Austen, Belinda (2007)
Ph.D. thesis, University of Birmingham.
Mutations in the ATM gene have previously been identified in CLL tumours. In this project, I have demonstrated that their detection would have prognostic value. With a prevalence of 12%, ATM mutations represent the commonest single gene defect to be detected in CLL tumours and they identified a subgroup of CLL patients that had a significant reduction in both treatment free and overall survival. Furthermore, ATM mutations provided prognostic information that was independent of age, clinical stage, the mutation status of the IGVH genes and TP53 mutations. The temporal acquisition of the ATM mutations and their relationship with loss of an ATM allele via a chromosomal 11q deletion provides clues into their mechanism of action. There was only a partial correlation between CLL tumours with mutations in the ATM gene and those with a chromosome 11q deletion. In certain cases, the ATM mutations represented germ-line changes and in others were acquired very early in the disease course raising the possibility that they might contribute to the initial clonal transformation process. However, in some CLL tumours, the ATM mutations had been acquired after the development of the tumour clone during disease progression indicating that there may be a step-wise acquisition of ATM allelic defects during the ontogeny of CLL. The ATM protein is the key coordinator of the cellular response to DNA double strand breaks. In this study, I showed that bi-allelic defects in the ATM gene lead to deficient ATM dependent responses, including the up regulation of p53, following both ionising irradiation and also treatment with the chemotherapeutic drug, Fludarabine. Thus an important mechanism accounting for the poor outcome in CLL patients with ATM mutations is likely to relate to chemo-resistance. Interestingly, there were differential responses to DNA damage with both irradiation and fludarabine amongst the category of tumours with an 11q deletion according to the status of the remaining ATM allele. Therefore, ATM mutations can stratify tumours with a chromosome 11q deletion into two functional subgroups. The identification of CLL tumours with ATM mutations would therefore predict those patients that will have a poor clinical outcome and be both more likely to require early treatment for their disease. Patients whose tumours had bi-allelic ATM defects will be expected to have deficient responses to DNA damaging chemotherapeutic drugs, while those with mono-allelic ATM defects might identify a group in whom the use of DNA damaging agents could provide selective pressure for the emergence of sub-clones that have subsequently acquired bi-allelic ATM defects.
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