{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T16:44:45Z","timestamp":1791305085111,"version":"4.3.1"},"reference-count":31,"publisher":"National Academy of Sciences","issue":"38","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2010,9,21]]},"abstract":"<jats:p>The Notch signaling pathway plays an important role in cellular proliferation, differentiation, and apoptosis. Unregulated activation of Notch signaling can result in excessive cellular proliferation and cancer. Human T-cell leukemia virus type 1 (HTLV-I) is the etiological agent of adult T-cell leukemia (ATL). The disease has a dismal prognosis and is invariably fatal. In this study, we report a high frequency of constitutively activated Notch in ATL patients. We found activating mutations in Notch in more than 30% of ATL patients. These activating mutations are phenotypically different from those previously reported in T-ALL leukemias and may represent polymorphisms for activated Notch in human cancers. Compared with the exclusive activating frameshift mutations in the proline, glutamic acid, serine, and threonine (PEST) domain in T-ALLs, those in ATLs have, in addition, single-substitution mutations in this domain leading to reduced CDC4\/Fbw7-mediated degradation and stabilization of the intracellular cleaved form of Notch1 (ICN1). Finally, we demonstrated that inhibition of Notch signaling by \u03b3-secretase inhibitors reduced tumor cell proliferation and tumor formation in ATL-engrafted mice. These data suggest that activated Notch may be important to ATL pathogenesis and reveal Notch1 as a target for therapeutic intervention in ATL patients.<\/jats:p>","DOI":"10.1073\/pnas.1010722107","type":"journal-article","created":{"date-parts":[[2010,9,7]],"date-time":"2010-09-07T22:21:32Z","timestamp":1283898092000},"page":"16619-16624","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":88,"title":["Notch signaling contributes to proliferation and tumor formation of human T-cell leukemia virus type 1\u2013associated adult T-cell leukemia"],"prefix":"10.1073","volume":"107","author":[{"given":"Joanna","family":"Pancewicz","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Kansas Medical Center, Kansas City, KS 66160;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Taylor","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Kansas Medical Center, Kansas City, KS 66160;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhik","family":"Datta","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Kansas Medical Center, Kansas City, KS 66160;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hicham H.","family":"Baydoun","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Kansas Medical Center, Kansas City, KS 66160;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas A.","family":"Waldmann","sequence":"additional","affiliation":[{"name":"Metabolism Branch, National Institutes of Health, Bethesda, MD 20892; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Hermine","sequence":"additional","affiliation":[{"name":"Unit\u00e9 Mixte de Recherche 8603, Necker Hospital, Centre National de la Recherche Scientifique, 75743 Paris Cedex 15, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Nicot","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Kansas Medical Center, Kansas City, KS 66160;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2010,9,7]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2008.229"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.284.5415.770"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/377355a0"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri2304"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1880"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M101343200"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.4161\/cc.4.10.2058"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1102160"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.77.12.7415"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.81.8.2534"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.7604283"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1208783"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2290"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1210766"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.24.21.9265-9273.2004"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20070876"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.4161\/cbt.1.4.2"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-02-0514"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/82644"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1636"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.162.6.2169"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI35090"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-02-136762"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.22972"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.1900"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-08-039883"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-07-102632"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.18.2428"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-12-4956"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-05-2832"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm984"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1010722107","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T20:15:05Z","timestamp":1649794505000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1010722107"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,9,7]]},"references-count":31,"journal-issue":{"issue":"38","published-print":{"date-parts":[[2010,9,21]]}},"alternative-id":["10.1073\/pnas.1010722107"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1010722107","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.5331956.5281054","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,9,7]]},"assertion":[{"value":"2010-09-07","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}