HTLV-1 bZIP factor HBZ promotes cell proliferation and genetic instability by activating oncomiRs

Viruses disrupt the host cell microRNA network to facilitate their replication. HTLV-1 replication relies on the clonal expansion of its host CD4+ and CD8+ T-cells, yet this virus causes adult T-cell leukemia/lymphoma (ATLL) that typically has a CD4+ phenotype. The viral oncoprotein Tax, which is rarely expressed in ATLL cells, has long been recognized for its involvement in tumor initiation by promoting cell proliferation, genetic instability, and miRNA dysregulation. Meanwhile, HBZ is expressed in both untransformed infected cells and ATLL cells, and is involved in sustaining cell proliferation and silencing virus expression. Here, we show that an HBZ/miRNA axis promotes cell proliferation and genetic instability as indicated by comet assays that showed increased numbers of DNA strand breaks. Expression profiling of miRNA revealed that infected CD4+ cells, but not CD8+ T-cells, overexpressed oncogenic miRNAs, including miR-17 and miR-21. HBZ activated these miRNAs via a post-transcriptional mechanism. These effects were alleviated by knocking down miR-21 or miR-17 and by ectopic expression of OBFC2A, a DNA damage factor that is down-regulated by miR-17 and miR-21 in HTLV-1 infected CD4+ T-cells. These findings extend the oncogenic potential of HBZ and suggest that viral expression might be involved in the remarkable genetic instability of ATLL cells.