{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T21:22:26Z","timestamp":1790976146471,"version":"4.1.0"},"reference-count":22,"publisher":"American Society of Hematology","issue":"6","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2006,3,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>NOTCH1 is frequently mutated in human precursor T-cell lymphoblastic leukemia\/lymphoma (pre-T LBL). In the current study, we found that 13 of 19 cell lines and 29 of 49 primary tumors from SCL\/LMO1, OLIG2\/LMO1, OLIG2, LMO1, NUP98\/HOXD13, and p27-\/-\/SMAD3+\/- mice had Notch1 mutations in either the heterodimerization (HD) or the glutamic acid\/serine\/threonine (PEST) domain but not both. Thymocytes from clinically healthy SCL\/LMO1 mice aged 5 weeks did not have Notch1 mutations, whereas thymocytes from clinically healthy SCL\/LMO1 mice aged 8 to 12 weeks did have Notch1 mutations and formed tumors upon transplantation into nude mice. Remarkably, all of the HD domain mutations that we identified were single-base substitutions, whereas all of the PEST domain mutations were insertions or deletions, half of which mapped to 1 of 2 mutational \u201chot spots.\u201d Taken together, these findings indicate that Notch1 mutations are very frequent events that are acquired relatively early in the process of leukemic transformation and are important for leukemic cell growth. (Blood. 2006;107: 2540-2543)<\/jats:p>","DOI":"10.1182\/blood-2005-07-3013","type":"journal-article","created":{"date-parts":[[2005,11,11]],"date-time":"2005-11-11T01:24:39Z","timestamp":1131672279000},"page":"2540-2543","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":107,"title":["Notch1 mutations are important for leukemic transformation in murine models of precursor-T leukemia\/lymphoma"],"prefix":"10.1182","volume":"107","author":[{"given":"Ying-Wei","family":"Lin","sequence":"first","affiliation":[{"name":"From the Genetics Branch and Laboratory for Cell Regulation and Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca A.","family":"Nichols","sequence":"additional","affiliation":[{"name":"From the Genetics Branch and Laboratory for Cell Regulation and Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J.","family":"Letterio","sequence":"additional","affiliation":[{"name":"From the Genetics Branch and Laboratory for Cell Regulation and Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter D.","family":"Aplan","sequence":"additional","affiliation":[{"name":"From the Genetics Branch and Laboratory for Cell Regulation and Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"key":"2019111711373275000_REF1","doi-asserted-by":"crossref","unstructured":"Ellisen LW, Bird J, West DC, et al. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell.1991;66: 649-661.","DOI":"10.1016\/0092-8674(91)90111-B"},{"key":"2019111711373275000_","doi-asserted-by":"crossref","unstructured":"Hadland BK, Huppert SS, Kanungo J, et al. A requirement for Notch1 distinguishes 2 phases of definitive hematopoiesis during development. Blood.2004;104: 3097-3105.","DOI":"10.1182\/blood-2004-03-1224"},{"key":"2019111711373275000_","doi-asserted-by":"crossref","unstructured":"Pui JC, Allman D, Xu L, et al. Notch1 expression in early lymphopoiesis influences B versus T lineage determination. Immunity.1999;11: 299-308.","DOI":"10.1016\/S1074-7613(00)80105-3"},{"key":"2019111711373275000_REF4","doi-asserted-by":"crossref","unstructured":"Radtke F, Wilson A, Mancini SJ, MacDonald HR. Notch regulation of lymphocyte development and function. Nat Immunol.2004;5: 247-253.","DOI":"10.1038\/ni1045"},{"key":"2019111711373275000_REF5","doi-asserted-by":"crossref","unstructured":"Aster JC, Xu L, Karnell FG, Patriub V, Pui JC, Pear WS. Essential roles for ankyrin repeat and transactivation domains in induction of T-cell leukemia by notch1. Mol Cell Biol.2000;20: 7505-7515.","DOI":"10.1128\/MCB.20.20.7505-7515.2000"},{"key":"2019111711373275000_REF6","doi-asserted-by":"crossref","unstructured":"Weng AP, Ferrando AA, Lee W, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science.2004;306: 269-271.","DOI":"10.1126\/science.1102160"},{"key":"2019111711373275000_REF7","doi-asserted-by":"crossref","unstructured":"Aplan PD, Jones CA, Chervinsky DS, et al. An scl gene product lacking the transactivation domain induces bony abnormalities and cooperates with LMO1 to generate T-cell malignancies in transgenic mice. EMBO J.1997;16: 2408-2419.","DOI":"10.1093\/emboj\/16.9.2408"},{"key":"2019111711373275000_REF8","doi-asserted-by":"crossref","unstructured":"Lin YW, Deveney R, Barbara M, et al. Olig2 (NHLHB1), a HLH transcription factor, contributes to leukemogenesis in concert with LMO1. Cancer Res.2005;65: 7151-7158.","DOI":"10.1158\/0008-5472.CAN-05-1400"},{"key":"2019111711373275000_REF9","doi-asserted-by":"crossref","unstructured":"McGuire EA, Rintoul CE, Sclar GM, Korsmeyer SJ. Thymic overexpression of Ttg-1 in transgenic mice results in T-cell acute lymphoblastic leukemia\/lymphoma. Mol Cell Biol.1992;12: 4186-4196.","DOI":"10.1128\/MCB.12.9.4186"},{"key":"2019111711373275000_REF10","doi-asserted-by":"crossref","unstructured":"Lin YW, Slape C, Zhang Z, Aplan PD. NUP98-HOXD13 transgenic mice develop a highly penetrant, severe myelodysplastic syndrome that progresses to acute leukemia. Blood.2005;106: 287-295.","DOI":"10.1182\/blood-2004-12-4794"},{"key":"2019111711373275000_REF11","doi-asserted-by":"crossref","unstructured":"Wolfraim LA, Walz TM, James Z, Fernandez T, Letterio JJ. p21Cip1 and p27Kip1 act in synergy to alter the sensitivity of naive T cells to TGF-beta-mediated G1 arrest through modulation of IL-2 responsiveness. J Immunol.2004;173: 3093-3102.","DOI":"10.4049\/jimmunol.173.5.3093"},{"key":"2019111711373275000_REF12","doi-asserted-by":"crossref","unstructured":"Ferrando AA, Neuberg DS, Dodge RK, et al. Prognostic importance of TLX1 (HOX11) oncogene expression in adults with T-cell acute lymphoblastic leukaemia. Lancet.2004;363: 535-536.","DOI":"10.1016\/S0140-6736(04)15542-6"},{"key":"2019111711373275000_REF13","doi-asserted-by":"crossref","unstructured":"Aplan PD, Nakahara K, Orkin SH, Kirsch IR. The SCL gene product: a positive regulator of erythroid differentiation. EMBO J.1992;11: 4073-4081.","DOI":"10.1002\/j.1460-2075.1992.tb05500.x"},{"key":"2019111711373275000_REF14","doi-asserted-by":"crossref","unstructured":"Tonon G, Modi S, Wu L, et al. t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway. Nat Genet.2003;33: 208-213.","DOI":"10.1038\/ng1083"},{"key":"2019111711373275000_REF15","doi-asserted-by":"crossref","unstructured":"Hitoshi S, Alexson T, Tropepe V, et al. Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells. Genes Dev.2002;16: 846-858.","DOI":"10.1101\/gad.975202"},{"key":"2019111711373275000_REF16","doi-asserted-by":"crossref","unstructured":"Chervinsky DS, Lam DH, Zhao XF, Melman MP, Aplan PD. Development and characterization of T cell leukemia cell lines established from SCL\/LMO1 double transgenic mice. Leukemia.2001;15: 141-147.","DOI":"10.1038\/sj.leu.2401997"},{"key":"2019111711373275000_REF17","doi-asserted-by":"crossref","unstructured":"Chervinsky DS, Zhao XF, Lam DH, Ellsworth M, Gross KW, Aplan PD. Disordered T-cell development and T-cell malignancies in SCL LMO1 double-transgenic mice: parallels with E2A-deficient mice. Mol Cell Biol.1999;19: 5025-5035.","DOI":"10.1128\/MCB.19.7.5025"},{"key":"2019111711373275000_REF18","unstructured":"Chervinsky DS, Lam DH, Melman MP, Gross KW, Aplan PD. scid thymocytes with TCRbeta gene rearrangements are targets for the oncogenic effect of SCL and LMO1 transgenes. Cancer Res.2001;61: 6382-6387."},{"key":"2019111711373275000_REF19","doi-asserted-by":"crossref","unstructured":"Harfe BD, Jinks-Robertson S. DNA mismatch repair and genetic instability. Annu Rev Genet.2000;34: 359-399.","DOI":"10.1146\/annurev.genet.34.1.359"},{"key":"2019111711373275000_","doi-asserted-by":"crossref","unstructured":"Denver DR, Morris K, Lynch M, Thomas WK. High mutation rate and predominance of insertions in the Caenorhabditis elegans nuclear genome. Nature.2004;430: 679-682.","DOI":"10.1038\/nature02697"},{"key":"2019111711373275000_REF21","doi-asserted-by":"crossref","unstructured":"Rosenberg SM, Hastings PJ. Genomes: worming into genetic instability. Nature.2004;430: 625-626.","DOI":"10.1038\/430625a"},{"key":"2019111711373275000_REF22","doi-asserted-by":"crossref","unstructured":"Herblot S, Steff AM, Hugo P, Aplan PD, Hoang T. SCL and LMO1 alter thymocyte differentiation: inhibition of E2A-HEB function and pre-T alpha chain expression. Nat Immunol.2000;1: 138-144.","DOI":"10.1038\/77819"}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/107\/6\/2540\/1286289\/zh800606002540.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/107\/6\/2540\/1286289\/zh800606002540.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,4,10]],"date-time":"2020-04-10T20:00:20Z","timestamp":1586548820000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/107\/6\/2540\/22067\/Notch1-mutations-are-important-for-leukemic"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,3,15]]},"references-count":22,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2006,3,15]]}},"URL":"https:\/\/doi.org\/10.1182\/blood-2005-07-3013","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2006,3,15]]}}}