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In Mexico, its higher incidence and lower survival suggest a role for epigenetic factors like DNA methylation (DNAme). We conducted an epigenome-wide association study (EWAS) to define the methylation landscape and identify the profiles associated with ALL and relapse. Bone marrow or peripheral blood samples from pediatric ALL patients at diagnosis and controls without ALL were analyzed using an Infinium MethylationEPIC v2.0 array. Differential methylation was assessed using the ChAMP package. We identified a significant hypermethylated profile in ALL patients compared to controls. Probes in MAD1L1 and RPTOR contained the most differentially methylated CpG sites. Key affected pathways included proliferation, neurotransmission, and neuronal signaling. Survival analysis revealed that hypomethylation of four specific CpGs\u2014cg01052776 (RNH1), cg20747787, cg05001671, and cg01767116 (FBXL22)\u2014was significantly associated with an increased risk of relapse, highlighting their potential as prognostic biomarkers. This study underscores the importance of epigenetic mechanisms in pediatric ALL.<\/jats:p>","DOI":"10.3390\/ijms262110261","type":"journal-article","created":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T01:14:02Z","timestamp":1761182042000},"page":"10261","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Comprehensive Epigenome-Wide Profiling Reveals Distinctive DNA Methylation Signatures and Potential Prognostic Biomarkers in Mexican Pediatric B-ALL"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2118-7287","authenticated-orcid":false,"given":"Alan Alberto","family":"Fong-L\u00f3pez","sequence":"first","affiliation":[{"name":"Laboratorio de Innovaci\u00f3n y Medicina de Precisi\u00f3n, N\u00facleo \u201cA\u201d, Instituto Nacional de Medicina Gen\u00f3mica (INMEGEN), Mexico City 14610, Mexico"},{"name":"Programa de Doctorado en Biomedicina y Biotecnolog\u00eda Molecular, Escuela Nacional de Ciencias Biol\u00f3gicas, Instituto Polit\u00e9cnico Nacional, Mexico City 07738, Mexico"},{"name":"Laboratorio de Citopatolog\u00eda Ambiental, Departamento de Morfolog\u00eda, Escuela Nacional de Ciencias Biol\u00f3gicas, Instituto Polit\u00e9cnico Nacional, Campus Zacatenco, Mexico City 07738, Mexico"},{"name":"Facultad de Ciencias Qu\u00edmico-Biol\u00f3gicas, Universidad Aut\u00f3noma de Sinaloa, Culiac\u00e1n Rosales 80030, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8070-9727","authenticated-orcid":false,"given":"Juan Carlos","family":"N\u00fa\u00f1ez-Enr\u00edquez","sequence":"additional","affiliation":[{"name":"Divisi\u00f3n de Investigaci\u00f3n en Salud, Hospital de Pediatr\u00eda \u201cDr. Silvestre Frenk Freund\u201d, Centro M\u00e9dico Nacional \u201cSiglo XXI\u201d, Instituto Mexicano del Seguro Social (IMSS), Mexico City 06720, 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