Purpose: Mismatch repair (MMR) defects have been associated with resistance to cytotoxic agents, including thiopurines, used in the treatment of haematological malignancies. We therefore compared the MMR status of bone marrow samples obtained from children with acute lymphoblastic leukaemia (ALL) presentation and relapse. We also investigated the relationship between expression of the MMR proteins (MLH1 and MSH2) in leukaemic blasts and relapsefree survival.
Patients and Methods: Diagnostic bone marrow trephine sections from 62 children with ALL were examined for MLH1 and MSH2 expression by immunohistochemistry. In 15 cases, sections from matched trephine specimens at relapse were also available for study. Bone marrow aspirates taken from the same patients at presentation, during remission and at relapse were also assessed for defective mismatch repair using microsatellite instability (MSI) analysis. Methylation analysis of the promoter region of the MLH1 gene and mutational screening of MLH1 and MSH2 were carried out on specimens from patients who demonstrated MSI.
Results: MSI was detectable in specimens from two patients at relapse. Matched samples at presentation did not show instability. Immunohistochemistry demonstrated reduced expression of MLH1 and MSH2 protein in these cases but this was not associated with MLH1 promoter methylation or mutation of either the MLH1 or MSH2 gene. Patients who demonstrated high MLH1 protein expression in blast cells at diagnosis showed a trend towards reduced probability of relapse but this did not achieve statistical significance, possibly due to the relatively small cohort size. No association was seen with high or low MSH2 expression.
Conclusion: These observations suggest that impaired MMR may be associated with relapse in childhood ALL, possibly due to reduced sensitivity to thiopurines used in continuing therapy. Further study is warranted to determine if there is an association between reduced expression of MMR proteins at diagnosis and the probability of relapse.