Abstract
Abstract
Adult T-cell leukemia/lymphoma (ATL) is an aggressive HTLV-1–associated malignancy with poor responses to chemotherapy. Although constitutive NF-κB activation is a hallmark of ATL, its persistence in Tax-negative (Type I) ATL—where Tax is irreversibly silenced—remains unresolved. Here, we identify Fra-2 as a coactivator of NF-κB p65 that redirects p65’s transcriptional activity toward inflammatory genes. Mechanistically, Fra-2 interacts with the Rel homology domain of p65 via its bZIP domain, enhancing p65 DNA-binding activity without altering nuclear localization. The HTLV-1 antisense protein HBZ disrupts Fra-2/JunD AP-1 complexes while stabilizing Fra-2/p65, as shown by co-immunoprecipitation, BiFC, and PICO assays. This rewiring selectively enhances NF-κB-dependent transcription of IL-1 β, which is elevated in ATL patient sera and cells independently of proviral load. Chromatin immunoprecipitation revealed Fra-2 recruitment to NF-κB response elements in the IL1β promoter, an effect amplified by HBZ. Pharmacological inhibition of IL-1 signaling with Anakinra or anti-IL-1β antibodies restored doxorubicin sensitivity in primary ATL cells. Together, these findings establish the Fra-2–NF-κB–IL-1β axis as a driver of chemoresistance in Tax-negative ATL and a therapeutically targetable vulnerability.