CircRNA signatures define ATLL subtypes and uncover the HBZ-DHX9 axis in tumor survival

Circular RNAs (CircRNAs) are emerging as critical regulators in leukemia biology; however, their role in Adult T-cell Leukemia/Lymphoma (ATLL) remains unexplored. In this study, we provide the first comprehensive profiling of circRNAs in ATLL subtypes, uncovering distinct circRNA signatures in acute, chronic, and lymphoma forms of the disease. Notably, circAFF2(3) was markedly upregulated in aggressive ATLL subtypes, suggesting its involvement in disease progression. Functional assays revealed that circAFF2(3) promotes cell viability in HTLV-1-transformed T cells, highlighting its potential as a tumor-promoting factor. Mechanistically, we demonstrate that the HTLV-1 viral protein HBZ interacts with the RNA helicase DHX9, a key regulator of circRNA biogenesis, and inhibits its unwinding activity at intronic regions flanking circularized exons, including those responsible for circAFF2(3) production. These findings establish the HBZ-DHX9 axis as a critical mechanism driving circRNA dysregulation and tumor survival in ATLL, offering new opportunities for biomarker discovery and therapeutic intervention.