HTLV-I tax related dysfunction of cell cycle regulators and oncogenesis ofadult T cell leukemia

HTLV-I is causually related to the oncogenesis of adult T cell leukemia (AT L). However, the precise mechanism of HTLV-I oncogenesis is unclear. HTLV-I Tax protein functions as an activator of various cellular genes, including IL-2, IL-2 receptor-alpha, and c-fos through the activation of nuclear tra nsfer factors such as NF-kappaB and SRF, and also potently activates trascr iption of viral genes through CREB/ATF sites in the viral LTR. However, Tax activation or HTLV-I infected T cells through the above pathways induces p olyclonal proliferation of the cells in vitro: Tax however may function onl y transiently in the immediate pont-infection period following infection in vivo. The long latent period of 60 years from infection to onset of diseas e suggests other mechanisms for ATL oncogenesis. Recent studies suggest tha t the malignant transformation of ATL is a multi-hit phenomena, suggesting that discrete genetic events are responsible for ATL oncogenesis. These gen etic events could be responsible for the different stages of ATL smoldering , chronic, lymphoma, and acute type, p16 and p53 genes are important negati ve regulators of the cell cycle and are often found to he mutated in neopla sms. Recent studies including ours demonstrated a high frequency of alterat ion of these two genes in primary ATL cells, Furthermore, alteration of the two genes is associated with acute but not chronic type ATL. In addition, p16 gene alteration is linked to the growth rate of ATL cells, suggesting t hat the alteration of these cell cycle regulatory genes may be related to p rogression from smoldering or chronic to acute or lymphoma type ATL. Tax ma y he involved in mutagenesis of these gents through suppression of DNA-beta polymerase gene expression during the process from latent period to acute/ lymphoma type. Once transformation occurs, activation of the pathway betwee n Tax and the three nuclear transfer factors, NF-kappaB, SRF, and CREB/ATF, contributes to establish the aggressive manifestations of acute/lymphoma. type ATL cells.