{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T05:43:58Z","timestamp":1750052638249,"version":"3.40.5"},"reference-count":35,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2021,3,11]],"date-time":"2021-03-11T00:00:00Z","timestamp":1615420800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science, and Technology","doi-asserted-by":"crossref","award":["15K09452"],"award-info":[{"award-number":["15K09452"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science, and Technology","doi-asserted-by":"crossref","award":["18K08352"],"award-info":[{"award-number":["18K08352"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science, and Technology","doi-asserted-by":"crossref","award":["17H04227"],"award-info":[{"award-number":["17H04227"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science, and Technology","doi-asserted-by":"crossref","award":["26293247"],"award-info":[{"award-number":["26293247"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Sanikai"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>The <jats:italic>Ten Eleven Translocation 1<\/jats:italic> (<jats:italic>TET1<\/jats:italic>) gene encodes an epigenetic modifying molecule that is involved in demethylation of 5-methylcytosine. In hematological malignancies, loss-of-function mutations of <jats:italic>TET2<\/jats:italic>, which is one of the <jats:italic>TET<\/jats:italic> family genes including <jats:italic>TET1<\/jats:italic>, are frequently found, while the mutations of <jats:italic>TET1<\/jats:italic> are not. However, clinical studies have revealed that <jats:italic>TET1<\/jats:italic> is highly expressed in some cases of the hematological malignancies including acute myeloid leukemia. Indeed, studies by mouse models using conventional <jats:italic>Tet1<\/jats:italic> knockout mice demonstrated that <jats:italic>Tet1<\/jats:italic> is involved in myeloid leukemogenesis by <jats:italic>Mixed Lineage Leukemia<\/jats:italic> (<jats:italic>MLL)<\/jats:italic> fusion gene or <jats:italic>TET2<\/jats:italic> mutant. Meanwhile, the other study showed that <jats:italic>Tet1<\/jats:italic> is highly expressed in hematopoietic stem cells (HSCs), and that deletion of <jats:italic>Tet1<\/jats:italic> in HSCs enhances potential self-renewal capacity, which is potentially associated with myeloid leukemogenesis. To examine the role of <jats:italic>Tet1<\/jats:italic> in myeloid leukemogenesis more precisely, we generated novel conditional <jats:italic>Tet1<\/jats:italic>-knockout mice, which were used to generate the compound mutant mice by crossing with the inducible <jats:italic>MLL-ENL<\/jats:italic> transgenic mice that we developed previously. The leukemic immortalization <jats:italic>in vitro<\/jats:italic> was not critically affected by conditional ablation of <jats:italic>Tet1<\/jats:italic> in HSCs with the induced expression of <jats:italic>MLL-ENL<\/jats:italic> or in hematopoietic progenitor cells retrovirally transduced with <jats:italic>MLL-ENL<\/jats:italic>. In addition, the leukemic phenotypes caused by the induced expression of <jats:italic>MLL-ENL in vivo<\/jats:italic> was not also critically affected in the compound mutant mouse model by conditional ablation of <jats:italic>Tet1<\/jats:italic>, although we found that the expression of <jats:italic>Evi1<\/jats:italic>, which is one of critical target genes of <jats:italic>MLL<\/jats:italic> fusion gene, in tumor cells was remarkably low under <jats:italic>Tet1<\/jats:italic>-ablated condition. These results revealed that <jats:italic>Tet1<\/jats:italic> was dispensable for the myeloid leukemogenesis by <jats:italic>MLL-ENL<\/jats:italic>, suggesting that the therapeutic application of Tet1 inhibition may need careful assessment.<\/jats:p>","DOI":"10.1371\/journal.pone.0248425","type":"journal-article","created":{"date-parts":[[2021,3,11]],"date-time":"2021-03-11T18:31:48Z","timestamp":1615487508000},"page":"e0248425","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Tet1 is not required for myeloid leukemogenesis by MLL-ENL in novel mouse models"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1774-7843","authenticated-orcid":true,"given":"Ryoichi","family":"Ono","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masahiro","family":"Masuya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naokazu","family":"Inoue","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Makoto","family":"Shinmei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satomi","family":"Ishii","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuri","family":"Maegawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bishnu Devi","family":"Maharjan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naoyuki","family":"Katayama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tetsuya","family":"Nosaka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,3,11]]},"reference":[{"issue":"Suppl","key":"pone.0248425.ref001","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/ng1089","article-title":"Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals","volume":"33","author":"R Jaenisch","year":"2003","journal-title":"Nat Genet"},{"key":"pone.0248425.ref002","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1038\/s41580-019-0143-1","article-title":"The roles of DNA, RNA and histone methylation in ageing and cancer","volume":"20","author":"EM 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