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Pediatric B-ALL is generally associated with high cure rates, while adult forms of the disease are often more aggressive and less responsive to treatment. This review examines the age-specific genetic and epigenetic landscapes that contribute to this disparity, revealing how the nature and timing of molecular alterations point to fundamentally different leukemogenic processes. Favorable genetic aberrations, such as ETV6::RUNX1 and hyperdiploidy, are predominant in children, whereas adults more frequently present with high-risk features, including BCR::ABL1 fusions and IKZF1 deletions. Epigenetic distinctions are similarly age-dependent, involving divergent patterns of DNA methylation, histone modifications, and non-coding RNA expression. For example, pediatric B-ALL frequently harbors mutations in epigenetic regulators like SETD2 and CREBBP, while adult B-ALL is more commonly affected by alterations in TET2 and IDH1\/2. These molecular differences are not only prognostic but also mechanistic, reflecting distinct developmental trajectories and vulnerabilities. Understanding these age-driven transitions is essential for improving risk stratification and developing precision therapies tailored to the unique biology of B-ALL across the lifespan.<\/jats:p>","DOI":"10.3390\/ijms26188774","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T10:27:12Z","timestamp":1757500032000},"page":"8774","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Age-Driven Genetic and Epigenetic Heterogeneity in B-ALL"],"prefix":"10.3390","volume":"26","author":[{"given":"Yoana","family":"Veselinova","sequence":"first","affiliation":[{"name":"Cancer Epigenetics, Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4490-6093","authenticated-orcid":false,"given":"Manel","family":"Esteller","sequence":"additional","affiliation":[{"name":"Cancer Epigenetics, Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain"},{"name":"Instituci\u00f3 Catalana de Recerca i Estudis Avan\u00e7ats (ICREA) and Universitat Pompeu Fabra, 08010 Barcelona, Spain"},{"name":"Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), 08036 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red C\u00e1ncer (CIBERONC), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4084-6815","authenticated-orcid":false,"given":"Gerardo","family":"Ferrer","sequence":"additional","affiliation":[{"name":"Cancer Epigenetics, Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red C\u00e1ncer (CIBERONC), 28029 Madrid, Spain"},{"name":"Institut d\u2019Investigaci\u00f3 en Ci\u00e8ncies de la Salut Germans Trias i Pujol, 08916 Badalona, Spain"},{"name":"Karches Center for Oncology Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1038\/s41572-024-00525-x","article-title":"Acute Lymphoblastic Leukaemia","volume":"10","author":"Pagliaro","year":"2024","journal-title":"Nat. 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