{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T08:50:39Z","timestamp":1785919839078,"version":"3.56.0"},"reference-count":40,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Aberrant DNA methylation is a hallmark of acute myeloid leukemia (AML) and contributes to leukemogenesis, treatment response, and clinical heterogeneity. While genome-wide methylation studies have identified prognostic methylation signatures, the impact of DNA methylation within pharmacologic pathways and AML-relevant disease genes remains incompletely understood. We investigated the association of DNA methylation in genes of pharmacokinetic\/pharmacodynamic (PK\/PD) pathways of drugs used to treat AML and in myeloid leukemia-related genes with treatment outcomes in pediatric AML. Methods: DNA methylation profiles from 924 pediatric AML patients treated on Children\u2019s Oncology Group trials (AAML1031, AAML0531, and AAML03P1\u2014available publicly) were analyzed as a discovery cohort. A validation cohort included 159 patients treated on the AML02 trial. A total of 2296 variable CpG sites mapping to 65 PK\/PD genes and 107 AML biology\/leukemia stemness genes were evaluated. Associations between CpG methylation, gene expression, event-free survival (EFS), overall survival (OS), and measurable residual disease after induction I (MRD1) were assessed using Cox proportional hazards, logistic regression, and correlation analyses. Results: Twenty-three CpG sites in PK\/PD genes and forty-two CpG sites in AML-related genes were significantly associated with at least one clinical endpoint after Bonferroni correction (p &lt; 2.17 \u00d7 10\u22125). Hypermethylation of drug transporters ABCA3, ABCC1, and SLC22A1, as well as pharmacologically relevant genes MPO, NOS3, and CTPS1, was associated with inferior survival and\/or increased MRD1 positivity. Among AML biology genes, methylation of ETV6, NOTCH1, RUNX1, KIT, MPL, DNMT3A, and DNMT3B demonstrated consistent associations with outcomes across discovery and validation cohorts. Several genes exhibited significant inverse correlations between DNA methylation and gene expression, including MPO, KIT, MPL, SPINK2, and DNMT3B, supporting functional epigenetic regulation. Notably, hypermethylation of ABCA3, MPO, and MPL was reproducibly associated with poor OS and EFS in both cohorts. Conclusions: DNA methylation of key pharmacologic and leukemia-related genes is associated with clinical outcomes in pediatric AML. These findings identify biologically and clinically relevant epigenetic biomarkers that may improve risk stratification and support the development of precision medicine approaches incorporating DNA methylation profiling and epigenetic therapies in pediatric AML.<\/jats:p>","DOI":"10.3390\/cancers18152467","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T13:23:20Z","timestamp":1785504200000},"page":"2467","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["DNA Methylation of Pharmacologic and Leukemia-Related Genes Predicts Clinical Outcomes in Pediatric Acute Myeloid Leukemia"],"prefix":"10.3390","volume":"18","author":[{"given":"Naifah","family":"Alshameri","sequence":"first","affiliation":[{"name":"Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA"},{"name":"University of Hail, Hail 81451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7318-9137","authenticated-orcid":false,"given":"Francisco","family":"Marchi","sequence":"additional","affiliation":[{"name":"Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4396-7460","authenticated-orcid":false,"given":"Xueyuan","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Health Promotion\/Disease Prevention, University of Tennessee Health Science Center, Memphis, TN 38163, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey E.","family":"Rubnitz","sequence":"additional","affiliation":[{"name":"Ascentage Pharma Group, Rockville, MD 20850, USA"},{"name":"Department of Oncology, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9956-5647","authenticated-orcid":false,"given":"Raul C.","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Department of Oncology, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soheil","family":"Meshinchi","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanley B.","family":"Pounds","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0411-0007","authenticated-orcid":false,"given":"Jatinder K.","family":"Lamba","sequence":"additional","affiliation":[{"name":"Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA"},{"name":"UF Health Cancer Center, University of Florida, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,31]]},"reference":[{"key":"ref_1","first-page":"7","article-title":"Cancer statistics, 2019","volume":"69","author":"Siegel","year":"2019","journal-title":"CA Cancer J. 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