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Studies have demonstrated that m6<\/jats:sup>A RNA<\/jats:styled-content> methylation\u2010modifying enzymes play crucial roles in the onset and progression of AML<\/jats:styled-content>. However, their clinical relevance remains undefined, and the mechanisms underlying their modulation of AML<\/jats:styled-content> have yet to be elucidated.<\/jats:p><\/jats:sec>Results<\/jats:title>The expression levels of the m6<\/jats:sup>A RNA<\/jats:styled-content>\u2010modifying enzymes METTL3<\/jats:styled-content>, METTL14<\/jats:styled-content>, WTAP<\/jats:styled-content>, FTO<\/jats:styled-content> and ALKBH5<\/jats:styled-content> were elevated in AML<\/jats:styled-content> patients. METTL3<\/jats:styled-content>\u2010positive AML<\/jats:styled-content> is often accompanied by DNMT3A<\/jats:styled-content> mutations and is also an independent poor prognostic factor for AML<\/jats:styled-content> patients. Following METTL3<\/jats:styled-content> knockdown, we observed a decrease in the m6<\/jats:sup>A<\/jats:styled-content> level of the mitochondrial oxidative stress gene PGC<\/jats:styled-content>\u20101\u03b1 in K562<\/jats:styled-content> and MV4<\/jats:styled-content>\u201011 cells. We analyzed the expression levels of PGC<\/jats:styled-content>\u20101\u03b1 and METTL3 mRNA<\/jats:styled-content> in 105 patients with primary AML<\/jats:styled-content>. The expression levels of PGC<\/jats:styled-content>\u20101\u03b1 and METTL3 mRNA<\/jats:styled-content> were positively correlated. Similar to METTL3<\/jats:styled-content> knockdown, PGC<\/jats:styled-content>\u20101\u03b1 gene knockdown resulted in increased phosphorylation of the key signaling molecules P38<\/jats:styled-content>, c\u2010Jun and ERK1<\/jats:styled-content>\/2 in the MAPK<\/jats:styled-content> signaling pathway, and decreased mRNA<\/jats:styled-content> levels of SOD1<\/jats:styled-content>, GPX1<\/jats:styled-content>, catalase and UCP2<\/jats:styled-content> in the antioxidant system of K562<\/jats:styled-content> cells. Analysis of the TCGA<\/jats:styled-content> and GSE13159<\/jats:styled-content> datasets, along with samples from West China Hospital, revealed that patients exhibiting high PGC<\/jats:styled-content>\u20101\u03b1 expression had a poor prognosis.<\/jats:p><\/jats:sec>Conclusion<\/jats:title>The m6<\/jats:sup>A<\/jats:styled-content> methylation\u2010modifying enzyme METTL3<\/jats:styled-content> is an independent prognostic factor for poor prognosis in AML<\/jats:styled-content> patients. PGC<\/jats:styled-content>\u20101\u03b1 is a downstream signaling molecule of METTL3<\/jats:styled-content>, and METTL3<\/jats:styled-content> affects its expression by regulating the m6<\/jats:sup>A<\/jats:styled-content> level of PGC<\/jats:styled-content>\u20101\u03b1. PGC<\/jats:styled-content>\u20101\u03b1 acts as an oncogene in AML<\/jats:styled-content> by affecting the MAPK<\/jats:styled-content> pathway and antioxidant system.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cam4.70771","type":"journal-article","created":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T08:46:51Z","timestamp":1743756411000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["METTL3<\/scp>, an Independent Adverse Prognostic Factor for AML<\/scp>, Promotes the Development of AML<\/scp> by Modulating the PGC<\/scp>\u20101\u03b1\u2013MAPK<\/scp> Pathway and PGC<\/scp>\u20101\u03b1\u2013Antioxidant System Axis"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-1061-5131","authenticated-orcid":false,"given":"Yuqian","family":"Tang","sequence":"first","affiliation":[{"name":"Department of Hematology West China Hospital, Sichuan University Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Hematology West China Hospital, Sichuan University Chengdu Sichuan China"},{"name":"Department of Hematology First Affiliated Hospital of Zhengzhou University Zhengzhou Henan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wu","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Hematology West China Hospital, Sichuan University Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojia","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hematology West China Hospital, Sichuan University Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Hematology West China Hospital, Sichuan University Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiwen","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Hematology West China Hospital, Sichuan University Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Hematology West China Hospital, Sichuan University Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2437-9348","authenticated-orcid":false,"given":"Yuping","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Hematology West China Hospital, Sichuan University Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,4,2]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.05.003"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2902"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.05.014"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2017.100"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature15377"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2017.10.005"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj2880233"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00239-002-2339-8"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2014.3"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.687"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2012.10.015"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2017.10"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1007412"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2017.99"},{"issue":"8","key":"e_1_2_10_16_1","first-page":"4328","article-title":"METTL3 Promotes the Progression of Nasopharyngeal Carcinoma Through Mediating M6A Modification of EZH2","volume":"24","author":"Meng Q. 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