Genome–epigenome crosstalk in T-cell lymphomas: from maps to mechanisms

T-cell lymphomas are clinically and biologically heterogeneous malignancies that comprise ~ 10% of non-Hodgkin lymphomas. 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-κB/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.