{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T13:05:42Z","timestamp":1790859942674,"version":"4.1.0"},"reference-count":40,"publisher":"Rockefeller University Press","issue":"12","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2008,11,24]]},"abstract":"<jats:p>Mutations resulting in overexpression of intracellular Notch1 (ICN1) are frequently observed in human T cell acute lymphoblastic leukemia (T-ALL). We have determined the consequences of ICN1 overexpression from retroviral vectors introduced into bone marrow cells. Early consequences are the generation of polyclonal nontumorigenic CD4+8+ T cell receptor (TCR)-\u03b1\u03b2+ cells that do not qualify as tumor precursors despite the observation that they overexpress Notch 1 and c-Myc and degrade the tumor suppressor E2A by posttranslational modification. The first tumorigenic cells are detected among more immature CD4\u22128+TCR-\u03b1\u03b2\u2212 cells that give rise to monoclonal tumors with a single, unique TCR-\u03b2 chain and diverse TCR-\u03b1 chains, pinpointing malignant transformation to a stage after pre-TCR signaling and before completion of TCR-\u03b1 rearrangement. In T-ALL, E2A deficiency is accompanied by further transcriptional up-regulation of c-Myc and concomitant dysregulation of the c-Myc-p53 axis at the transcriptional level. Even though the tumors consist of phenotypically heterogeneous cells, no evidence for tumor stem cells was found. As judged by array-based comparative genomic hybridization (array CGH) and spectral karyotype (SKY) analysis, none of the tumors arise because of genomic instability.<\/jats:p>","DOI":"10.1084\/jem.20081561","type":"journal-article","created":{"date-parts":[[2008,11,4]],"date-time":"2008-11-04T01:58:40Z","timestamp":1225763920000},"page":"2851-2861","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":85,"title":["Oncogenesis of T-ALL and nonmalignant consequences of overexpressing intracellular NOTCH1"],"prefix":"10.1084","volume":"205","author":[{"given":"Xiaoyu","family":"Li","sequence":"first","affiliation":[{"name":"1Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fotini","family":"Gounari","sequence":"additional","affiliation":[{"name":"1Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115"},{"name":"2Department of Medicine, University of Chicago, Chicago, IL 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexei","family":"Protopopov","sequence":"additional","affiliation":[{"name":"1Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khashayarsha","family":"Khazaie","sequence":"additional","affiliation":[{"name":"1Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115"},{"name":"3Department of Microbiology-Immunology, Northwestern University, Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald","family":"von Boehmer","sequence":"additional","affiliation":[{"name":"1Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2008,11,3]]},"reference":[{"key":"2023072920082193500_BIB1","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1126\/science.284.5415.770","volume":"284","year":"1999","journal-title":"Science."},{"key":"2023072920082193500_BIB2","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1084\/jem.20070876","volume":"204","year":"2007","journal-title":"J. Exp. Med."},{"key":"2023072920082193500_BIB3","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.1084\/jem.20070872","volume":"204","year":"2007","journal-title":"J. Exp. Med."},{"key":"2023072920082193500_BIB4","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1126\/science.1102160","volume":"306","year":"2004","journal-title":"Science."},{"key":"2023072920082193500_BIB5","doi-asserted-by":"crossref","first-page":"18261","DOI":"10.1073\/pnas.0606108103","volume":"103","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072920082193500_BIB6","doi-asserted-by":"crossref","first-page":"2096","DOI":"10.1101\/gad.1450406","volume":"20","year":"2006","journal-title":"Genes Dev."},{"key":"2023072920082193500_BIB7","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/S1097-2765(00)80367-6","volume":"4","year":"1999","journal-title":"Mol. Cell."},{"key":"2023072920082193500_BIB8","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1101\/gad.10.15.1930","volume":"10","year":"1996","journal-title":"Genes Dev."},{"key":"2023072920082193500_BIB9","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1084\/jem.20060268","volume":"203","year":"2006","journal-title":"J. Exp. Med."},{"key":"2023072920082193500_BIB10","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1097\/01.moh.0000143965.90813.70","volume":"11","year":"2004","journal-title":"Curr. Opin. Hematol."},{"key":"2023072920082193500_BIB11","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/314103a0","volume":"314","year":"1985","journal-title":"Nature."},{"key":"2023072920082193500_BIB12","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1038\/315232a0","volume":"315","year":"1985","journal-title":"Nature."},{"key":"2023072920082193500_BIB13","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/0092-8674(81)90016-7","volume":"66","year":"1991","journal-title":"Cell."},{"key":"2023072920082193500_BIB14","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1038\/375795a0","volume":"375","year":"1995","journal-title":"Nature."},{"key":"2023072920082193500_BIB15","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1038\/nri1633","volume":"5","year":"2005","journal-title":"Nat. Rev. Immunol."},{"key":"2023072920082193500_BIB16","doi-asserted-by":"crossref","first-page":"4782","DOI":"10.1128\/MCB.17.8.4782","volume":"17","year":"1997","journal-title":"Mol. Cell. Biol."},{"key":"2023072920082193500_BIB17","doi-asserted-by":"crossref","first-page":"11322","DOI":"10.1073\/pnas.162373999","volume":"99","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072920082193500_BIB18","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1038\/sj.embor.7400013","volume":"4","year":"2003","journal-title":"EMBO Rep."},{"key":"2023072920082193500_BIB19","doi-asserted-by":"crossref","first-page":"5780","DOI":"10.1093\/emboj\/cdg567","volume":"22","year":"2003","journal-title":"EMBO J."},{"key":"2023072920082193500_BIB20","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/S1535-6108(03)00301-5","volume":"4","year":"2003","journal-title":"Cancer Cell."},{"key":"2023072920082193500_BIB21","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1016\/j.cell.2007.03.043","volume":"129","year":"2007","journal-title":"Cell."},{"key":"2023072920082193500_BIB22","doi-asserted-by":"crossref","first-page":"6274","DOI":"10.1073\/pnas.082005599","volume":"99","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072920082193500_BIB23","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/S1074-7613(01)00088-7","volume":"14","year":"2001","journal-title":"Immunity."},{"key":"2023072920082193500_BIB24","first-page":"235","volume":"2","year":"2001","journal-title":"Nat. Immunol."},{"key":"2023072920082193500_BIB25","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1128\/MCB.23.2.655-664.2003","volume":"23","year":"2003","journal-title":"Mol. Cell. Biol."},{"key":"2023072920082193500_BIB26","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1038\/nrm1703","volume":"6","year":"2005","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2023072920082193500_BIB27","doi-asserted-by":"crossref","first-page":"2104","DOI":"10.1182\/blood.V95.6.2104","volume":"95","year":"2000","journal-title":"Blood."},{"key":"2023072920082193500_BIB28","doi-asserted-by":"crossref","first-page":"2658","DOI":"10.1101\/gad.13.20.2658","volume":"13","year":"1999","journal-title":"Genes Dev."},{"key":"2023072920082193500_BIB29","doi-asserted-by":"crossref","first-page":"2678","DOI":"10.1101\/gad.13.20.2678","volume":"13","year":"1999","journal-title":"Genes Dev."},{"key":"2023072920082193500_BIB30","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1038\/nature05886","volume":"447","year":"2007","journal-title":"Nature."},{"key":"2023072920082193500_BIB31","doi-asserted-by":"crossref","first-page":"2797","DOI":"10.1182\/blood-2002-10-3091","volume":"101","year":"2003","journal-title":"Blood."},{"key":"2023072920082193500_BIB32","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/S1535-6108(02)00018-1","volume":"1","year":"2002","journal-title":"Cancer Cell."},{"key":"2023072920082193500_BIB33","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/S1535-6108(02)00032-6","volume":"1","year":"2002","journal-title":"Cancer Cell."},{"key":"2023072920082193500_BIB34","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1146\/annurev.immunol.15.1.433","volume":"15","year":"1997","journal-title":"Annu. Rev. Immunol."},{"key":"2023072920082193500_BIB35","doi-asserted-by":"crossref","first-page":"3788","DOI":"10.1073\/pnas.062050599","volume":"99","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072920082193500_BIB36","first-page":"305","volume":"108","year":"2006","journal-title":"Blood."},{"key":"2023072920082193500_BIB37","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1038\/ni1234","volume":"6","year":"2005","journal-title":"Nat. Immunol."},{"key":"2023072920082193500_BIB38","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1016\/S0092-8674(02)00770-5","volume":"109","year":"2002","journal-title":"Cell."},{"key":"2023072920082193500_BIB39","first-page":"1696","volume":"104","year":"2004","journal-title":"Blood."},{"key":"2023072920082193500_BIB40","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1038\/ni779","volume":"3","year":"2002","journal-title":"Nat. Immunol."}],"container-title":["The Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/205\/12\/2851\/1909735\/jem_20081561.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/205\/12\/2851\/1909735\/jem_20081561.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,29]],"date-time":"2023-07-29T20:08:48Z","timestamp":1690661328000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/205\/12\/2851\/47125\/Oncogenesis-of-T-ALL-and-nonmalignant-consequences"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,11,3]]},"references-count":40,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2008,11,24]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.20081561","relation":{},"ISSN":["1540-9538","0022-1007"],"issn-type":[{"value":"1540-9538","type":"electronic"},{"value":"0022-1007","type":"print"}],"subject":[],"published":{"date-parts":[[2008,11,3]]}}}