{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T04:29:45Z","timestamp":1791174585317,"version":"4.1.0"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,7,29]],"date-time":"2015-07-29T00:00:00Z","timestamp":1438128000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Leukemia"],"published-print":{"date-parts":[[2016,1]]},"DOI":"10.1038\/leu.2015.206","type":"journal-article","created":{"date-parts":[[2015,7,29]],"date-time":"2015-07-29T06:41:30Z","timestamp":1438152090000},"page":"39-47","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":65,"title":["Impact of PTEN abnormalities on outcome in pediatric patients with T-cell acute lymphoblastic leukemia treated on the MRC UKALL2003 trial"],"prefix":"10.1038","volume":"30","author":[{"given":"S","family":"Jenkinson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A A","family":"Kirkwood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N","family":"Goulden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Vora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D C","family":"Linch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R E","family":"Gale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,7,29]]},"reference":[{"key":"BFleu2015206_CR1","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1200\/JCO.2004.99.153","volume":"22","author":"R Herold","year":"2004","unstructured":"Herold R, von Stackelberg A, Hartmann R, Eisenreich B, Henze G . Acute lymphoblastic leukemia-relapse study of the Berlin-Frankfurt-Munster Group. (ALL-REZ BFM) experience: early treatment intensity makes the difference. J Clin Oncol 2004; 22: 569\u2013570.","journal-title":"J Clin Oncol"},{"key":"BFleu2015206_CR2","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1038\/nature05690","volume":"446","author":"CG Mullighan","year":"2007","unstructured":"Mullighan CG, Goorha S, Radtke I, Miller CB, Coustan-Smith E, Dalton JD et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 2007; 446: 758\u2013764.","journal-title":"Nature"},{"key":"BFleu2015206_CR3","doi-asserted-by":"publisher","first-page":"1377","DOI":"10.1126\/science.1164266","volume":"322","author":"CG Mullighan","year":"2008","unstructured":"Mullighan CG, Phillips LA, Su X, Ma J, Miller CB, Shurtleff SA et al. Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. Science 2008; 322: 1377\u20131380.","journal-title":"Science"},{"key":"BFleu2015206_CR4","doi-asserted-by":"publisher","first-page":"4178","DOI":"10.1182\/blood-2008-06-165027","volume":"112","author":"JJ Yang","year":"2008","unstructured":"Yang JJ, Bhojwani D, Yang W, Cai X, Stocco G, Crews K et al. Genome-wide copy number profiling reveals molecular evolution from diagnosis to relapse in childhood acute lymphoblastic leukemia. Blood 2008; 112: 4178\u20134183.","journal-title":"Blood"},{"key":"BFleu2015206_CR5","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1200\/JCO.2010.30.7405","volume":"29","author":"CH Pui","year":"2011","unstructured":"Pui CH, Carroll WL, Meshinchi S, Arceci RJ . Biology, risk stratification, and therapy of pediatric acute leukemias: an update. J Clin Oncol 2011; 29: 551\u2013565.","journal-title":"J Clin Oncol"},{"key":"BFleu2015206_CR6","doi-asserted-by":"publisher","first-page":"3918","DOI":"10.1182\/blood-2008-10-184069","volume":"113","author":"V Asnafi","year":"2009","unstructured":"Asnafi V, Buzyn A, Le Noir S, Baleydier F, Simon A, Beldjord K et al. NOTCH1\/FBXW7 mutation identifies a large subgroup with favorable outcome in adult T-cell acute lymphoblastic leukemia (T-ALL): a Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) study. Blood 2009; 113: 3918\u20133924.","journal-title":"Blood"},{"key":"BFleu2015206_CR7","doi-asserted-by":"publisher","first-page":"2005","DOI":"10.1038\/leu.2010.203","volume":"24","author":"C Kox","year":"2010","unstructured":"Kox C, Zimmermann M, Stanulla M, Leible S, Schrappe M, Ludwig WD et al. The favorable effect of activating NOTCH1 receptor mutations on long-term outcome in T-ALL patients treated on the ALL-BFM 2000 protocol can be separated from FBXW7 loss of function. Leukemia 2010; 24: 2005\u20132013.","journal-title":"Leukemia"},{"key":"BFleu2015206_CR8","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/leu.2012.176","volume":"27","author":"S Jenkinson","year":"2013","unstructured":"Jenkinson S, Koo K, Mansour MR, Goulden N, Vora A, Mitchell C et al. Impact of NOTCH1\/FBXW7 mutations on outcome in pediatric T-cell acute lymphoblastic leukemia patients treated on the MRC UKALL 2003 trial. Leukemia 2013; 27: 41\u201347.","journal-title":"Leukemia"},{"key":"BFleu2015206_CR9","doi-asserted-by":"publisher","first-page":"4352","DOI":"10.1200\/JCO.2009.22.0996","volume":"27","author":"MR Mansour","year":"2009","unstructured":"Mansour MR, Sulis ML, Duke V, Foroni L, Jenkinson S, Koo K et al. Prognostic implications of NOTCH1 and FBXW7 mutations in adults with T-cell acute lymphoblastic leukemia treated on the MRC UKALLXII\/ECOG E2993 protocol. J Clin Oncol 2009; 27: 4352\u20134356.","journal-title":"J Clin Oncol"},{"key":"BFleu2015206_CR10","doi-asserted-by":"publisher","first-page":"2014","DOI":"10.1038\/leu.2010.204","volume":"24","author":"L Zuurbier","year":"2010","unstructured":"Zuurbier L, Homminga I, Calvert V, te Winkel ML, Buijs-Gladdines JG, Kooi C et al. NOTCH1 and\/or FBXW7 mutations predict for initial good prednisone response but not for improved outcome in pediatric T-cell acute lymphoblastic leukemia patients treated on DCOG or COALL protocols. Leukemia 2010; 24: 2014\u20132022.","journal-title":"Leukemia"},{"key":"BFleu2015206_CR11","doi-asserted-by":"publisher","first-page":"2023","DOI":"10.1038\/leu.2010.205","volume":"24","author":"E Clappier","year":"2010","unstructured":"Clappier E, Collette S, Grardel N, Girard S, Suarez L, Brunie G et al. NOTCH1 and FBXW7 mutations have a favorable impact on early response to treatment, but not on outcome, in children with T-cell acute lymphoblastic leukemia (T-ALL) treated on EORTC trials 58881 and 58951. Leukemia 2010; 24: 2023\u20132031.","journal-title":"Leukemia"},{"key":"BFleu2015206_CR12","doi-asserted-by":"publisher","first-page":"1405","DOI":"10.3324\/haematol.2011.059030","volume":"97","author":"L Zuurbier","year":"2012","unstructured":"Zuurbier L, Petricoin EF 3rd, Vuerhard MJ, Calvert V, Kooi C, Buijs-Gladdines JG et al. The significance of PTEN and AKT aberrations in pediatric T-cell acute lymphoblastic leukemia. Haematologica 2012; 97: 1405\u20131413.","journal-title":"Haematologica"},{"key":"BFleu2015206_CR13","doi-asserted-by":"publisher","first-page":"928","DOI":"10.3324\/haematol.2012.073585","volume":"98","author":"OR Bandapalli","year":"2013","unstructured":"Bandapalli OR, Zimmermann M, Kox C, Stanulla M, Schrappe M, Ludwig WD et al. NOTCH1 activation clinically antagonizes the unfavorable effect of PTEN inactivation in BFM-treated children with precursor T-cell acute lymphoblastic leukemia. Haematologica 2013; 98: 928\u2013936.","journal-title":"Haematologica"},{"key":"BFleu2015206_CR14","doi-asserted-by":"publisher","first-page":"4333","DOI":"10.1200\/JCO.2012.48.5292","volume":"31","author":"A Trinquand","year":"2013","unstructured":"Trinquand A, Tanguy-Schmidt A, Ben Abdelali R, Lambert J, Beldjord K, Lengline E et al. Toward a NOTCH1\/FBXW7\/RAS\/PTEN-based oncogenetic risk classification of adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study. J Clin Oncol 2013; 31: 4333\u20134342.","journal-title":"J Clin Oncol"},{"key":"BFleu2015206_CR15","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1038\/ni1234","volume":"6","author":"M Ciofani","year":"2005","unstructured":"Ciofani M, Zuniga-Pflucker JC . Notch promotes survival of pre-T cells at the beta-selection checkpoint by regulating cellular metabolism. Nat Immunol 2005; 6: 881\u2013888.","journal-title":"Nat Immunol"},{"key":"BFleu2015206_CR16","doi-asserted-by":"publisher","first-page":"1203","DOI":"10.1038\/nm1636","volume":"13","author":"T Palomero","year":"2007","unstructured":"Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K, Ciofani M et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med 2007; 13: 1203\u20131210.","journal-title":"Nat Med"},{"key":"BFleu2015206_CR17","doi-asserted-by":"publisher","first-page":"966","DOI":"10.1038\/nature05886","volume":"447","author":"RS Maser","year":"2007","unstructured":"Maser RS, Choudhury B, Campbell PJ, Feng B, Wong KK, Protopopov A et al. Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers. Nature 2007; 447: 966\u2013971.","journal-title":"Nature"},{"key":"BFleu2015206_CR18","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1182\/blood-2009-02-206722","volume":"114","author":"A Gutierrez","year":"2009","unstructured":"Gutierrez A, Sanda T, Grebliunaite R, Carracedo A, Salmena L, Ahn Y et al. High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia. Blood 2009; 114: 647\u2013650.","journal-title":"Blood"},{"key":"BFleu2015206_CR19","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.1182\/blood-2008-10-186536","volume":"114","author":"M Remke","year":"2009","unstructured":"Remke M, Pfister S, Kox C, Toedt G, Becker N, Benner A et al. High-resolution genomic profiling of childhood T-ALL reveals frequent copy-number alterations affecting the TGF-beta and PI3K-AKT pathways and deletions at 6q15-16.1 as a genomic marker for unfavorable early treatment response. Blood 2009; 114: 1053\u20131062.","journal-title":"Blood"},{"key":"BFleu2015206_CR20","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1038\/leu.2009.209","volume":"24","author":"PY Jotta","year":"2010","unstructured":"Jotta PY, Ganazza MA, Silva A, Viana MB, da Silva MJ, Zambaldi LJ et al. Negative prognostic impact of PTEN mutation in pediatric T-cell acute lymphoblastic leukemia. Leukemia 2010; 24: 239\u2013242.","journal-title":"Leukemia"},{"key":"BFleu2015206_CR21","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1038\/nature10725","volume":"481","author":"J Zhang","year":"2012","unstructured":"Zhang J, Ding L, Holmfeldt L, Wu G, Heatley SL, Payne-Turner D et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 2012; 481: 157\u2013163.","journal-title":"Nature"},{"key":"BFleu2015206_CR22","doi-asserted-by":"publisher","first-page":"10182","DOI":"10.1073\/pnas.96.18.10182","volume":"96","author":"MM Georgescu","year":"1999","unstructured":"Georgescu MM, Kirsch KH, Akagi T, Shishido T, Hanafusa H . The tumor-suppressor activity of PTEN is regulated by its carboxyl-terminal region. Proc Natl Acad Sci USA 1999; 96: 10182\u201310187.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFleu2015206_CR23","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1182\/blood-2014-03-562751","volume":"124","author":"RD Mendes","year":"2014","unstructured":"Mendes RD, Sarmento LM, Cante-Barrett K, Zuurbier L, Buijs-Gladdines JG, Povoa V et al. PTEN microdeletions in T-cell acute lymphoblastic leukemia are caused by illegitimate RAG-mediated recombination events. Blood 2014; 124: 567\u2013578.","journal-title":"Blood"},{"key":"BFleu2015206_CR24","doi-asserted-by":"publisher","first-page":"3373","DOI":"10.1182\/blood-2008-03-147587","volume":"112","author":"T Kindler","year":"2008","unstructured":"Kindler T, Cornejo MG, Scholl C, Liu J, Leeman DS, Haydu JE et al. K-RasG12D-induced T-cell lymphoblastic lymphoma\/leukemias harbor Notch1 mutations and are sensitive to gamma-secretase inhibitors. Blood 2008; 112: 3373\u20133382.","journal-title":"Blood"},{"key":"BFleu2015206_CR25","doi-asserted-by":"publisher","first-page":"18219","DOI":"10.1074\/jbc.M113.475376","volume":"288","author":"G Kong","year":"2013","unstructured":"Kong G, Du J, Liu Y, Meline B, Chang YI, Ranheim EA et al. Notch1 gene mutations target KRAS G12D-expressing CD8+ cells and contribute to their leukemogenic transformation. J Biol Chem 2013; 288: 18219\u201318227.","journal-title":"J Biol Chem"},{"key":"BFleu2015206_CR26","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1038\/sj.leu.2403272","volume":"18","author":"JP Perentesis","year":"2004","unstructured":"Perentesis JP, Bhatia S, Boyle E, Shao Y, Ou Shu X, Steinbuch M et al. RAS oncogene mutations and outcome of therapy for childhood acute lymphoblastic leukemia. Leukemia 2004; 18: 685\u2013692.","journal-title":"Leukemia"},{"key":"BFleu2015206_CR27","doi-asserted-by":"publisher","first-page":"2571","DOI":"10.1084\/jem.20112239","volume":"208","author":"P Van Vlierberghe","year":"2011","unstructured":"Van Vlierberghe P, Ambesi-Impiombato A, Perez-Garcia A, Haydu JE, Rigo I, Hadler M et al. ETV6 mutations in early immature human T cell leukemias. J Exp Med 2011; 208: 2571\u20132579.","journal-title":"J Exp Med"},{"key":"BFleu2015206_CR28","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1111\/j.1365-2141.2010.08132.x","volume":"149","author":"A Qureshi","year":"2010","unstructured":"Qureshi A, Mitchell C, Richards S, Vora A, Goulden N . Asparaginase-related venous thrombosis in UKALL 2003- re-exposure to asparaginase is feasible and safe. Br J Haematol 2010; 149: 410\u2013413.","journal-title":"Br J Haematol"},{"key":"BFleu2015206_CR29","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1046\/j.1365-2141.1998.00574.x","volume":"100","author":"NJ Goulden","year":"1998","unstructured":"Goulden NJ, Knechtli CJ, Garland RJ, Langlands K, Hancock JP, Potter MN et al. Minimal residual disease analysis for the prediction of relapse in children with standard-risk acute lymphoblastic leukaemia. Br J Haematol 1998; 100: 235\u2013244.","journal-title":"Br J Haematol"},{"key":"BFleu2015206_CR30","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1038\/nrc3037","volume":"11","author":"MC Hollander","year":"2011","unstructured":"Hollander MC, Blumenthal GM, Dennis PA . PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nat Rev Cancer 2011; 11: 289\u2013301.","journal-title":"Nat Rev Cancer"},{"key":"BFleu2015206_CR31","doi-asserted-by":"publisher","first-page":"3762","DOI":"10.1172\/JCI34616","volume":"118","author":"A Silva","year":"2008","unstructured":"Silva A, Yunes JA, Cardoso BA, Martins LR, Jotta PY, Abecasis M et al. PTEN posttranslational inactivation and hyperactivation of the PI3K\/Akt pathway sustain primary T cell leukemia viability. J Clin Invest 2008; 118: 3762\u20133774.","journal-title":"J Clin Invest"},{"key":"BFleu2015206_CR32","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1016\/j.ccr.2013.10.022","volume":"24","author":"E Piovan","year":"2013","unstructured":"Piovan E, Yu J, Tosello V, Herranz D, Ambesi-Impiombato A, Da Silva AC et al. Direct reversal of glucocorticoid resistance by AKT inhibition in acute lymphoblastic leukemia. Cancer Cell 2013; 24: 766\u2013776.","journal-title":"Cancer Cell"},{"key":"BFleu2015206_CR33","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1016\/j.ccr.2014.01.032","volume":"25","author":"JS Blackburn","year":"2014","unstructured":"Blackburn JS, Liu S, Wilder JL, Dobrinski KP, Lobbardi R, Moore FE et al. Clonal evolution enhances leukemia-propagating cell frequency in T cell acute lymphoblastic leukemia through Akt\/mTORC1 pathway activation. Cancer Cell 2014; 25: 366\u2013378.","journal-title":"Cancer Cell"},{"key":"BFleu2015206_CR34","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1016\/j.cell.2014.03.027","volume":"157","author":"A Papa","year":"2014","unstructured":"Papa A, Wan L, Bonora M, Salmena L, Song MS, Hobbs RM et al. Cancer-associated PTEN mutants act in a dominant-negative manner to suppress PTEN protein function. Cell 2014; 157: 595\u2013610.","journal-title":"Cell"},{"key":"BFleu2015206_CR35","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1146\/annurev-genet-120213-092314","volume":"48","author":"M Gerlinger","year":"2014","unstructured":"Gerlinger M, McGranahan N, Dewhurst SM, Burrell RA, Tomlinson I, Swanton C . Cancer: evolution within a lifetime. Annu Rev Genet 2014; 48: 215\u2013236.","journal-title":"Annu Rev Genet"},{"key":"BFleu2015206_CR36","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1084\/jem.20110105","volume":"208","author":"E Clappier","year":"2011","unstructured":"Clappier E, Gerby B, Sigaux F, Delord M, Touzri F, Hernandez L et al. Clonal selection in xenografted human T cell acute lymphoblastic leukemia recapitulates gain of malignancy at relapse. J Exp Med 2011; 208: 653\u2013661.","journal-title":"J Exp Med"},{"key":"BFleu2015206_CR37","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1038\/nature03918","volume":"436","author":"Z Chen","year":"2005","unstructured":"Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA, Niki M et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 2005; 436: 725\u2013730.","journal-title":"Nature"},{"key":"BFleu2015206_CR38","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/nrc3860","volume":"15","author":"LM Thorpe","year":"2015","unstructured":"Thorpe LM, Yuzugullu H, Zhao JJ . PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer 2015; 15: 7\u201324.","journal-title":"Nat Rev Cancer"}],"container-title":["Leukemia"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.nature.com\/articles\/leu2015206.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/leu2015206","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/doifinder\/10.1038\/leu.2015.206","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"},{"URL":"http:\/\/www.nature.com\/articles\/leu2015206.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,18]],"date-time":"2023-05-18T18:05:12Z","timestamp":1684433112000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/leu2015206"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,7,29]]},"references-count":38,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2016,1]]}},"alternative-id":["BFleu2015206"],"URL":"https:\/\/doi.org\/10.1038\/leu.2015.206","relation":{},"ISSN":["0887-6924","1476-5551"],"issn-type":[{"value":"0887-6924","type":"print"},{"value":"1476-5551","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,7,29]]},"assertion":[{"value":"14 April 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 June 2015","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 July 2015","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 July 2015","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}