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Identifying DNA Mutations in Purified Hematopoietic Stem/Progenitor Cells
Published on: February 24, 2014
Reduced expression of human mismatch repair genes in adult T-cell leukemia
Hiroaki Morimoto1, Junichi Tsukada, Yoshihiko Kominato
1First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
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.
Insights
Adult T-cell leukemia (ATL) shows suppressed DNA mismatch repair (MMR) gene expression, particularly hMSH2 and hPMS1. Promoter methylation inhibits hPMS1, indicating defects in MMR systems in ATL.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- DNA mismatch repair (MMR) genes are crucial for genomic stability.
- Defects in MMR are implicated in various cancers, including leukemia.
- Adult T-cell leukemia (ATL) is an aggressive hematologic malignancy with poorly understood molecular mechanisms.
Purpose of the Study:
- To investigate the expression of key DNA mismatch repair (MMR) genes in primary leukemic cells from ATL patients.
- To determine if MMR gene expression is altered in ATL compared to normal lymphocytes.
- To explore the potential mechanisms, such as promoter methylation, underlying MMR gene dysregulation in ATL.
Main Methods:
- Reverse transcription-polymerase chain reaction (RT-PCR) to quantify MMR gene mRNA levels.
- Western blot analysis to assess MMR protein expression.
- Methylation-specific PCR to detect promoter methylation of MMR genes.
- Treatment with 5-aza-2'-deoxycytidine to assess the role of DNA methylation.
Main Results:
- All 11 primary ATL samples exhibited reduced or lost expression of at least two MMR genes.
- Expression of hMSH2 and hPMS1 was reduced in all ATL cases, with proteins undetectable in some.
- Methylation of the hPMS1 promoter was observed in all tested ATL cases.
- hPMS1 expression was restored by a demethylation agent, suggesting methylation-driven silencing.
Conclusions:
- Primary ATL cells display significant defects in both human MutS and human MutL mismatch repair systems.
- hPMS1 gene expression is frequently silenced by promoter methylation in ATL.
- These MMR gene defects may contribute to the genomic instability observed in adult T-cell leukemia.
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