Adult T-cell Leukaemia/lymphoma with Multiple Integrations of Human T-cell Lymphotropic Virus Type I Proviral DNA: Differing Clinical Features Are Linked to Varied Proviral Integration.

Multiple integrations of human T-cell lymphotropic virus type I (HTLV-I) proviral DNA are occasionally found in tumor cells from patients with adult T-cell leukaemia/lymphoma (ATL). However, the clinical implications of multiple integrations of HTLV-I in ATL have not been well established. We studied 95 patients with ATL to elucidate the relationship between the multiple integrations of HTLV-I and the clinical characteristics. The proviral DNA of HTLV-I was examined by standard Southern blot analysis using the probe of an entire HTLV-I genome and the endonucleases with or without cleavage sites within the provirus. Multiple integrations of HTLV-I were detected in eight patients as extraordinary multiple bands; five patients showed multiple bands of the same intensity, and the remaining three showed multiple bands of differing intensities. The patients were divided into two groups based on these band patterns. One group was considered to exhibit one tumour cell clone carrying multiple copies of the provirus, whereas the other was considered to exhibit multiple tumour cell clones, each carrying one copy of the provirus. The former group of patients manifested a highly aggressive clinical course with frequent peculiar organ infiltrations, including the retina, uvea and muscle, along with the presence of large peripheral leukaemic T cells having flower-like nuclei. The latter group demonstrated an indolent clinical course with skin lesions or small leukaemic T cells having cleaved or lobulated nuclei. These findings suggest that the pattern of multiple HTLV-integrations into the tumor cell(s) has clinical implications in ATL. This may help to explain the heterogeneity of this disease.