HTLV-1 Tax and HBZ cooperatively promote leukemogenesis through miR-155-mediated PTEN suppression and PI3K-Akt activation

Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATLL), but the full scope of its oncogenic mechanisms remains elusive. While the viral oncoprotein Tax drives early oncogenesis, its expression is frequently silenced in later stages of ATLL, whereas the HTLV-1 basic leucine zipper factor (HBZ) is constitutively expressed throughout infection. This shifting viral expression profile underscores the critical need to define HBZ-specific oncogenic mechanisms. Here, we identify miR-155 as a key oncogenic driver in ATLL and reveal a novel, HBZ-dependent post-transcriptional regulatory axis that sustains its overexpression. We confirm Tax-mediated transcriptional activation of miR-155 but further demonstrate that HBZ enhances miR-155 maturation by elevating Dicer expression and promoting its processing of pre-miR-155. The elevated miR-155 promotes tumorigenesis through targeting PTEN and activating PI3K-Akt pathway. Functional studies demonstrate that miR-155 overexpression drives ATLL progression by enhancing proliferation and inhibiting apoptosis, while its inhibition reverses these malignant phenotypes. Xenograft models confirm that miR-155 blockade significantly reduces tumor growth. Our results uncover a cooperative mechanism by which HTLV-1 Tax and HBZ jointly drive miR-155 overexpression to promote leukemogenesis and identify miR-155 as a potential therapeutic target in ATLL. IMPORTANCE: Adult T-cell leukemia/lymphoma (ATLL) is an aggressive cancer caused by HTLV-1 with limited treatment options. We show that HTLV-1 hijacks the host microRNA miR-155 to drive tumor growth. While the viral protein Tax activates miR-155 transcription, we discovered that HBZ-constitutively expressed even when Tax is silenced-sustains miR-155 expression by upregulating Dicer and enhancing miR-155 processing. Elevated miR-155 then suppresses PTEN and activates the PI3K-Akt pathway, promoting cancer cell proliferation. Importantly, blocking miR-155 significantly reduces tumor growth in mouse models, identifying miR-155 as a promising therapeutic target for ATLL.