Abstract 6409: Epigenetic regulation of drug and disease related genes impact outcomes in pediatric AML

Abstract DNA methylation is dysregulated in Acute Myeloid Leukemia (AML), which can have significant impact on regulation and expression levels of genes involved in Pharmacokinetic/Pharmacodynamics of AML chemotherapy as well as genes involved in AML pathogenesis. Thus, in this study we evaluated methylation levels of these genes for association with outcome, in pediatric AML patients. DNA methylation data available from GEO and GDC datasets and gene expression data available from TARGET for the discovery cohort of patient treated on Children’s Oncology Group clinical trials (n=924) were evaluated by Cox proportional hazard analysis for association with event-free survival (EFS) and overall survival (OS) and Minimal Residual Disease after induction I (MRD1). The results were validated in an independent cohort of patients treated on AML02 trial (n=159). We identified 23 CpGs in drug pathway genes, and 43 CpGs within AML relevant genes, that were associated with at least one endpoint at p< 2.17×10-5. These included, ABCA3, a drug efflux transporter, with higher methylation associated with poor OS (HR= 1.23, p <10−12), EFS (HR= 1.14, p <10−10), and greater MRD1 positivity (p <10−5). KIT hypermethylation was associated with unfavorable outcomes (OS, HR= 1.22, p <10−9; EFS, HR= 1.15, p <10−7). Among other genes DNMT3B hypermethylation was also predictive of detrimental survival (OS, HR= 1.143, p= 0.04). These results were replicated in the validation cohort. Our study shows significant age-adjusted correlations between DNA methylation of some CpGs sites and gene expression level. In conclusion, this focused approach demonstrated impact of variation in DNA methylation of key genes of relevance to AML drugs or pathogenesis on clinical outcome in AML opening up opportunities to predict outcome and strategically utilize hypomethylating agents to improve outcome. Citation Format: Naifah Alshameri, Francisco Marchi, Xueyuan Cao, Stanley Pounds, Jatinder Lamba. Epigenetic regulation of drug and disease related genes impact outcomes in pediatric AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6409.