Reduced expression of human mismatch repair genes in adult T-cell leukemia

Abstract

In this study, we investigated the expression of six human DNA mismatch repair (MMR) genes, human MutS homologues 2 (hMSH2), 3 (hMSHS), and 6 (hMSH6), human MutL homologue 1 (hMLH1), human post-meiotic segregations 1 (hPMS1) and 2 (hPMS2), in primary leukemic cells obtained from 11 patients with acute-type adult T-cell leukemia (ATL) by using reverse transcription-polymarase chain reaction (RT-PCR). In contrast to normal peripheral lymphocytes, all primary ATL samples had reduced or loss of expression of two or more MMR genes, and the expression of several MMR genes was simultaneously suppressed in each ATL patient. Abnormal expression of hMSH2, hMSH3, hMSH6, hMLH1, and hPMS1 was observed more frequently than that of hPMS2. In particular, expression of hMSH2 and hPMS1 was reduced in all cases. Western blot analysis further showed reduced expression of both hMSH2 and hPMS1 proteins in all five cases examined. In three out of the 5 cases, both of the two proteins were undetectable. Interestingly, methylation-specific PCR indicated methylation of hPMS1 promoter in all of four ATL cases examined. hPMS1 expression, but not hMSH2 expression, was restored by treatment with a DNA demethylation agent, 5-aza-2′- deoxycytidine, suggesting that methylation plays a crucial role in inhibition of the hPMS1 gene expression in ATL. Our results demonstrate that defect of both human MutS and human MutL systems in primary ATL cells. © 2005 Wiley-Liss, Inc.