{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T11:30:15Z","timestamp":1790508615322,"version":"4.1.0"},"reference-count":45,"publisher":"National Academy of Sciences","issue":"5","license":[{"start":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T00:00:00Z","timestamp":1738022400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32370625"],"award-info":[{"award-number":["32370625"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"MOST | National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFA1800400"],"award-info":[{"award-number":["2023YFA1800400"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,2,4]]},"abstract":"<jats:p>\n                    Ten-eleven translocation (TET) enzymes oxidize 5-methylcytosine (mC) in DNA, contributing to the regulation of gene transcription. Diverse mutations of TET2 are frequently found in various blood cancers, yet the full scope of their functional consequences has been unexplored. Here, we report that a subset of TET2 mutations identified in leukemia patients alter the substrate specificity of TET2 from acting on mC to thymine. This neomorphic activity results from substitutions at key residues involved in the interactions with the mC base, including Asn1387 and His1904. Recombinant human TET2 proteins harboring the mutation of these residues can catalyze the oxidation of thymine to 5-hydroxymethyluracil (hmU) and 5-formyluracil (fU). Exogenous expression of the mutant TET2 Asn1387Thr (N1387T) in HEK293T cells leads to hmU accumulation, with levels further increased in cells lacking the glycosylase SMUG1. Endogenous knock-in of N1300T, the murine equivalent of N1387T, in mouse embryonic stem cells induces hmU production, causing DNA lesions and transcriptional activation of DNA damage response genes. N1300T cells accumulate more additional mutations with extended culture and exhibit heightened sensitivity to ATR inhibition compared to\n                    <jats:italic>Tet2<\/jats:italic>\n                    knockout cells. Our study reveals that certain patient-derived TET2 mutations can acquire unexpected gain-of-function activities beyond impairing mC oxidation, offering a fresh perspective on the diverse molecular etiology of mutant TET2-related leukemogenesis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2418318122","type":"journal-article","created":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T13:40:11Z","timestamp":1738071611000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":9,"title":["Neomorphic leukemia-derived mutations in the TET2 enzyme induce genome instability via a substrate shift from 5-methylcytosine to thymine"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-2175-7577","authenticated-orcid":false,"given":"Guang-Bo","family":"Jin","sequence":"first","affiliation":[{"name":"Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Chinese Academy of Medical Sciences (RU069) and Zhongshan-Xuhui Hospital, Medical College of Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shao-Qin","family":"Rong","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Chinese Academy of Medical Sciences (RU069) and Zhongshan-Xuhui Hospital, Medical College of Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-Rui","family":"Yin","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Chinese Academy of Medical Sciences (RU069) and Zhongshan-Xuhui Hospital, Medical College of Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhou-Hao","family":"Deng","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Chinese Academy of Medical Sciences (RU069) and Zhongshan-Xuhui Hospital, Medical College of Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Ding","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Chinese Academy of Medical Sciences (RU069) and Zhongshan-Xuhui Hospital, Medical College of Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-Yao","family":"Sheng","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Chinese Academy of Medical Sciences (RU069) and Zhongshan-Xuhui Hospital, Medical College of Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai","family":"Gao","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Chinese Academy of Medical Sciences (RU069) and Zhongshan-Xuhui Hospital, Medical College of Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7689-5678","authenticated-orcid":false,"given":"Rahul M.","family":"Kohli","sequence":"additional","affiliation":[{"name":"Epigenetics Institute, University of Pennsylvania","place":["Philadelphia"]},{"name":"Department of Medicine, University of Pennsylvania","place":["Philadelphia"]},{"name":"Department of Biochemistry and Biophysics, University of Pennsylvania","place":["Philadelphia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3240-3141","authenticated-orcid":false,"given":"Guo-Liang","family":"Xu","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Chinese Academy of Medical Sciences (RU069) and Zhongshan-Xuhui Hospital, Medical College of Fudan University","place":["Shanghai, China"]},{"name":"Key Laboratory of Epigenetic Regulation and Intervention, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2306-3456","authenticated-orcid":false,"given":"Dan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Center for Medical Research and Innovation, Shanghai Pudong Hospital, Institutes of Biomedical Sciences, Chinese Academy of Medical Sciences (RU069), Medical College of Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,1,28]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1170116"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1210944"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1210597"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12038-019-9973-4"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2018.01.011"},{"key":"e_1_3_4_6_2","first-page":"1590","article-title":"Clonal hematopoiesis: Mechanisms driving dominance of stem cell clones","volume":"136","author":"Challen G. 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