{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T14:07:05Z","timestamp":1791900425504,"version":"4.3.4"},"reference-count":47,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T00:00:00Z","timestamp":1771891200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense RCRP program","doi-asserted-by":"publisher","award":["HT9425-24-1-0932"],"award-info":[{"award-number":["HT9425-24-1-0932"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["2P20GM121293"],"award-info":[{"award-number":["2P20GM121293"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"name":"UAMS Team Science Award","award":["AWD-104823"],"award-info":[{"award-number":["AWD-104823"]}]},{"name":"Marion B. Lyon New Scientist Development Award","award":["LYON5069"],"award-info":[{"award-number":["LYON5069"]}]},{"name":"UAMS start-up funds"},{"name":"WPRCI vouchers"},{"DOI":"10.13039\/100008231","name":"Arkansas Bioscience Institute","doi-asserted-by":"crossref","award":["ABIRC4426"],"award-info":[{"award-number":["ABIRC4426"]}],"id":[{"id":"10.13039\/100008231","id-type":"DOI","asserted-by":"crossref"}]},{"name":"European Union\u2019s Seventh Framework Program","award":["282510"],"award-info":[{"award-number":["282510"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: DNMT3B is frequently overexpressed in molecular subsets of acute myeloid leukemia (AML) and is associated with poor prognosis. Unlike DNMT3A, DNMT3B is rarely mutated, suggesting dysregulation through epigenetic mechanisms. The regulatory basis and downstream consequences of DNMT3B overexpression in AML remain incompletely defined. Methods: We integrated analyses of BeatAML, TCGA, and BLUEPRINT cohorts with multi-omic profiling (RNA-seq, DNA methylation, ATAC-seq, and proteomics) in DNMT3B-high AML models. Nanaomycin A (NanA) was used as a DNMT3B-directed functional probe to interrogate cis-regulatory remodeling, transcriptional circuitry, and apoptotic dependencies. Results: DNMT3B overexpression was linked to enhancer-associated chromatin activation rather than recurrent genetic mutation, particularly in CEBPA- and NPM1-mutant AML. NanA exposure produced focal epigenomic remodeling, including 6900 differentially methylated CpGs, with 268 CpGs located within regions of altered chromatin accessibility. These changes were accompanied by coordinated transcriptomic and proteomic reprogramming enriched for cell-cycle, checkpoint, and stress-response pathways. Functionally, DNMT3B perturbation induced redistribution of cell-cycle phases with increased S-phase fraction and progressive apoptosis. Transcriptional profiling demonstrated induction of BH3-only sensitizers (NOXA, PUMA), repression of BCL2, and compensatory upregulation of MCL1 and BCL-XL, collectively reshaping apoptotic dependency. Combined DNMT3B perturbation and BCL2 inhibition produced cooperative cytotoxicity in DNMT3B-high AML models. Conclusion: DNMT3B functions as a context-dependent epigenetic regulator linking enhancer-associated chromatin organization with proliferative control and apoptotic resistance in AML. DNMT3B-directed epigenetic perturbation remodels cis-regulatory circuitry and is associated with increased venetoclax responsiveness, supporting DNMT3B-governed networks as a candidate co-targeting axis in high-risk AML.<\/jats:p>","DOI":"10.3390\/cancers18050723","type":"journal-article","created":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T12:19:23Z","timestamp":1771935563000},"page":"723","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["DNMT3B Controls Enhancer-Linked Chromatin and Cell Cycle Networks in Acute Myeloid Leukemia"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-6029-3212","authenticated-orcid":false,"given":"Arundhati","family":"Chavan","sequence":"first","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Pediatrics, Arkansas Children\u2019s Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pritam","family":"Biswas","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Pediatrics, Arkansas Children\u2019s Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8822-0547","authenticated-orcid":false,"given":"Kimberly","family":"Stephens","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6555-3031","authenticated-orcid":false,"given":"Samrat","family":"Roy Choudhury","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Pediatrics, Arkansas Children\u2019s Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/B978-0-12-380866-0.60002-2","article-title":"DNA methylation and cancer","volume":"70","author":"Kulis","year":"2010","journal-title":"Adv. Genet."},{"key":"ref_2","first-page":"1","article-title":"Cancer as an epigenetic disease: DNA methylation and chromatin alterations in human tumours","volume":"196","author":"Esteller","year":"2002","journal-title":"J. Pathol. A J. Pathol. Soc. Great Br. Irel."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1002\/cbic.201000195","article-title":"Structure and function of mammalian DNA methyltransferases","volume":"12","author":"Jurkowska","year":"2011","journal-title":"Chembiochem"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2395","DOI":"10.1093\/hmg\/9.16.2395","article-title":"The DNA methyltransferases of mammals","volume":"9","author":"Bestor","year":"2000","journal-title":"Hum. Mol. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2424","DOI":"10.1056\/NEJMoa1005143","article-title":"DNMT3A mutations in acute myeloid leukemia","volume":"363","author":"Ley","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Hayette, S., Thomas, X., Jallades, L., Chabane, K., Charlot, C., Tigaud, I., Gazzo, S., Morisset, S., Cornillet-Lefebvre, P., and Plesa, A. (2012). High DNA methyltransferase DNMT3B levels: A poor prognostic marker in acute myeloid leukemia. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0051527"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5594","DOI":"10.1128\/MCB.23.16.5594-5605.2003","article-title":"Establishment and maintenance of genomic methylation patterns in mouse embryonic stem cells by Dnmt3a and Dnmt3b","volume":"23","author":"Chen","year":"2003","journal-title":"Mol. Cell Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1182\/blood-2015-07-655928","article-title":"Increased DNA methylation of Dnmt3b targets impairs leukemogenesis","volume":"127","author":"Schulze","year":"2016","journal-title":"Blood"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1038\/leu.2014.267","article-title":"Prognostic and biologic significance of DNMT3B expression in older patients with cytogenetically normal primary acute myeloid leukemia","volume":"29","author":"Niederwieser","year":"2015","journal-title":"Leukemia"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e233","DOI":"10.1038\/bcj.2014.51","article-title":"High DNA-methyltransferase 3B expression predicts poor outcome in acute myeloid leukemia, especially among patients with co-occurring NPM1 and FLT3 mutations","volume":"4","author":"Monteferrario","year":"2014","journal-title":"Blood Cancer J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"11453","DOI":"10.1038\/ncomms11453","article-title":"DNMT3B isoforms without catalytic activity stimulate gene body methylation as accessory proteins in somatic cells","volume":"7","author":"Duymich","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1177271919846454","DOI":"10.1177\/1177271919846454","article-title":"Oncogenic Roles and Inhibitors of DNMT1, DNMT3A, and DNMT3B in Acute Myeloid Leukaemia","volume":"14","author":"Wong","year":"2019","journal-title":"Biomark. Insights"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1016\/j.ccell.2022.07.002","article-title":"Integrative analysis of drug response and clinical outcome in acute myeloid leukemia","volume":"40","author":"Bottomly","year":"2022","journal-title":"Cancer Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1016\/j.celrep.2018.12.098","article-title":"Chromatin-Based Classification of Genetically Heterogeneous AMLs into Two Distinct Subtypes with Diverse Stemness Phenotypes","volume":"26","author":"Yi","year":"2019","journal-title":"Cell Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.cell.2015.11.062","article-title":"Functional genomic landscape of human breast cancer drivers, vulnerabilities, and resistance","volume":"164","author":"Marcotte","year":"2016","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1111\/cas.16069","article-title":"Enhancer-activated RET confers protection against oxidative stress to KMT2A-rearranged acute myeloid leukemia","volume":"115","author":"Frett","year":"2024","journal-title":"Cancer Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"W247","DOI":"10.1093\/nar\/gkp464","article-title":"Pscan: Finding over-represented transcription factor binding site motifs in sequences from co-regulated or co-expressed genes","volume":"37","author":"Zambelli","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/S0040-4020(02)01424-2","article-title":"Modern methods for the synthesis of substituted naphthalenes","volume":"59","author":"Rousseau","year":"2003","journal-title":"Tetrahedron"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/nrm2308","article-title":"The BCL-2 protein family: Opposing activities that mediate cell death","volume":"9","author":"Youle","year":"2008","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1038\/nrm2952","article-title":"Mitochondria and cell death: Outer membrane permeabilization and beyond","volume":"11","author":"Tait","year":"2010","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1038\/onc.2009.39","article-title":"BH3-only proteins in apoptosis and beyond: An overview","volume":"27","author":"Lomonosova","year":"2008","journal-title":"Oncogene"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/s41392-025-02176-0","article-title":"The BCL2 family: From apoptosis mechanisms to new advances in targeted therapy","volume":"10","author":"Vogler","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1038\/s43018-020-00126-z","article-title":"Fatty acid metabolism underlies venetoclax resistance in acute myeloid leukemia stem cells","volume":"1","author":"Stevens","year":"2020","journal-title":"Nat. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1158\/2159-8290.CD-18-0140","article-title":"A Novel MCL1 Inhibitor Combined with Venetoclax Rescues Venetoclax-Resistant Acute Myelogenous Leukemia","volume":"8","author":"Ramsey","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3015","DOI":"10.1158\/1535-7163.MCT-10-0609","article-title":"Nanaomycin A Selectively Inhibits DNMT3B and Reactivates Silenced Tumor Suppressor Genes in Human Cancer Cells","volume":"9","author":"Kuck","year":"2010","journal-title":"Mol. Cancer Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1186\/s13046-019-1442-2","article-title":"DNMT3b\/OCT4 expression confers sorafenib resistance and poor prognosis of hepatocellular carcinoma through IL-6\/STAT3 regulation","volume":"38","author":"Lai","year":"2019","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1038\/s41588-022-01241-6","article-title":"Evidence that direct inhibition of transcription factor binding is the prevailing mode of gene and repeat repression by DNA methylation","volume":"54","author":"Kaluscha","year":"2022","journal-title":"Nat. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1038\/s41568-019-0143-7","article-title":"The broken cycle: E2F dysfunction in cancer","volume":"19","author":"Kent","year":"2019","journal-title":"Nat. Rev. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"101843","DOI":"10.1016\/j.gendis.2025.101843","article-title":"Transcriptional rewiring by enhancer methylation in CBFA2T3-GLIS2-driven pediatric acute megakaryoblastic leukemia","volume":"13","author":"Choudhury","year":"2026","journal-title":"Genes. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1101\/gad.13.12.1501","article-title":"CDK inhibitors: Positive and negative regulators of G1-phase progression","volume":"13","author":"Sherr","year":"1999","journal-title":"Genes. Dev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1007\/s00109-016-1475-3","article-title":"Cyclin D1, cancer progression, and opportunities in cancer treatment","volume":"94","author":"Qie","year":"2016","journal-title":"J. Mol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3220","DOI":"10.1080\/15384101.2015.1084445","article-title":"Targeting CDK6 in cancer: State of the art and new insights","volume":"14","author":"Tadesse","year":"2015","journal-title":"Cell Cycle"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1182\/blood-2018-08-868752","article-title":"Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia","volume":"133","author":"DiNardo","year":"2019","journal-title":"Blood"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1182\/blood.V128.22.101.101","article-title":"Upregulation of MAPK\/MCL-1 Maintaining Mitochondrial Oxidative Phosphorylation Confers Acquired Resistance to BCL-2 Inhibitor Venetoclax in AML","volume":"128","author":"Zhang","year":"2016","journal-title":"Blood"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Liu, J., Chen, Y., Yu, L., and Yang, L. (2022). Mechanisms of venetoclax resistance and solutions. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.1005659"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1002\/jha2.663","article-title":"Venetoclax with decitabine or azacitidine in the first-line treatment of acute myeloid leukemia","volume":"4","author":"Bouligny","year":"2023","journal-title":"EJHaem"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1007\/s00018-018-2783-2","article-title":"Enhancer DNA methylation in acute myeloid leukemia and myelodysplastic syndromes","volume":"75","author":"Benetatos","year":"2018","journal-title":"Cell Mol. Life Sci."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Kim, D.J. (2025). The Role of the DNA Methyltransferase Family and the Therapeutic Potential of DNMT Inhibitors in Tumor Treatment. Curr. Oncol., 32.","DOI":"10.3390\/curroncol32020088"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"100838","DOI":"10.1016\/j.isci.2020.100838","article-title":"DNMT3B Oncogenic Activity in Human Intestinal Cancer Is Not Linked to CIMP or BRAFV600E Mutation","volume":"23","author":"MacKenzie","year":"2020","journal-title":"iScience"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1038\/s41587-019-0201-4","article-title":"Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype","volume":"37","author":"Kim","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"R106","DOI":"10.1186\/gb-2010-11-10-r106","article-title":"Differential expression analysis for sequence count data","volume":"11","author":"Anders","year":"2010","journal-title":"Genome Biol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Searle, B.C., Pino, L.K., Egertson, J.D., Ting, Y.S., Lawrence, R.T., MacLean, B.X., Vill\u00e9n, J., and MacCoss, M.J. (2018). Chromatogram libraries improve peptide detection and quantification by data independent acquisition mass spectrometry. Nat. Commun., 9.","DOI":"10.1038\/s41467-018-07454-w"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"25625","DOI":"10.1021\/acsomega.0c02564","article-title":"proteiNorm\u2014A User-Friendly Tool for Normalization and Analysis of TMT and Label-Free Protein Quantification","volume":"5","author":"Graw","year":"2020","journal-title":"ACS Omega"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"S96","DOI":"10.1093\/bioinformatics\/18.suppl_1.S96","article-title":"Variance stabilization applied to microarray data calibration and to the quantification of differential expression","volume":"18","author":"Huber","year":"2002","journal-title":"Bioinformatics"},{"key":"ref_45","unstructured":"Bolstad, B. (R Package, 2019). R Package, PreprocessCore: A collection of pre-processing functions."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3114","DOI":"10.1021\/pr401264n","article-title":"Normalyzer: A Tool for Rapid Evaluation of Normalization Methods for Omics Data Sets","volume":"13","author":"Chawade","year":"2014","journal-title":"J. Proteome Res."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/5\/723\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T05:26:00Z","timestamp":1772083560000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/5\/723"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,24]]},"references-count":47,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["cancers18050723"],"URL":"https:\/\/doi.org\/10.3390\/cancers18050723","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,24]]}}}