Transcriptional rewiring of NF-κB by HBZ and Fra-2 drives inflammatory chemoresistance in Tax-negative adult T-cell leukemia/lymphoma
Tram, J.; Marty, L.; Mourouvin, c.; Abrantes, M.; Cesaire, R.; Helias, P.; Baccini, V.; Mesnard, J.-M.; PELOPONESE, J.-M.
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Adult T-cell leukemia/lymphoma (ATL) is an aggressive HTLV-1-associated malignancy with poor responses to chemotherapy. Although constitutive NF-kB 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-kB 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-kB-dependent transcription of IL-1b, which is elevated in ATL patient sera and cells independently of proviral load. Chromatin immunoprecipitation revealed Fra-2 recruitment to NF-kB response elements in the IL1b promoter, an effect amplified by HBZ. Pharmacological inhibition of IL-1 signaling with anakinra or anti-IL-1b antibodies restored doxorubicin sensitivity in primary ATL cells. Together, these findings establish the Fra-2-NF-kB-IL-1b axis as a driver of chemoresistance in tax-negative ATL and a therapeutically targetable vulnerability.
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