Article révisé par les pairs
Résumé : Human T-cell Leukemia Virus type 1 (HTLV-1) drives Adult T-cell Leukemia/Lymphoma (ATLL) through sustained expression of the viral oncoprotein HBZ. Although HBZ is known to reshape host transcriptional programs, its role in post-transcriptional regulation in ATLL remains poorly understood. Here, we uncover a mechanism by which HBZ reprograms circular RNA (circRNA) biogenesis to support leukemic cell survival. Comprehensive circRNA profiling across ATLL subtypes revealed extensive circRNA remodeling, with distinct signatures associated with aggressive ATLL subtypes. Among these, circAFF2(3) is markedly upregulated in aggressive ATLL, and functional analyses show that its expression enhances, whereas its silencing reduces, the survival of HTLV-1-transformed T cells. Mechanistically, we show that HBZ interacts with the RNA helicase DHX9 and inhibits its helicase activity at intronic double-stranded RNA structures flanking circularized exons. Using both endogenous and synthetic circRNAs, we demonstrate that this inhibition allows RNA duplexes to persist, thereby promoting back-splicing and the accumulation of DHX9-sensitive circRNAs, including circAFF2(3). Together, these findings reveal that HTLV-1 hijacks host RNA helicase activity to reprogram circRNA biogenesis, identifying the HBZ-DHX9 axis as a novel post-transcriptional mechanism contributing to ATLL development.

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