{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T05:35:50Z","timestamp":1767591350113,"version":"3.48.0"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T00:00:00Z","timestamp":1767571200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This study aimed to characterize TET2 mutations in CN-AML, assess their clinical features, and evaluate the prognostic impact of VAF and clonal hierarchy on overall survival (OS) and relapse-free survival (RFS).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A cohort of 206 adult CN-AML patients was analyzed for the presence of\n                      <jats:italic>TET2<\/jats:italic>\n                      mutation characteristics, variant allele frequency (VAF) and clonal status. Clinical and prognostic implications were evaluated through survival analyses and validated by the Beat AML public database.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>TET2<\/jats:italic>\n                      mutations were detected in 18.9% of CN-AML patients, with a median age of 55 years, significantly older than\n                      <jats:italic>TET2<\/jats:italic>\n                      wild-type patients (\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.001). OS and RFS were no difference in the high-VAF group and low-VAF group. Patients with dominant\n                      <jats:italic>TET2<\/jats:italic>\n                      mutations exhibited significantly shorter OS and RFS compared to subclonal group (\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.05). Multivariate Cox regression identified dominant\n                      <jats:italic>TET2<\/jats:italic>\n                      mutations as an independent adverse prognostic factor for OS (HR = 2.026,\n                      <jats:italic>P<\/jats:italic>\n                      = 0.039). A nomogram model based on these findings demonstrated robust predictive performance (AUC = 0.735) and was validated by the Beat AML database.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      The prognostic impact of\n                      <jats:italic>TET2<\/jats:italic>\n                      mutations is not determined by VAF, but rather by\n                      <jats:italic>TET2<\/jats:italic>\n                      clonal dominance and the interplay between mutations within the same clone.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2025.1730830","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T05:31:42Z","timestamp":1767591102000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Dominant TET2 mutations predict adverse prognosis in cytogenetically normal acute myeloid leukemia patients"],"prefix":"10.3389","volume":"15","author":[{"given":"Zhuanghui","family":"Hao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingjing","family":"Xia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sicheng","family":"Bian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miaoke","family":"Song","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingyi","family":"Feng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuo","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huichao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaofang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wanfang","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianmei","family":"Chang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fanggang","family":"Ren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xufeng","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiuhua","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongwei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2022016867","article-title":"Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN","volume":"140","author":"D\u00f6hner","year":"2022","journal-title":"Blood."},{"key":"B2","doi-asserted-by":"publisher","first-page":"16010","DOI":"10.1038\/nrdp.2016.10","article-title":"Acute myeloid leukaemia","volume":"2","author":"Khwaja","year":"2016","journal-title":"Nat Rev Dis Primers."},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1516192","article-title":"Genomic classification and prognosis in acute myeloid leukemia","volume":"374","author":"Papaemmanuil","year":"2016","journal-title":"N Engl J Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1111\/ijlh.12802","article-title":"Mutation profile and associated clinical features in Chinese patients with cytogenetically normal acute myeloid leukemia","volume":"40","author":"Wang","year":"2018","journal-title":"Int J Lab Hematol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.5764","article-title":"The impact of DNMT3A variant allele frequency and two different comutations on patients with de novo cytogenetically normal acute myeloid leukemia","volume":"12","author":"Chen","year":"2023","journal-title":"Cancer Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.16341","article-title":"Clonal hierarchy of main molecular lesions in acute myeloid leukaemia","volume":"190","author":"Herudkova","year":"2020","journal-title":"Br J Haematol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.71.2208","article-title":"Genomics of acute myeloid leukemia diagnosis and pathways","volume":"35","author":"Bullinger","year":"2017","journal-title":"J Clin Oncol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1007\/s00432-021-03641-3","article-title":"Ten-eleven translocase: key regulator of the methylation landscape in cancer","volume":"147","author":"Shekhawat","year":"2021","journal-title":"J Cancer Res Clin Oncol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/s43587-023-00505-y","article-title":"TET2 modulates spatial relocalization of heterochromatin in aged hematopoietic stem and progenitor cells","volume":"3","author":"Hong","year":"2023","journal-title":"Nat Aging."},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.00210","article-title":"TET2 function in hematopoietic Malignancies, immune regulation, and DNA repair","volume":"9","author":"Feng","year":"2019","journal-title":"Front Oncol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3109\/10428194.2014.893308","article-title":"Prognostic significance of Tet methylcytosine dioxygenase 2 (TET2) gene mutations in adult patients with acute myeloid leukemia: a meta-analysis","volume":"55","author":"Liu","year":"2014","journal-title":"Leuk Lymphoma."},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.32.7742","article-title":"TET2 mutations improve the new European LeukemiaNet risk classification of acute myeloid leukemia: a Cancer and Leukemia Group B study","volume":"29","author":"Metzeler","year":"2011","journal-title":"J Clin Oncol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1007\/s10238-024-01297-0","article-title":"TET2 mutations contribute to adverse prognosis in acute myeloid leukemia (AML): results from a comprehensive analysis of 502 AML cases and the Beat AML public database","volume":"24","author":"Pan","year":"2024","journal-title":"Clin Exp Med"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-02-339747","article-title":"TET2 mutation is an unfavorable prognostic factor in acute myeloid leukemia patients with intermediate-risk cytogenetics","volume":"118","author":"Chou","year":"2011","journal-title":"Blood."},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-08-733196","article-title":"Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel","volume":"129","author":"D\u00f6hner","year":"2017","journal-title":"Blood."},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1080\/10428194.2022.2081323","article-title":"The characteristics and clinical prognosis analysis of ASXL1 mutations in Chinese adult patients with primary cytogenetically normal acute myeloid leukemia by next-generation sequencing","volume":"63","author":"Xu","year":"2022","journal-title":"Leuk Lymphoma."},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2021004631","article-title":"Impact of PTPN11 mutations on clinical outcome analyzed in 1529 patients with acute myeloid leukemia","volume":"5","author":"Stasik","year":"2021","journal-title":"Blood Adv"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0810069","article-title":"Mutation in TET2 in myeloid cancers","volume":"360","author":"Delhommeau","year":"2009","journal-title":"N Engl J Med"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2021006242","article-title":"Molecular, clinical, and prognostic implications of PTPN11 mutations in acute myeloid leukemia","volume":"6","author":"Fobare","year":"2022","journal-title":"Blood Adv"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2890","article-title":"MutationTaster2: mutation prediction for the deep-sequencing age","volume":"11","author":"Schwarz","year":"2014","journal-title":"Nat Methods"},{"key":"B21","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1038\/s41597-024-03327-8","article-title":"Analysis of AlphaMissense data in different protein groups and structural context","volume":"11","author":"Tordai","year":"2024","journal-title":"Sci Data."},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth0410-248","article-title":"A method and server for predicting damaging missense mutations","volume":"7","author":"Adzhubei","year":"2010","journal-title":"Nat Methods"},{"key":"B23","doi-asserted-by":"publisher","first-page":"5327","DOI":"10.1038\/s41467-020-19119-8","article-title":"Clonal evolution of acute myeloid leukemia revealed by high-throughput single-cell genomics","volume":"11","author":"Morita","year":"2020","journal-title":"Nat Commun"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-018-0034-z","article-title":"Persistence of pre-leukemic clones during first remission and risk of relapse in acute myeloid leukemia","volume":"32","author":"Rothenberg-Thurley","year":"2018","journal-title":"Leukemia."},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/nature10738","article-title":"Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing","volume":"481","author":"Ding","year":"2012","journal-title":"Nature."},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2020.254623","article-title":"Monitoring of clonal evolution of acute myeloid leukemia identifies the leukemia subtype, clinical outcome and potential new drug targets for post-remission strategies or relapse","volume":"106","author":"Onecha","year":"2021","journal-title":"Haematologica."},{"key":"B27","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1038\/s41392-023-01537-x","article-title":"TET (Ten-eleven translocation) family proteins: structure, biological functions and applications","volume":"8","author":"Zhang","year":"2023","journal-title":"Signal Transduct Target Ther"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2011.326","article-title":"Landscape of TET2 mutations in acute myeloid leukemia","volume":"26","author":"Weissmann","year":"2012","journal-title":"Leukemia."},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.22191","article-title":"TET2 mutations in cytogenetically normal acute myeloid leukemia: clinical implications and evolutionary patterns","volume":"53","author":"Damm","year":"2014","journal-title":"Genes Chromosomes Cancer."},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1080\/10428194.2022.2126278","article-title":"Loss of TET2 with reduced genomic 5-hmC is associated with adverse-risk AML","volume":"63","author":"Pethusamy","year":"2022","journal-title":"Leuk Lymphoma."},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/nature09586","article-title":"Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2","volume":"468","author":"Ko","year":"2010","journal-title":"Nature."},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0623-z","article-title":"Functional genomic landscape of acute myeloid leukaemia","volume":"562","author":"Tyner","year":"2018","journal-title":"Nature."},{"key":"B33","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1186\/s12929-020-00674-7","article-title":"Genomic landscape in acute myeloid leukemia and its implications in risk classification and targeted therapies","volume":"27","author":"Hou","year":"2020","journal-title":"J BioMed Sci"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.22806","article-title":"Clonal evolution of acute myeloid leukemia from diagnosis to relapse","volume":"58","author":"Vosberg","year":"2019","journal-title":"Genes Chromosomes Cancer."},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1324297111","article-title":"Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission","volume":"111","author":"Corces-Zimmerman","year":"2014","journal-title":"Proc Natl Acad Sci U S A."},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2012.48","article-title":"Clonal evolution of acute leukemia genomes","volume":"32","author":"Jan","year":"2013","journal-title":"Oncogene."},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1002\/hon.2393","article-title":"Clonal evolution detected with conventional cytogenetic analysis is a potent prognostic factor in adult patients with relapsed AML","volume":"36","author":"Shimizu","year":"2018","journal-title":"Hematol Oncol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2864-x","article-title":"Single-cell mutation analysis of clonal evolution in myeloid Malignancies","volume":"587","author":"Miles","year":"2020","journal-title":"Nature."},{"key":"B39","doi-asserted-by":"publisher","first-page":"11119","DOI":"10.1038\/s41598-019-47297-z","article-title":"Clonal evolution and changes in two AML patients detected with A novel single-cell DNA sequencing platform","volume":"9","author":"Xu","year":"2019","journal-title":"Sci Rep"},{"key":"B40","doi-asserted-by":"publisher","first-page":"6209","DOI":"10.1038\/s41467-023-41994-0","article-title":"Single-cell analysis reveals altered tumor microenvironments of relapse- and remission-associated pediatric acute myeloid leukemia","volume":"14","author":"Mumme","year":"2023","journal-title":"Nat Commun"},{"key":"B41","doi-asserted-by":"publisher","first-page":"9402","DOI":"10.1038\/s41467-024-53535-4","article-title":"Single-cell landscape of innate and acquired drug resistance in acute myeloid leukemia","volume":"15","author":"Wegmann","year":"2024","journal-title":"Nat Commun"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2007.12.9791","article-title":"How to build and interpret a nomogram for cancer prognosis","volume":"26","author":"Iasonos","year":"2008","journal-title":"J Clin Oncol"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2025.1730830\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T05:31:43Z","timestamp":1767591103000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2025.1730830\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,5]]},"references-count":42,"alternative-id":["10.3389\/fonc.2025.1730830"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2025.1730830","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,5]]},"article-number":"1730830"}}