Roles of HTLV-1 Tax in Leukemogenesis of Human T-Cells

Abstract

Human T-cell leukemia/lymphoma virus type 1 (HTLV-1), a member of the delta-retrovirus family, is an oncogenic retrovirus that is etiologically associated with adult T-cell leukemia (ATL) (Hinuma et al., 1981, Poiesz et al., 1980, Yoshida et al., 1982) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) (Gessain et al., 1985, Osame et al., 1986). ATL is characterized by an aggressive CD4+ T-cell malignancy with resistance to anticancer therapeutics. It is currently estimated that HTLV-1 infects 10-20 million people in the world, endemically southwestern Japan, Africa, South America and the Caribbean basin (Proietti et al., 2005). HTLV-1 transmission mainly occurs from mother to child through breast milk followed by infection to child cells in a cell-cell contact manner (Kinoshita et al., 1987). Approximately 2-5% of HTLV-1-infected individuals develop ATL after a long latent period. The average Japanese ATL patients are 60 years old. Accumulation of genetic and epigenetic changes in provirus and host genes during the latent period is thought to be essential for immortalization and transformation of T-cells. However the pathogenesis of ATL by HTLV-1 remains incompletely understood. Like other retroviruses, HTLV-1 provirus genome structure genes, gag, pro, pol, and env are flanked by 5’ and 3’ long terminal repeat (LTR). Besides the prototype genes, the HTLV-1 genome has the 1.6 kb pX region in the 3’ terminal region. The pX region codes for several non-structural molecules Tax1, Rex, p12, p13, p30, p21 and HBZ by combination of the reading frames and alternative splicing (Figure 1) (Nicot et al., 2005). Tax1 was initially identified as a trans-acting transcriptional activator of the HTLV-1 promoter in LTR, leading to virus replication (Fujisawa et al., 1985, Sodroski et al., 1984). Tax1 has the ability to modulate transcription of cellular genes through activation of at least three cellular transcriptional factors NF-B, CREB/ATF and AP-1 (Yoshida, 2001). Tax1-mediated dysregulation of gene expression is believed to be implicated in cellular immortalization and transformation through multistep processes. Cell immortaliztion and transformation generally require at least three steps: cell growth promotion, prevention of apoptosis and escape from senescence. Involvement of Tax1 in three steps has been studies intensively and extensively; Introduction of the Tax1 gene induces phenotypic transformation in fibroblast cell lines (Tanaka et al., 1990), neoplastic transformation of primary rat fibroblast in cooperation with the ras oncogene, persistent interleukin (IL) 2-dependent growth of primary T-cells in vitro (Akagi et al., 1995, Grassmann et al., 1989), and development of tumors and