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pmid:40171845
METTL3, an Independent Adverse Prognostic Factor for AML, Promotes the Development of AML by Modulating the PGC-1α-MAPK Pathway and PGC-1α-Antioxidant System Axis.
Yuqian Tang · Xiaoyan Liu · Wu Ye · Xiaojia Wang · Xiaoyu Wei · Yiwen Du · Ying Zhang · Yuping Gong
Cancer medicine · 2025 doi:10.1002/cam4.70771
Paper
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Experiment
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Data
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Analysis
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Execution
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Complete file
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Studies have demonstrated that m6A RNA methylation-modifying enzymes play crucial roles in the onset and progression of AML. However, their clinical relevance remains undefined, and the mechanisms underlying their modulation of AML have yet to be elucidated.\nRESULTS: The expression levels of the m6A RNA-modifying enzymes METTL3, METTL14, WTAP, FTO and ALKBH5 were elevated in AML patients. METTL3-positive AML is often accompanied by DNMT3A mutations and is also an independent poor prognostic factor for AML patients. Following METTL3 knockdown, we observed a decrease in the m6A level of the mitochondrial oxidative stress gene PGC-1α in K562 and MV4-11 cells. We analyzed the expression levels of PGC-1α and METTL3 mRNA in 105 patients with primary AML. The expression levels of PGC-1α and METTL3 mRNA were positively correlated. Similar to METTL3 knockdown, PGC-1α gene knockdown resulted in increased phosphorylation of the key signaling molecules P38, c-Jun and ERK1/2 in the MAPK signaling pathway, and decreased mRNA levels of SOD1, GPX1, catalase and UCP2 in the antioxidant system of K562 cells. Analysis of the TCGA and GSE13159 datasets, along with samples from West China Hospital, revealed that patients exhibiting high PGC-1α expression had a poor prognosis.\nCONCLUSION: The m6A methylation-modifying enzyme METTL3 is an independent prognostic factor for poor prognosis in AML patients. PGC-1α is a downstream signaling molecule of METTL3, and METTL3 affects its expression by regulating the m6A level of PGC-1α. PGC-1α acts as an oncogene in AML by affecting the MAPK pathway and antioxidant system.", "claims": [{"id": "claim-method", "statement": "Univariate and multivariate Cox regression analyses were used to evaluate the effects of various factors on survival. Survival curves were plotted using the Kaplan–Meier method and compared using the log‐rank test. Additionally, FDR (False Discovery Rate) was utilized for multiple comparisons.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:40171845", "locator": "sections[15] \"Data Analysis\" paragraph 2", "quote": "Univariate and multivariate Cox regression analyses were used to evaluate the effects of various factors on survival. Survival curves were plotted using the Kaplan–Meier method and compared using the log‐rank test. Additionally, FDR (False Discovery Rate) was utilized for multiple comparisons."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The data that support the findings of this study are openly available in the TCGA at https://www.cbioportal.org and in the GEO at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE13159 reference number GSE13159 [22]. 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The data that support the findings of this study from patient samples are available from the corresponding author upon reasonable request."}], "state": "complete"}, {"id": "claim-target-result", "statement": "Positive METTL3 was found to be an independent adverse prognostic factor for AML (HR: 5.635, 95% CI: 1.147–27.694, p = 0.033), while positive WTAP expression was not.", "kind": "quantitative", "target": {"value": 95.0, "unit": "per cent", "tolerance": null, "source": "Positive METTL3 was found to be an independent adverse prognostic factor for AML (HR: 5.635, 95% CI: 1.147–27.694, p = 0.033), while positive WTAP expression was not."}, "evidence": [{"asset": "source:pmid:40171845", "locator": "sections[18] \"METTL3 and WTAP Indicate Poor Prognosis, With METTL3 as an Independent Prognostic Factor\" paragraph 4", "quote": "Positive METTL3 was found to be an independent adverse prognostic factor for AML (HR: 5.635, 95% CI: 1.147–27.694, p = 0.033), while positive WTAP expression was not."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "Positive METTL3 was found to be an independent adverse prognostic factor for AML (HR: 5.635, 95% CI: 1.147–27.694, p = 0.033), while positive WTAP expression was not.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:40171845"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. 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"GSM330230", "GSM330231", "GSM330232", "GSM330233", "GSM330234", "GSM330235", "GSM330236", "GSM330237", "GSM330238", "GSM330239", "GSM330240", "GSM330241", "GSM330242", "GSM330243", "GSM330244", "GSM330245", "GSM330246", "GSM330247", "GSM330248", "GSM330249", "GSM330250", "GSM330251", "GSM330252", "GSM330253", "GSM330254", "GSM330255", "GSM330256", "GSM330257", "GSM330258", "GSM330259", "GSM330260", "GSM330261", "GSM330262", "GSM330263", "GSM330264", "GSM330265", "GSM330266", "GSM330267", "GSM330268", "GSM330269", "GSM330270", "GSM330271", "GSM330272", "GSM330273", "GSM330274", "GSM330275", "GSM330276", "GSM330277", "GSM330278", "GSM330279", "GSM330280", "GSM330281", "GSM330282", "GSM330283", "GSM330284", "GSM330285", "GSM330286", "GSM330287", "GSM330288", "GSM330289", "GSM330290", "GSM330291", "GSM330292", "GSM330293", "GSM330294", "GSM330295", "GSM330296", "GSM330297", "GSM330298", "GSM330299", "GSM330300", "GSM330301", "GSM330302", "GSM330303", "GSM330304", "GSM330305", "GSM330306", "GSM330307", "GSM330308", "GSM330309", "GSM330310", "GSM330317", "GSM330318", "GSM330319", "GSM330320", "GSM330321", "GSM330322", "GSM330323", "GSM330324", "GSM330325", "GSM330326", "GSM330327", "GSM330328", "GSM330329", "GSM330330", "GSM330331", "GSM330332", "GSM330333", "GSM330334", "GSM330335", "GSM330336", "GSM330337", "GSM330338", "GSM330339", "GSM330340", "GSM330341", "GSM330342", "GSM330343", "GSM330344", "GSM330345", "GSM330346", "GSM330347", "GSM330348", "GSM330349", "GSM330350", "GSM330351", "GSM330352", "GSM330353", "GSM330354", "GSM330355", "GSM330356", "GSM330357", "GSM330358", "GSM330359", "GSM330360", "GSM330361", "GSM330362", "GSM330363", "GSM330364", "GSM330365", "GSM330366", "GSM330367", "GSM330368", "GSM330369", "GSM330370", "GSM330371", "GSM330372", "GSM330373", "GSM330374", "GSM330375", "GSM330376", "GSM330377", "GSM330378", "GSM330379", "GSM330380", "GSM330381", "GSM330382", "GSM330383", "GSM330384", "GSM330385", "GSM330386", "GSM330387", "GSM330388", "GSM330389", "GSM330390", "GSM330391", "GSM330392", "GSM330393", "GSM330394", "GSM330395", "GSM330396", "GSM330397", "GSM330398", "GSM330399", "GSM330400", "GSM330401", "GSM330402", "GSM330403", "GSM330404", "GSM330405", "GSM330406", "GSM330407", "GSM330408", "GSM330409", "GSM330410", "GSM330411", "GSM330412", "GSM330413", "GSM330414", "GSM330415", "GSM330416", "GSM330417", "GSM330418", "GSM330419", "GSM330420", "GSM330421", "GSM330422", "GSM330423", "GSM330424", "GSM330425", "GSM330426", "GSM330427", "GSM330428", "GSM330429", "GSM330430", "GSM330431", "GSM330432", "GSM330433", "GSM330434", "GSM330435", "GSM330436", "GSM330437", "GSM330438", "GSM330439", "GSM330440", "GSM330441", "GSM330442", "GSM330443", "GSM330444", "GSM330445", "GSM330446", "GSM330447", "GSM330448", "GSM330449", "GSM330450", "GSM330451", "GSM330452", "GSM330453", "GSM330454", "GSM330455", "GSM330456", "GSM330457", "GSM330458", "GSM330459", "GSM330460", "GSM330461", "GSM330462", "GSM330463", "GSM330464", "GSM330465", "GSM330466", "GSM330467", "GSM330468", "GSM330469", "GSM330470", "GSM330471", "GSM330472", "GSM330473", "GSM330474", "GSM330475", "GSM330476", "GSM330477", "GSM330478", "GSM330479", "GSM330480", "GSM330481", "GSM330482", "GSM330483", "GSM330484", "GSM330485", "GSM330486", "GSM330487", "GSM330488", "GSM330489", "GSM330490", "GSM330491", "GSM330492", "GSM330493", "GSM330494", "GSM330495", "GSM330496", "GSM330497", "GSM330498", "GSM330499", "GSM330500", "GSM330501", "GSM330502", "GSM330503", "GSM330504", "GSM330505", "GSM330506", "GSM330507", "GSM330508", "GSM330509", "GSM330510", "GSM330511", "GSM330512", "GSM330513", "GSM330514", "GSM330515", "GSM330516", "GSM330517", "GSM330518", "GSM330519", "GSM330520", "GSM330521", "GSM330522", "GSM330523", "GSM330524", "GSM330525", "GSM330526", "GSM330527", "GSM330528", "GSM330529", "GSM330530", "GSM330531", "GSM330532", "GSM330533", "GSM330534", "GSM330535", "GSM330536", "GSM330537", "GSM330538", "GSM330539", "GSM330540", "GSM330541", "GSM330542", "GSM330543", "GSM330544", "GSM330545", "GSM330546", "GSM330547", "GSM330548", "GSM330549", "GSM330550", "GSM330551", "GSM330552", "GSM330553", "GSM330554", "GSM330555", "GSM330556", "GSM330557", "GSM330558", "GSM330559", "GSM330560", "GSM330561", "GSM330562", "GSM330563", "GSM330564", "GSM330565", "GSM330566", "GSM330567", "GSM330568", "GSM330569", "GSM330570", "GSM330571", "GSM330572", "GSM330573", "GSM330574", "GSM330575", "GSM330576", "GSM330577", "GSM330578", "GSM330579", "GSM330580", "GSM330581", "GSM330582", "GSM330583", "GSM330584", "GSM330585", "GSM330586", "GSM330587", "GSM330588", "GSM330589", "GSM330590", "GSM330591", "GSM330592", "GSM330593", "GSM330594", "GSM330595", "GSM330596", "GSM330597", "GSM330598", "GSM330599", "GSM330600", "GSM330601", "GSM330602", "GSM330603", "GSM330604", "GSM330605", "GSM330606", "GSM330607", "GSM330608", "GSM330609", "GSM330610", "GSM330611", "GSM330612", "GSM330613", "GSM330614", "GSM330615", "GSM330616", "GSM330617", "GSM330618", "GSM330619", "GSM330620", "GSM330621", "GSM330622", "GSM330623", "GSM330624", "GSM330625", "GSM330626", "GSM330627", "GSM330628", "GSM330629", "GSM330630", "GSM330631", "GSM330632", "GSM330633", "GSM330634", "GSM330635", "GSM330636", "GSM330637", "GSM330638", "GSM330639", "GSM330640", "GSM330641", "GSM330642", "GSM330643", "GSM330644", "GSM330645", "GSM330646", "GSM330647", "GSM330648", "GSM330649", "GSM330650", "GSM330651", "GSM330652", "GSM330653", "GSM330654", "GSM330655", "GSM330656", "GSM330657", "GSM330658", "GSM330659", "GSM330660", "GSM330661", "GSM330662", "GSM330663", "GSM330664", "GSM330665", "GSM330666", "GSM330667", "GSM330668", "GSM330669", "GSM330670", "GSM330671", "GSM330672", "GSM330673", "GSM330674", "GSM330675", "GSM330676", "GSM330677", "GSM330678", "GSM330679", "GSM330680", "GSM330681", "GSM330682", "GSM330683", "GSM330684", "GSM330685", "GSM330686", "GSM330687", "GSM330688", "GSM330689", "GSM330690", "GSM330691", "GSM330692", "GSM330693", "GSM330694", "GSM330695", "GSM330696", "GSM330697", "GSM330698", "GSM330699", "GSM330700", "GSM330701", "GSM330702", "GSM330703", "GSM330704", "GSM330705", "GSM330706", "GSM330707", "GSM330708", "GSM330709", "GSM330710", "GSM330711", "GSM330712", "GSM330713", "GSM330714", "GSM330715", "GSM330716", "GSM330717", "GSM330718", "GSM330719", "GSM330720", "GSM330721", "GSM330722", "GSM330723", "GSM330724", "GSM330725", "GSM330726", "GSM330727", "GSM330728", "GSM330729", "GSM330730", "GSM330731", "GSM330732", "GSM330733", "GSM330734", "GSM330735", "GSM330736", "GSM330737", "GSM330738", "GSM330739", "GSM330740", "GSM330741", "GSM330742", "GSM330743", "GSM330744", "GSM330745", "GSM330746", "GSM330747", "GSM330748", "GSM330749", "GSM330750", "GSM330751", "GSM330752", "GSM330753", "GSM330754", "GSM330755", "GSM330756", "GSM330757", "GSM330758", "GSM330759", "GSM330760", "GSM330761", "GSM330762", "GSM330763", "GSM330764", "GSM330765", "GSM330766", "GSM330767", "GSM330768", "GSM330769", "GSM330770", "GSM330771", "GSM330772", "GSM330773", "GSM330774", "GSM330775", "GSM330776", "GSM330777", "GSM330778", "GSM330779", "GSM330780", "GSM330781", "GSM330782", "GSM330783", "GSM330784", "GSM330785", "GSM330786", "GSM330787", "GSM330788", "GSM330789", "GSM330790", "GSM330791", "GSM330792", "GSM330793", "GSM330794", "GSM330795", "GSM330796", "GSM330797", "GSM330798", "GSM330799", "GSM330800", "GSM330801", "GSM330802", "GSM330803", "GSM330804", "GSM330805", "GSM330806", "GSM330807", "GSM330808", "GSM330809", "GSM330810", "GSM330811", "GSM330812", "GSM330813", "GSM330814", "GSM330815", "GSM330816", "GSM330817", "GSM330818", "GSM330819", "GSM330820", "GSM330821", "GSM330822", "GSM330823", "GSM330824", "GSM330825", "GSM330826", "GSM330827", "GSM330828", "GSM330829", "GSM330830", "GSM330831", "GSM330832", "GSM330833", "GSM330834", "GSM330835", "GSM330836", "GSM330837", "GSM330838", "GSM330839", "GSM330840", "GSM330841", "GSM330842", "GSM330843", "GSM330844", "GSM330845", "GSM330846", "GSM330847", "GSM330848", "GSM330849", "GSM330850", "GSM330851", "GSM330852", "GSM330853", "GSM330854", "GSM330855", "GSM330856", "GSM330857", "GSM330858", "GSM330859", "GSM330860", "GSM330861", "GSM330862", "GSM330863", "GSM330864", "GSM330865", "GSM330866", "GSM330867", "GSM330868", "GSM330869", "GSM330870", "GSM330871", "GSM330872", "GSM330873", "GSM330874", "GSM330875", "GSM330876", "GSM330877", "GSM330878", "GSM330879", "GSM330880", "GSM330881", "GSM330882", "GSM330883", "GSM330884", "GSM330885", "GSM330886", "GSM330887", "GSM330888", "GSM330889", "GSM330890", "GSM330891", "GSM330892", "GSM330893", "GSM330894", "GSM330895", "GSM330896", "GSM330897", "GSM330898", "GSM330899", "GSM330900", "GSM330901", "GSM330902", "GSM330903", "GSM330904", "GSM330905", "GSM330906", "GSM330907", "GSM330908", "GSM330909", "GSM330910", "GSM330911", "GSM330912", "GSM330913", "GSM330914", "GSM330915", "GSM330916", "GSM330917", "GSM330918", "GSM330919", "GSM330920", "GSM330921", "GSM330922", "GSM330923", "GSM330924", "GSM330925", "GSM330926", "GSM330927", "GSM330928", "GSM330929", "GSM330930", "GSM330931", "GSM330932", "GSM330933", "GSM330934", "GSM330935", "GSM330936", "GSM330937", "GSM330938", "GSM330939", "GSM330940", "GSM330941", "GSM330942", "GSM330943", "GSM330944", "GSM330945", "GSM330946", "GSM330947", "GSM330948", "GSM330949", "GSM330950", "GSM330951", "GSM330952", "GSM330953", "GSM330954", "GSM330955", "GSM330956", "GSM330957", "GSM330958", "GSM330959", "GSM330960", "GSM330961", "GSM330962", "GSM330963", "GSM330964", "GSM330965", "GSM330966", "GSM330967", "GSM330968", "GSM330969", "GSM330970", "GSM330971", "GSM330972", "GSM330973", "GSM330974", "GSM330975", "GSM330976", "GSM330977", "GSM330978", "GSM330979", "GSM330980", "GSM330981", "GSM330982", "GSM330983", "GSM330984", "GSM330985", "GSM330986", "GSM330987", "GSM330988", "GSM330989", "GSM330990", "GSM330991", "GSM330992", "GSM330993", "GSM330994", "GSM330995", "GSM330996", "GSM330997", "GSM330998", "GSM330999", "GSM331000", "GSM331001", "GSM331002", "GSM331003", "GSM331004", "GSM331005", "GSM331006", "GSM331007", "GSM331008", "GSM331009", "GSM331010", "GSM331011", "GSM331012", "GSM331013", "GSM331014", "GSM331015", "GSM331016", "GSM331017", "GSM331018", "GSM331019", "GSM331020", "GSM331021", "GSM331022", "GSM331023", "GSM331024", "GSM331025", "GSM331026", "GSM331027", "GSM331028", "GSM331029", "GSM331030", "GSM331031", "GSM331032", "GSM331033", "GSM331034", "GSM331035", "GSM331036", "GSM331037", "GSM331038", "GSM331039", "GSM331040", "GSM331041", "GSM331042", "GSM331043", "GSM331044", "GSM331045", "GSM331046", "GSM331047", "GSM331048", "GSM331049", "GSM331050", "GSM331051", "GSM331052", "GSM331053", "GSM331054", "GSM331055", "GSM331056", "GSM331057", "GSM331058", "GSM331059", "GSM331060", "GSM331061", "GSM331062", "GSM331063", "GSM331064", "GSM331065", "GSM331066", "GSM331067", "GSM331068", "GSM331069", "GSM331070", "GSM331071", "GSM331072", "GSM331073", "GSM331074", "GSM331075", "GSM331076", "GSM331077", "GSM331078", "GSM331079", "GSM331080", "GSM331081", "GSM331082", 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Following METTL3 knockdown, we observed a decrease in the m6A level of", "ere positively correlated. Similar to METTL3 knockdown, PGC-1α gene knockdown resulted in increased", "ed. Similar to METTL3 knockdown, PGC-1α gene knockdown resulted in increased phosphorylation of the"], "order_basis": "paper_text_order:740", "id": "assay:1"}, {"role": "data_generation", "definition_id": "cell_culture", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["itochondrial oxidative stress gene PGC-1α in K562 and MV4-11 cells. We analyzed the expression", "talase and UCP2 in the antioxidant system of K562 cells. Analysis of the TCGA and GSE13159 dat", "n DMEM medium supplemented with 10% FBS. All cell lines were maintained at 37°C in a humidified atmosphere with 5% C", "tology, West China Hospital. K562 cells were cultured in RPMI 1640 medium supplemented with 10% FBS;"], "order_basis": "paper_text_order:844", "id": "assay:2"}, {"role": "data_generation", "definition_id": "western_blot", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["AML patients (n = 112); (B) A representative Western blot (WB) image demonstrating the expression of m", "China Hospital (n = 108); (D) Representative Western Blot analysis showing PGC‐1α protein expression;"], "order_basis": "paper_text_order:3802", "id": "assay:3"}, {"role": "analysis", "definition_id": "survival_analysis", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["cox_ph"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["Univariate and multivariate Cox regression analyses were used to evaluate the effects of various factors on survival. 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