Introduction
Human T-cell leukemia virus (HTLV) was isolated from a cutaneous T-cell lymphoma patient by Gallo and his colleagues (Poiesz et al., 1980) and adult T-cell leukemia virus (ATLV) was isolated from patients with adult T-cell leukemia (ATL) in Japan (Yoshida et al., 1982). Originally, these two viral isolates were thought to be different since they were isolated from apparently different tumors. However, we have shown that HTLV in the Caribbean and ATLV in Japan are the same virus (Watanabe et al., 1983(Watanabe et al., , 1984) ) and the patient from which HTLV was isolated was identified as an atypical case of ATL (Bunn et al., 1983).
The HTLV is exogenous for humans (Reitz et al., 1981;Yoshida et al., 1982;Yoshida, 1983) and distinct from known animal retroviruses with respect to the nucleotide sequence of the provirus genome (Seiki et al., 1982(Seiki et al., , 1983)). However, HTLV replicates by the same mechanism as known animal retroviruses (Seiki et al., 1982). Furthermore, HTLV was shown to be closely associated with a unique T-cell malignancy, ATL (Uchiyama et al., 1977), by extensive surveys of antibodies against the viral proteins (Hinuma et al., 1981, 1982; Robert-Guroff et al., 1982; Blattner et al., 1982). The association of the virus with ATL was also demonstrated by detecting the provirus genome in the leukemic cells of ATL patients (Yoshida et al., 1982;Wang-Staal et al., 1983). Analysis of the total nucleotide sequence of the viral genome lead to the conclusion that HTLV has no typical transforming gene (Seiki et al., 1983). This was consistent with the finding that no part of the HTLV genome showed significant hybridization with normal human DNA (Seiki et al., 1983).
Based on this information, it seemed important to study whether HTLV is directly involved in the leukemogenesis of ATL and whether the virus is associated with any other types of lymphomas or leukemias. Therefore, we looked for the provirus genome in fresh tumor cells from 210 cases of lymphoma or leukemia obtained from endemic areas in Japan. The results showed that the provirus genome was integrated in the tumor cells from all 122 cases of ATL tested, but not in those of other types of lymphomas or leukemias, indicating that HTLV integration in the target cells is a prerequisite for ATL development. However, no common site for HTLV integration was found in fresh leukemic cells. Thus, the results do not support direct activation of cellular one gene by the LTR sequence of the integrated proviral genome. A trans-acting factor as proposed for induction of ATL development.