Adult T-cell leukemia/lymphoma: molecular pathogenesis, emerging therapies, and future directions

Adult T-cell leukemia/lymphoma (ATLL) is a rare and aggressive malignancy of mature T-cells caused by chronic infection with Human T-cell Leukemia Virus Type 1 (HTLV-1). Despite advances in understanding its pathobiology, ATLL remains associated with poor clinical outcomes, largely due to intrinsic chemoresistance and immune evasion mechanisms driven by viral oncogenes and acquired genetic alterations. The discovery of frequent mutations in TCR/NF-κB, JAK/STAT, and apoptotic pathways has unveiled novel therapeutic vulnerabilities, while agents such as mogamulizumab have demonstrated clinical efficacy in relapsed settings. Antiviral therapies and allogeneic hematopoietic stem cell transplantation (allo-HSCT) represent pillars of treatment for selected patients, but durable remissions remain rare. This review comprehensively summarizes the molecular underpinnings of ATLL, highlights the evolving therapeutic landscape, and discusses emerging research directions aimed at improving patient outcomes.