Abstract
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.
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References
Karran P and Bignami M: DNA damage tolerance, mismatch repair and genome instability. Bioessays. 1994, 16:833–839
Chung DC and Rustgi AK: DNA mismatch repair and cancer. Gastroenterology. 1995 109:1685–1699
Kolodner R: Biochemistry and genetics of eukaryotic mismatch repair. Genes Dev. 1996 10:1433–1442
Aquilina G, Giammarioli AM, Zijno A, Muccio AD, Dogliotti E, Bignami M: Tolerance to O6-methylguanine and 6-thioguanine cytotoxic effects: a cross-resistant phenotype in Af-methylnitrosourea-resistant Chinese hamster ovary cells. Cancer Res 1990, 50:4248–4253
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© 1999 Springer Science+Business Media New York
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Matheson, E.C., Hall, A.G. (1999). Expression of DNA Mismatch Repair Proteins in Acute Lymphoblastic Leukaemia and Normal Bone Marrow. In: Kaspers, G.J.L., Pieters, R., Veerman, A.J.P. (eds) Drug Resistance in Leukemia and Lymphoma III. Advances in Experimental Medicine and Biology, vol 457. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-4811-9_64
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DOI: https://doi.org/10.1007/978-1-4615-4811-9_64
Publisher Name: Springer, Boston, MA
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