Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignant disease of CD4-positive T lymphocytes caused by infection with human T-cell leukemia virus type -I (HTLV-I). HTLV-I causes ATLL in 3-5% of infected individuals after a long latent period of 40-60 years, the advanced acute ATLL remains of poor prognosis. Such a long latent period suggests that multistep tumorigenic events are involved in the development of ATLL, although the detailed mechanism of leukemogenesis remains to be elucidated so far. Identification of the specific genes for the ATLL progression is one of the critical points for the development of the effective treatments for the ATLL patients. The gene silencing by the epigenetic events have been recognized to be an important mechanism for the carcinogenesis and/or leukemognesis as well as genetic events. Aberrant CpG island methylation in promoter regions of the genes have been investigated in various human malignancies and revealed to be associated with the loss of gene function. The aim of the present study is to investigate the status of the promoter-associated CpG island methylation among several phases of ATLL, and explore whether the CpG island methylator phenotype (CIMP) could be detected or not among HTLV- I carrier, smoldering ATLL and acute ATLL We analyzed the methylation frequencies of the SHP-1, p15, p16, p73, HCAD, DAPK, hMLH, MGMT genes by methylation-specific-PCR (MSP) assay in healthy volunteer (n=13), HTLV- I carrier (n=10), smoldering ATLL (n=10), acute ATLL (n=25). We observed that the number of the CpG island methylated genes increased as the disease progression. Significant differences of the methylation status were found between healthy volunteer and HTLV-I carrier; HTLV-I carrier and acute ATLL smoldering ATLL and acute ATLL. Present data also showed that the average numbers of methylated genes increased according to the progression of the ATLL stages; 0.5 methylated genes for normal PBMC, 1.6 genes for HTLV-I carrier, 1.9 genes for smoldering ATLL and 3.6 genes for acute ATLL among 8 genes which we examined. (P < 0.05,Fisher's exact.) There were correlations between hypermethylation of the 2 genes: SHP-1 and p16 (P=0.048), p16 and DAPK (P=0.024), DAPK and MGMT (P=0.031), DAPK and HCAD (P=0.042). We defined the CIMP as the presence of more than three methylated genes among the eight genes investigated. The CIMP was found most frequently in acute ATLL and significant correlation was found between the presence of CIMP and the progression of ATLL. We could demonstrate the presence of CIMP phenotype in ATLL. Our findings strongly suggest that the presence of CIMP is deeply involved in the development and progression of ATLL in multistage leukemogenesis. Furthermore, CIMP status could provide a novel biomarker for ATLL, and may participate in a characteristic feature of malignant ATLL cells and an indicator for the therapy.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]