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 (hMSH3), 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-polymerase 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.

Impact of HTLV-I Tax on cell cycle progression and the cellular DNA damage repair response

“…To date, few studies have specifically investigated the role of HTLV-I infection or Tax expression on the MMR pathway. However, primary leukemic cells from 11 ATL patients showed a reduction or loss in expression of two or more MMR genes (Morimoto et al, 2005). The observation of microsatellite instability in primary leukemic cells from ATL patients (Hatta et al, 1998;Hayami et al, 1999), and the ability of Tax to repress pol b expression, as discussed above, support the possibility that Tax may interfere with MMR.…”

Estrogen Stimulates the Expression of Mismatch Repair Gene hMLH1 in Colonic Epithelial Cells

“…RT-PCR was carried out according to the method described by Morimoto et al (8). Primers used in this study were as follows: hMLH1, sense, 5′-GTGCTGGCAATCAAGG-GACCC-3′, anti-sense, 5′-CACGGTTGAGGCATTGGG-TAG-3′; hMSH2, sense, 5′-GTCGGCTTCGTGCGCTTCTTT-3′, anti-sense, 5′-TCTCTGGCCATCAACTGCGGA-3′; and β-actin, sense, 5′-ACACTGTGCCCATCTACGAGG-3′, antisense, 5′-AGGGGCCGGACTCGTCATACT-3′.…”

HTLV-1 Tax Oncoprotein Subverts the Cellular DNA Damage Response via Binding to DNA-dependent Protein Kinase

“…Transcriptional repression of human telomerase (hTert) by Tax may inhibit the addition of telomeric repeats to stabilize the ends of double-stranded DNA breaks (19). In addition, a reduction or loss of expression of two or more mismatch repair genes was observed in primary ATL leukemic cells (20).…”