Prof. Takatsuki and his colleagues reported adult T-cell leukemia (ATL) as the distinct clinical entity based on the clinical features including the presence of leukemic cells with characteristic nuclear shape (flower cells), skin lesion, hypercalcemia and frequent opportunistic infections, and mature T-cell immunophenotyped (Uchiyama T, et al, Blood, 1977). Importantly, they already predicted that ATL is caused by the pathogen since the birth places of ATL patients accumulated in the southwestern Japan (Kyushu and Okinawa). In 1980, Prof. Gallo and his colleagues reported the first human retrovirus, human T-cell leukemia virus (HTLV), from a patient with cutaneous T-cell lymphoma who was later diagnosed as ATL. Thereafter, it was established that HTLV causes ATL. Since Prof. Gallo found another human retrovirus, the first human retrovirus was named human T-cell leukemia virus type 1 (HTLV-1).
Detection of anti-HTV-1 antibody enables us to identify HTLV infected individuals, which discloses unique distribution of HTLV-1carriers in Japan and the world. In addition, serological studies disclosed clinical landscape of ATL. Based on clinical features, ATL is classified to 4 clinical subtypes: acute, chronic, lymphoma-type and smoldering types (Yamguchi K, et al, Blood, 1983). In addition, the familial clustering of ATL cases was prominent, suggesting that genetic or virological factors are involved in development of ATL. Serological analyses found that HTLV-1 mainly transmits from male to female in horizontal transmission. Another clinical feature of ATL is the frequent spontaneous remission, which suggests immunological mechanism.
Early studies of HTLV-1 focused on Tax, which not only transactivates viral genes transcription from the plus strand, but also influences cellular genes. However, Prof. Takatsuki's group thought that clinical ATL samples contain clue of leukemogenic mechanisms by HTLV-1. We found that Tax was not expressed in half of ATL cases, and 3 mechanisms of inactivation of Tax expression: deletion of 5′ long terminal repeat (LTR), DNA methylation of 5′LTR, and genetic changes of the tax gene (nonsense mutation, deletion and insertion), indicating that Tax is not necessary for maintenance of ATL (Tamiya S, et al, Blood, 1996). However, pX region and 3′LTR remain intact in all ATL cases, indicating that this region is critical for ATL. Thereafter, we showed that HTLV-1 bZIP factor (HBZ), which is encoded by the minus strand, plays critical roles for pathogenesis by HTLV-1.
ATL is the first human disease caused by retrovirus. Tremendous efforts on HTLV-1 research by many researchers contribute to studies of next human retrovirus, human immunodeficiency virus (HIV). Thus, discovery of ATL in association with identification of causative human retrovirus leads to great contribution to medical science.