{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T18:18:18Z","timestamp":1788286698724,"version":"build-2803163510"},"reference-count":51,"publisher":"National Academy of Sciences","issue":"36","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"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":["82574434"],"award-info":[{"award-number":["82574434"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82270172"],"award-info":[{"award-number":["82270172"]}],"id":[{"id":"10.13039\/501100001809","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":[[2026,9,8]]},"abstract":"<jats:p>\n                    Chromosomal translocations produce oncogenic fusion proteins such as AML1-ETO, which predominantly occupy gene promoters to induce transcriptional reprogramming in leukemia stem cells (LSCs), consequently driving the pathogenesis of t(8;21) acute myeloid leukemia (AML). However, whether AML1-ETO is recruited to additional regulatory DNA elements to orchestrate oncogenic gene expression programs has not been fully addressed. Here, we define AML1-ETO and H3K27ac CUT&amp;Tag landscapes in primary t(8;21) AML CD34\n                    <jats:sup>+<\/jats:sup>\n                    cells and t(8;21) AML cell lines, revealing AML1-ETO binding at a distal enhancer of the RNA N4-acetylcytidine (ac4C) writer N-acetyltransferase 10 (NAT10), thereby driving its transcriptional activation. Genetic ablation or pharmacological inhibition of NAT10 restricted the survival and self-renewal of LSCs in primary t(8;21) AML CD34\n                    <jats:sup>+<\/jats:sup>\n                    cells, as well as in a retroviral AML1-ETO9a-driven t(8;21) AML mouse model, establishing NAT10 as a potential therapeutic vulnerability. Mechanistically, NAT10 is recruited to glutathione S-transferase omega 2 (GSTO2) mRNA to catalyze ac4C modification, thereby enhancing transcript stability and reprogramming glutathione metabolism, as demonstrated by ac4C profiling, RNA immunoprecipitation (RIP), and dCas13b-NAT10-based analyses. Silencing of GSTO2 in primary t(8;21) AML CD34\n                    <jats:sup>+<\/jats:sup>\n                    cells decreased intracellular reduced glutathione (GSH) levels and compromised LSC survival and self-renewal, whereas GSTO2 overexpression or GSH supplementation largely rescued LSC maintenance following NAT10 loss. Collectively, these findings enrich and extend the understanding of AML1-ETO regulatory programs by linking distal enhancer activity to a NAT10\u2013GSTO2 ac4C\u2013GSH axis that integrates epigenomic, posttranscriptional, and metabolic reprogramming to sustain LSC stemness, highlighting this circuit as a potential therapeutic vulnerability in t(8;21) AML.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2608310123","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T17:58:11Z","timestamp":1788285491000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["AML1-ETO hijacks a distal enhancer of NAT10 to reprogram glutathione metabolism and sustain leukemia stem cell stemness"],"prefix":"10.1073","volume":"123","author":[{"given":"Shuyi","family":"Li","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01vy4gh70","id-type":"ROR","asserted-by":"publisher"}],"name":"Shenzhen University International Cancer Center, Department of Hematology and Oncology, Hematology Institution, Shenzhen University General Hospital, International Science and Technology Cooperation: Carson Cancer Stem Cell Vaccines R&D Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen University","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shujiao","family":"He","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01vy4gh70","id-type":"ROR","asserted-by":"publisher"}],"name":"Shenzhen University International Cancer Center, Department of Hematology and Oncology, Hematology Institution, Shenzhen University General Hospital, International Science and Technology Cooperation: Carson Cancer Stem Cell Vaccines R&D Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen University","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3354-1811","authenticated-orcid":false,"given":"Yongwei","family":"Su","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01vy4gh70","id-type":"ROR","asserted-by":"publisher"}],"name":"Shenzhen University International Cancer Center, Department of Hematology and Oncology, Hematology Institution, Shenzhen University General Hospital, International Science and Technology Cooperation: Carson Cancer Stem Cell Vaccines R&D Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen University","place":["Shenzhen, China"]},{"id":[{"id":"https:\/\/ror.org\/01vy4gh70","id-type":"ROR","asserted-by":"publisher"}],"name":"Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen University","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Wang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01vy4gh70","id-type":"ROR","asserted-by":"publisher"}],"name":"Shenzhen University International Cancer Center, Department of Hematology and Oncology, Hematology Institution, Shenzhen University General Hospital, International Science and Technology Cooperation: Carson Cancer Stem Cell Vaccines R&D Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen University","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiran","family":"Wang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01vy4gh70","id-type":"ROR","asserted-by":"publisher"}],"name":"Shenzhen University International Cancer Center, Department of Hematology and Oncology, Hematology Institution, Shenzhen University General Hospital, International Science and Technology Cooperation: Carson Cancer Stem Cell Vaccines R&D Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen University","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Xu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01vy4gh70","id-type":"ROR","asserted-by":"publisher"}],"name":"Shenzhen University International Cancer Center, Department of Hematology and Oncology, Hematology Institution, Shenzhen University General Hospital, International Science and Technology Cooperation: Carson Cancer Stem Cell Vaccines R&D Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen University","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Yu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01vy4gh70","id-type":"ROR","asserted-by":"publisher"}],"name":"Shenzhen University International Cancer Center, Department of Hematology and Oncology, Hematology Institution, Shenzhen University General Hospital, International Science and Technology Cooperation: Carson Cancer Stem Cell Vaccines R&D Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen University","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4415-3848","authenticated-orcid":false,"given":"Jingfeng","family":"Zhou","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01vy4gh70","id-type":"ROR","asserted-by":"publisher"}],"name":"Shenzhen University International Cancer Center, Department of Hematology and Oncology, Hematology Institution, Shenzhen University General Hospital, International Science and Technology Cooperation: Carson Cancer Stem Cell Vaccines R&D Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen University","place":["Shenzhen, 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Gerritsen Acute myeloid leukemia associated RUNX1 variants induce aberrant expression of transcription factor TCF4. 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Chen , NAT10\/ac4C\/FOXP1 promotes malignant progression and facilitates immunosuppression by reprogramming glycolytic metabolism in cervical cancer. Adv. Sci. (Weinheim, Baden-Wurttemberg, Germany) 10, e2302705 (2023).","journal-title":"Adv. Sci. 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Mandoli . The hematopoietic transcription factors RUNX1 and ERG prevent AML1-ETO oncogene overexpression and onset of the apoptosis program in t(8;21) AMLs. Cell Rep. 17 2087-2100 (2016).","DOI":"10.1016\/j.celrep.2016.08.082"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-015-1445-0"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-026-01949-1"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.ady0301"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-1533"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1443"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abh3462"},{"key":"e_1_3_4_51_2","unstructured":"S. Li AML1-ETO hijacks a distal enhancer of NAT10 to reprogram glutathione metabolism and sustain leukemia stem cell stemness. NCBI Sequence Read Archive. https:\/\/www.ncbi.nlm.nih.gov\/bioproject\/PRJNA1463779. Deposited 9 May 2026."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2608310123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T17:58:41Z","timestamp":1788285521000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2608310123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,1]]},"references-count":51,"journal-issue":{"issue":"36","published-print":{"date-parts":[[2026,9,8]]}},"alternative-id":["10.1073\/pnas.2608310123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2608310123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,1]]},"assertion":[{"value":"2026-03-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-01","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2608310123"}}