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DNA mismatch repair deficiency in therapy related acute myeloid leukaemia/myelodysplastic syndrome

Offman, Judith Muriel; (2004) DNA mismatch repair deficiency in therapy related acute myeloid leukaemia/myelodysplastic syndrome. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

DNA mismatch repair (MMR) defects occur in both sporadic and familial cancers and are associated with dramatic increases in spontaneous mutation rates. In the majority of repair-defective sporadic tumours, the hMLH1 MMR gene is inactivated epigenetically by promoter methylation. In both cultured cells and in tumours, deficient MMR is also associated with resistance to certain therapeutic drugs - particularly methylating agents and thiopurines. The incidence of therapy related cancer - a malignancy that follows therapeutic treatment - is increasing. Therapy-related acute myeloid leukaemia/myelodysplastic syndrome (t-AML/MDS) presently accounts for ≥10% of all AML/MDS cases. AML is a malignancy of myeloid progenitor cells. MDS comprises a group of disorders characterized by abnormal myeloid stem cell differentiation and often precedes t-AML. This thesis describes an investigation of possible relationships between defective MMR, t-AML/MDS, and drug treatment. DNA from a group of cancer therapy-related acute leukaemia (AL)/MDS cases was examined for the microsatellite instability (MSI) phenotype that is diagnostic for inactive MMR. More than 60% (16/25) were MSI+ compared to <4% (0/28) of de novo cases. hMLH1 promoter methylation was infrequent. It occurred in less than one-third of the MSI+ cases although it appeared to be more common among MSI+ therapy-related acute promyelocytic leukaemias. In view of the acknowledged resistance of MMR deficient cells to 6-thioguanine, possible connections between therapeutic thiopurine use and MST AML/MDS were examined. I demonstrated that chronic treatment with 6-thioguanine could be used to select MMR defective clones from repair-proficient human cells grown in tissue culture. The possible relationship between azathioprine - a thiopurine prodrug, widely used as an immunosuppressant following organ transplantation - and MSI+ t-AML/MDS was investigated. Together with Professor Gerhard Opelz, I analysed the incidence of AML among > 170,000 organ transplant patients. This revealed a significant excess of AML among transplant recipients. MMR deficiency was found to be frequent among transplant-related AML/MDS cases; seven of seven examined were MSI+.MMR defective (MST) tumours are highly genetically unstable. They accumulate frameshift mutations in coding sequences, which result in most cases in truncated and/or inactive proteins. Caspase-5 and FancD2 were identified as targets for addition/deletion mutations in MSI+ t-AML cases.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: DNA mismatch repair deficiency in therapy related acute myeloid leukaemia/myelodysplastic syndrome
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Health and environmental sciences; DNA mismatch repair; Leukemia
URI: https://discovery.ucl.ac.uk/id/eprint/10100407
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