[Molecular pathogenesis of adult T-cell leukemia/lymphoma]

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive peripheral T-cell malignancy caused by human T-cell leukemia virus type-1 (HTLV-1) infection. Genetic alterations are thought to contribute to the pathogenesis of ATLL alongside HTLV-1 products such as Tax and HBZ. Several large-scale genetic analyses have delineated the entire landscape of somatic alterations in ATLL, which is characterized by frequent alterations in T-cell receptor/NF-κB pathways and immune-related molecules. Notably, up to one-fourth of ATLL patients harbor structural variations disrupting the 3'-UTR of the PD-L1 gene, which facilitate escape of tumor cells from anti-tumor immunity. Among these alterations, PRKCB and IRF4 mutations, PD-L1 amplification, and CDKN2A deletion are associated with poor prognosis in ATLL. More recently, several single-cell transcriptome and immune repertoire analyses have revealed phenotypic features of premalignant cells and tumor heterogeneity as well as virus- and tumor-related changes of the non-malignant hematopoietic pool in ATLL. Here we summarize the current understanding of the molecular pathogenesis of ATLL, focusing on recent progress made by genetic, epigenetic, and single-cell analyses. These findings not only provide a deeper understanding of the molecular pathobiology of ATLL, but also have significant implications for diagnostic and therapeutic strategies.