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Outcomes with first-line chemotherapy remain poor. Over the past decade, integrative genomic and epigenomic studies have defined recurrent abnormalities converging on proximal T-cell antigen receptor\/costimulatory signaling to the NF-\u03baB\/NFAT, JAK\/STAT, PI3K\/AKT\/mTOR, and NOTCH pathways, alongside pervasive alterations in chromatin modifiers and the DNA methylation machinery. In this review, we frame the biology of peripheral T-cell lymphoma as two interdependent layers, including genetic events that establish constitutive signaling programs and epigenomic remodeling that stabilizes these outputs. We overview genomic alterations across major peripheral T-cell lymphoma entities and analyze epigenomic dysregulation, focusing on DNA methylation, enhancer regulation, and polycomb-mediated gene control. We highlight adult T-cell leukemia\/lymphoma as a paradigmatic dual-layer disease, summarize therapeutic approaches based on epigenetic traits, and discuss biomarker-guided strategies and challenges in translating integrated maps into durable disease control.<\/jats:p>","DOI":"10.1007\/s12185-025-04115-9","type":"journal-article","created":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T10:00:14Z","timestamp":1764151214000},"page":"487-495","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genome\u2013epigenome crosstalk in T-cell lymphomas: from maps to mechanisms"],"prefix":"10.1007","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8142-4686","authenticated-orcid":false,"given":"Makoto","family":"Yamagishi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,11,26]]},"reference":[{"key":"4115_CR1","doi-asserted-by":"publisher","first-page":"1664","DOI":"10.1182\/blood-2018-09-872549","volume":"133","author":"TB Heavican","year":"2019","unstructured":"Heavican TB, Bouska A, Yu J, Lone W, Amador C, Gong Q, et al. 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