"Recurrent PU.1 (SPI1) fusions in high-risk pediatric T cell acute lymphoblastic leukemia","volume":"49","author":"Seki","year":"2017","journal-title":"Nat. Genet."},{"key":"2023072603285550100_bib34","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1002\/gcc.22313","article-title":"Genetic characterization of T-PLL reveals two major biologic subgroups and JAK3 mutations as prognostic marker","volume":"55","author":"Stengel","year":"2016","journal-title":"Genes Chromosomes Cancer."},{"key":"2023072603285550100_bib35","doi-asserted-by":"publisher","first-page":"E4946","DOI":"10.1073\/pnas.1407079111","article-title":"Long-range enhancer activity determines Myc sensitivity to Notch inhibitors in T cell leukemia","volume":"111","author":"Yashiro-Ohtani","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072603285550100_bib36","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1016\/S0008-6363(99)00007-3","article-title":"The role of Bcl6 in mature cardiac myocytes","volume":"42","author":"Yoshida","year":"1999","journal-title":"Cardiovasc. Res."},{"key":"2023072603285550100_bib37","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1056\/NEJMoa1414799","article-title":"Somatic mutations and clonal hematopoiesis in aplastic anemia","volume":"373","author":"Yoshizato","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"2023072603285550100_bib38","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/nature10733","article-title":"A novel retinoblastoma therapy from genomic and epigenetic analyses","volume":"481","author":"Zhang","year":"2012","journal-title":"Nature."},{"key":"2023072603285550100_bib39","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1038\/nature10725","article-title":"The genetic basis of early T-cell precursor acute lymphoblastic leukaemia","volume":"481","author":"Zhang","year":"2012","journal-title":"Nature."}],"container-title":["Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/214\/10\/2901\/1755720\/jem_20170167.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/214\/10\/2901\/1755720\/jem_20170167.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T23:29:32Z","timestamp":1690327772000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/214\/10\/2901\/42266\/Internal-deletion-of-BCOR-reveals-a-tumor"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,8,21]]},"references-count":39,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2017,10,2]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.20170167","relation":{},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,8,21]]}}}