Molecular detection of pre‐atl state among healthy HTLV‐1 carriers in an endemic area of Japan

Adult T‐cell leukemia/lymphoma (ATL) usually develops after age 40 in Japan, suggesting a long latency since HTLV‐I is considered to be transmitted mainly from mothers to babies via breast milk. Our previous studies had suggested that HTLV‐I carriers who have a monoclonal integration of HTLV‐I proviral DNA in the peripheral blood cells, designated pre‐ATL, account for about 2% of healthy carriers and are at high risk of developing ATL Their ages ranged from 32 to 80 (median 57). Nevertheless, many cases of pre‐ATL showed a long‐lasting carrier state (10‐year probability around 90%). In the present investigation we conducted a large‐scale molecular detection of monoclonal integration in a population (481 cases) of healthy carriers with ages ranging from 16 to 82 (median 49) for the purpose of clarifying the earliest onset of this pre‐ATL state. Southern‐blot analysis of DNA extracted from peripheral blood mononuclear cells revealed 6 cases (1.2%) with a monoclonal band. All of these 6 were older than 40; no single positive case was found in 220 carriers under age 40. These results indicate that the molecularly detectable pre‐ATL state also develops after a long latency. Thus the pre‐ATL state seems to be a subtype of ATL showing an extremely indolent course of disease development, but not merely an early phase of all subtypes of ATL. We propose that, in order to reveal a promoter(s) responsible for the development of ATL from the pre‐ATL state, intensive epidemiological investigation of life style, eating habits, occupation and exposure to carcinogens must be conducted on this unique group prone to ATL. It is also important to perform such an epidemiological study on the general population of carriers by paying special attention to the first 3‐4 decades of each carrier's life in Japan and by comparing the data with those from carriers in different geographical areas of the world.