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Assessment of mismatch repair function in leukaemic cell lines and blasts from children with acute lymphoblastic
Elizabeth C Matheson1, Andrew G Hall
1The LRF Molecular Pharmacology Specialist Programme, Cancer Research Unit, Newcastle upon Tyne, UK.
Abstract:
Defects in the DNA mismatch repair (MMR) pathway have recently been shown to be associated with resistance to several of the cytotoxic drugs used in the treatment of children with acute lymphoblastic leukaemia (ALL). We have assessed the MMR status of a range of leukaemic cell lines using an in vitro repair assay and correlated this with protein expression of the best characterized components of the system. We have also assessed MMR in leukaemic blasts from a limited panel of children with ALL and related this to Ki67 expression as a measure of proliferative capacity. Out of nine leukaemic cell lines tested, five of the seven lymphoid lines showed little or no repair using the in vitro assay and had low MMR protein expression. In three (NALM-6, Reh and MOLT 4) MMR defects have not been previously reported. Immunohistochemistry of clinical samples showed a wide range of expression of MLH1, MSH2 and Ki67 in nine cases studied at presentation, with a highly statistically significant correlation between MLH1 and Ki67 expression (r(2) = 0.96, P < 0.0001, Pearson correlation). Western blotting demonstrated high expression of MLH1, PMS2, MSH2 and MSH6 proteins. In vitro analysis of G.T repair using lymphoblast cytosol from the same patients showed a wide range of proficiency, which was markedly reduced in one case studied at relapse. These results suggest that MMR defects are more common in leukaemic cell lines and acute lymphoblastic leukaemias than previously thought.
Insights
DNA mismatch repair (MMR) defects are common in acute lymphoblastic leukemia (ALL) cell lines and patient samples, potentially explaining resistance to chemotherapy. Our study identified previously unreported MMR deficiencies in ALL cell lines.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- DNA mismatch repair (MMR) pathway defects are linked to chemotherapy resistance in acute lymphoblastic leukemia (ALL).
- Understanding MMR status is crucial for optimizing ALL treatment strategies.
Purpose of the Study:
- To assess MMR status in ALL cell lines and clinical samples.
- To correlate MMR proficiency with protein expression and proliferative capacity (Ki67).
- To investigate the prevalence of MMR defects in ALL.
Main Methods:
- In vitro DNA mismatch repair (MMR) assay on leukaemic cell lines and patient blasts.
- Protein expression analysis (Western blotting, immunohistochemistry) of MMR components (MLH1, MSH2, PMS2, MSH6).
- Correlation analysis with Ki67 expression as a proliferation marker.
Main Results:
- Five of seven lymphoid ALL cell lines exhibited low MMR activity and protein expression.
- Previously unreported MMR defects were found in NALM-6, Reh, and MOLT 4 cell lines.
- A significant correlation (r(2) = 0.96, P < 0.0001) was observed between MLH1 and Ki67 expression in patient samples.
- MMR proficiency was reduced in a patient sample at relapse.
Conclusions:
- DNA mismatch repair (MMR) defects appear more prevalent in acute lymphoblastic leukemia (ALL) cell lines and patient leukemias than previously recognized.
- These findings suggest a potential mechanism for chemotherapy resistance in ALL.
- Further investigation into MMR status could inform personalized treatment approaches for ALL.
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