LEUKEMOGENESIS AND PROGRESSION OF ADULT T-CELL LEUKEMIA

Abstract

O-15 Following infection with human T-cell leukemia virus type I (HTLV-I), a long latent period is required for the development of frank adult T-cell leukemia (ATL), suggesting that accumulated genetic or epigenetic changes of the host genes are involved in leukemogenesis. In HTLV-I+ carriers, CD4+ memory T-cells increase in accordance with HTLV-I provirus load. In contrast, both CD4+ and CD8+ naive T-cells decrease, which might account for the immunodeficiency associated with HTLV-I infection. Phenotypes of increased CD4 memory T-cells are similar to those of ATL cells, suggesting that HTLV-I viral protein(s), especially Tax, promotes the proliferation of infected cells, leading to the onset of ATL. Cyclin-dependent kinase inhibitor, p16 gene, is one of tumor suppressor genes, whose deletions have been shown to be associated with high-grade malignant ATL. We examined the methylation profile of p16 in various HTLV-I-infected cell populations using methylation-specific PCR (MSPCR) following sodium bisulfite treatment. A high frequency of methylation of p16 gene was identified in ATL samples and HTLV-I-transformed cell lines. Sequencing of p16 revealed that the CpG sites of p16 were more frequently methylated in fresh leukemic cells than detected with MSPCR. Fresh leukemic cells isolated from acute and lymphoma-type ATL cases had more methylated sites than those from chronic or smoldering ATL cases. These data suggest that the CpG sites of p16 are methylated at greater levels as the disease progresses, resulting in the suppression of p16 expression. Although Tax has been shown to functionally inactivate p16, the methylation of p16 also appears to play a critical role in regulating p16 in HTLV-I-associated leukemogenesis.