{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T20:20:29Z","timestamp":1792700429335,"version":"4.5.0"},"reference-count":15,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T00:00:00Z","timestamp":1775088000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T00:00:00Z","timestamp":1775692800000},"content-version":"vor","delay-in-days":7,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100007311","name":"Deutsche Kinderkrebsstiftung","doi-asserted-by":"publisher","award":["DKS 2014.11"],"award-info":[{"award-number":["DKS 2014.11"]}],"id":[{"id":"10.13039\/501100007311","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007311","name":"Deutsche Kinderkrebsstiftung","doi-asserted-by":"publisher","award":["DKS 2016.24"],"award-info":[{"award-number":["DKS 2016.24"]}],"id":[{"id":"10.13039\/501100007311","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005972","name":"Deutsche Krebshilfe","doi-asserted-by":"publisher","award":["70112964 LBL 2018 trial"],"award-info":[{"award-number":["70112964 LBL 2018 trial"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Blood Cancer J."],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    T-cell lymphoblastic lymphoma (T-LBL) and T-cell acute lymphoblastic leukemia (T-ALL) originate from thymic T-cell precursors, with ongoing debate on whether they are variants of the same disease or distinct entities. For 211 patients, including pediatric and adult T-ALL and T-LBL cases, targeted next-generation sequencing and SNP-arrays were performed, and single-nucleotide variants, indels and copy-number variants (CNVs) were analyzed. We aimed to assess genetic differences between T-ALL and T-LBL across age. Generally, mutational landscape analysis identified mutated\n                    <jats:italic>PHF6<\/jats:italic>\n                    being associated with higher,\n                    <jats:italic>NOTCH1<\/jats:italic>\n                    with lower age at diagnosis for both T-LBL and T-ALL. Association of CNVs with higher age was evident for T-ALL, but not T-LBL. Analysis of clonal evolution revealed that CNVs \u2013 especially deletions and LOH in chromosome 9 (LOH_in_9p) \u2013 were observed as first mutational event in both pediatric T-ALL and T-LBL. The sequence of genetic events, starting with LOH_in_9p followed by mutations in\n                    <jats:italic>NOTCH1<\/jats:italic>\n                    , was significantly more frequent in pediatric T-ALL and T-LBL. Detailed evaluation of the patients\u2019 individual clonal evolution indicated that the proportion of malignant cells without\n                    <jats:italic>NOTCH<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>MT<\/jats:italic>\n                    <\/jats:sup>\n                    determines the risk of relapse (hazard ratio 1.032,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20094.65*10\n                    <jats:sup>\u22125<\/jats:sup>\n                    ). In T-ALL, aside from MRD, validated molecular markers for risk-group stratification remain limited. Our data suggest that molecular metrics analogous to those in T-LBL may help refining risk stratification in T-ALL as well.\n                  <\/jats:p>","DOI":"10.1038\/s41408-026-01488-w","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T18:33:41Z","timestamp":1775154821000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Molecular variants, clonal evolution and clinical relevance in pediatric and adult T-cell lymphoblastic neoplasia"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5011-0641","authenticated-orcid":false,"given":"Sarah","family":"Sandmann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"te Vrugt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerrit","family":"Randau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2278-5054","authenticated-orcid":false,"given":"Thomas","family":"Beder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Neumann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0939-8062","authenticated-orcid":false,"given":"Toni","family":"Lange","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amelie","family":"Alfert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Mueller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Hotfilder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinne","family":"Rossi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1039-2872","authenticated-orcid":false,"given":"Cornelia","family":"Eckert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Moericke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna Maria","family":"Horns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0365-3512","authenticated-orcid":false,"given":"Martin","family":"Zimmermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Varghese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Br\u00fcggemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1151-829X","authenticated-orcid":false,"given":"Birgit","family":"Burkhardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,2]]},"reference":[{"key":"1488_CR1","doi-asserted-by":"publisher","first-page":"2077","DOI":"10.1182\/blood-2011-03-338707","volume":"118","author":"M Schrappe","year":"2011","unstructured":"Schrappe M, Valsecchi MG, Bartram CR, Schrauder A, Panzer-Gr\u00fcmayer R, M\u00f6ricke A, et al. Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study. Blood. 2011;118:2077\u201384.","journal-title":"Blood"},{"key":"1488_CR2","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.1038\/s41375-024-02264-0","volume":"38","author":"M Neumann","year":"2024","unstructured":"Neumann M, Beder T, Bastian L, H\u00e4nzelmann S, Bultmann M, Wolgast N, et al. Molecular subgroups of T-cell acute lymphoblastic leukemia in adults treated according to pediatric-based GMALL protocols. Leukemia. 2024;38:1213\u201322.","journal-title":"Leukemia"},{"key":"1488_CR3","doi-asserted-by":"publisher","first-page":"2086","DOI":"10.3324\/haematol.2015.139162","volume":"102","author":"E Landmann","year":"2017","unstructured":"Landmann E, Burkhardt B, Zimmermann M, Meyer U, Woessmann W, Klapper W, et al. Results and conclusions of the European Intergroup EURO-LB02 trial in children and adolescents with lymphoblastic lymphoma. Haematologica. 2017;102:2086\u201396.","journal-title":"Haematologica"},{"key":"1488_CR4","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.exphem.2017.04.002","volume":"51","author":"S Lepretre","year":"2017","unstructured":"Lepretre S, Graux C, Touzart A, Macintyre E, Boissel N. Adult T-type lymphoblastic lymphoma: treatment advances and prognostic indicators. Exp Hematol. 2017;51:7\u201316.","journal-title":"Exp Hematol"},{"key":"1488_CR5","doi-asserted-by":"publisher","first-page":"1227","DOI":"10.1038\/s41379-022-01085-9","volume":"35","author":"C Bontoux","year":"2022","unstructured":"Bontoux C, Simonin M, Garnier N, Lhermitte L, Touzart A, Andrieu G, et al. Oncogenetic landscape of T-cell lymphoblastic lymphomas compared to T-cell acute lymphoblastic leukemia. Modern Pathol. 2022;35:1227\u201335.","journal-title":"Modern Pathol"},{"key":"1488_CR6","doi-asserted-by":"crossref","unstructured":"Te Vrugt M, Wessolowski JS, Randau G, Alfert A, M\u00fcller S, Scholten K, et al. Pediatric T-cell lymphoblastic lymphoma but not leukemia harbor TRB::NOTCH1 fusions with unfavorable outcome. Blood. 2024;144:1412\u20137.","DOI":"10.1182\/blood.2024025307"},{"key":"1488_CR7","doi-asserted-by":"crossref","unstructured":"Sandmann S, Richter S, Jiang X, Varghese J. Reconstructing clonal evolution-a systematic evaluation of current bioinformatics approaches. Int J Environ Res Public Health. 2023;20:5128.","DOI":"10.3390\/ijerph20065128"},{"key":"1488_CR8","doi-asserted-by":"publisher","first-page":"e893","DOI":"10.1097\/HS9.0000000000000893","volume":"7","author":"C Rizzari","year":"2023","unstructured":"Rizzari C, M\u00f6ricke A, Valsecchi MG, Conter V, Zimmermann M, Silvestri D, et al. Incidence and characteristics of hypersensitivity reactions to PEG-asparaginase observed in 6136 children with acute lymphoblastic leukemia enrolled in the AIEOP-BFM ALL 2009 study protocol. Hemasphere. 2023;7:e893.","journal-title":"Hemasphere"},{"key":"1488_CR9","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1126\/science.1102160","volume":"306","author":"Weng","year":"2004","unstructured":"Weng, Ferrando AP, Lee AA, Morris W, JPt, Silverman LB, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004;306:269\u201371.","journal-title":"Science"},{"key":"1488_CR10","doi-asserted-by":"publisher","first-page":"1082","DOI":"10.1038\/s41586-024-07807-0","volume":"632","author":"P P\u00f6l\u00f6nen","year":"2024","unstructured":"P\u00f6l\u00f6nen P, Di Giacomo D, Seffernick AE, Elsayed A, Kimura S, Benini F, et al. The genomic basis of childhood T-lineage acute lymphoblastic leukaemia. 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Integrative genomic analysis of pediatric T-cell lymphoblastic lymphoma reveals candidates of clinical significance. Blood. 2021;137:2347\u201359.","journal-title":"Blood"}],"container-title":["Blood Cancer Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41408-026-01488-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41408-026-01488-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41408-026-01488-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T08:33:35Z","timestamp":1775723615000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41408-026-01488-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,2]]},"references-count":15,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["1488"],"URL":"https:\/\/doi.org\/10.1038\/s41408-026-01488-w","relation":{},"ISSN":["2044-5385"],"issn-type":[{"value":"2044-5385","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,2]]},"assertion":[{"value":"16 October 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 February 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 March 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 April 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The ethical approval for adults was granted under the reference number D 466\/21 on March 31, 2021, by the Ethics Committee of the Medical Faculty at Christian-Albrechts-University (CAU) Kiel. The LBL Registry was approved by the Ethics Committee of the Faculty of Medicine at Justus Liebig University Giessen under the reference number 100\/02. The NHL-BFM Registry 2012 received approval from the Ethics Committee of the Medical Association of Westphalia-Lippe and the University of M\u00fcnster, with the reference number 2012-206-f-S. Similarly, the trial LBL 2018 was approved by the same ethics committee under the reference number 2019-037-f-A. The AIEOP-BFM ALL 2009 study was reviewed by the Ethics Committee of the University Medical Center Schleswig-Holstein. All methods were performed in accordance with the relevant guidelines and regulations.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}],"article-number":"57"}}