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Relapse in acute myeloid leukemia (AML) is frequently associated with chemoresistance, yet the molecular mechanisms driving this transition remain incompletely understood. To explore relapse-associated epigenetic remodeling, we reanalyzed publicly available Nanopore whole-genome methylation data from three AML patients with matched onset and relapse samples. We focused on CpG-poor transcription factor (TF)-associated regulatory regions, recently implicated as unconventional epigenetic hotspots in leukemia progression. Across all samples, relapse was characterized by a consistent gain in DNA methylation within CpG-poor TF regions, with all ranked loci demonstrating a positive mean Δβ shift. Heatmap visualization of the top-ranked regions revealed distinct clustering of relapse versus onset samples, supporting the presence of a coordinated epigenetic signature rather than random methylation drift. These findings suggest that relapse AML cells may acquire targeted methylation to suppress key regulatory networks involved in DNA repair, apoptosis, and growth control, thereby enabling therapeutic escape. This work highlights the potential utility of Nanopore methylation profiling as a real-time biomarker platform to detect relapse-associated epigenetic rewiring and guide precision treatment strategies.