Expression of DNA mismatch repair proteins in acute lymphoblastic leukaemia and normal bone marrow.
Errors during normal DNA synthesis may produce mismatched base pairs. 6-Mercaptopurine (6MP), given during continuing therapy in acute lymphoblastic leukaemia (ALL), undergoes intracellular activation to give cytotoxic thioguanine nucleotides which are then incorporated into the DNA of dividing cells in place of guanine. Cell death is thought to result from futile attempts at mismatch repair. Previous work has shown that cell lines with a defect in this pathway develop tolerance to incorporated 6-thioguanine bases. In order to investigate the possible relevance of mismatch repair to the chemosensitivty of blasts to 6MP, relative to normal tissues, we have measured the expression of the mismatch repair proteins MLH1, MSH2, PMS2 and MSH6 in blasts from children and adults with ALL and in normal bone marrows, using western blotting. Fifty cases of childhood ALL, 22 cases of adult ALL and 7 normal marrows have been studied. Expression of MSH2, and of MLH1 in all but three cases, was detectable in all the blasts studied. Noticeably, expression of MLH1 was not detected in any of the normal marrow samples. MSH2 was detected in 4 of the normal marrows. Expression of PMS2 was not detected in 29 cases of ALL and, like MLH1, was absent from each of the normal marrow samples. In contrast, MSH6 was detected in all of the normal marrows and all but 16 of the cases of ALL. There was no difference in expression between adults and children. These results may help to explain the relative sensitivity of leukaemic blasts to thiopurines at presentation as compared to normal bone marrow.
Matheson
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EC
LRF Molecular Pharmacology Group, CRU, Medical School, Newcastle-Upon-Tyne.
Hall
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AG
D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases; D000328:Adult; D020137:Base Pair Mismatch; D001752:Blast Crisis; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins; D002648:Child; D004260:DNA Repair; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D009687:Nuclear Proteins; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes