Multimodal functions of HTLV-1 in oncogenesis of adult T-cell leukemia-lymphoma.

Adult T-cell leukemia-lymphoma (ATL) is a malignancy of peripheral CD4+ T cells induced by human T-cell leukemia virus type 1 (HTLV-1). HTLV-1 encodes two oncogenic viral factors, Tax and HTLV-1 bZIP factor (HBZ) in the sense and antisense strands of the provirus respectively. Both Tax and HBZ dysregulate the expression and activities of a large number of host genes and cellular signaling pathways via their multimodal functions. Tax is a potent transactivator of viral replication and various cancer-related genes in HTLV-1-infected cells; however, Tax expression is generally suppressed in ATL cells owing to its high immunogenicity. Previously, we reported that Tax is transiently expressed in a small subpopulation of ATL cells, leading to drastic changes in the host transcriptional profile. In contrast, HBZ is conserved and expressed in all ATL patients. The HBZ gene is thought to be essential in the pathogenesis of HTLV-1. It is unique in that its transcript not only encodes HBZ protein but also acts in a similar way to long non-coding RNAs. Among the functions of HBZ, activation of the TGF-β/Smad pathway is critical for proliferation of ATL cells. These multimodal actions of Tax and HBZ genes are thought to be critical for ATL leukemogenesis.