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Title: AML1/ETO promotes a mutator phenotype in t(8;21) acute myeloid leukaemia
Author: Forster, Victoria Jane
Awarding Body: University of Newcastle Upon Tyne
Current Institution: University of Newcastle upon Tyne
Date of Award: 2012
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The AM L1/ETO fusion protein in t(8;21) acute myeloid leukaemia is not sufficient for leukaemogenesis, but requires the acquisition of additional co-operating mutations. The "mutator phenotype" model of cancer suggests that the normal mutation rate in human somatic cells is not sufficient to mediate transformation, and that initiating mutations that increase the mutation rate are an essential "driver." As such, the major hypothesis of this thesis is that AML1/ETO confers a mutator phenotype and predisposes cells to the acquisition of co-operating mutations. Using cell lines transduced with the AML1/ETO fusion gene, investigations described within this thesis show that AML1/ETO confers a mutator phenotype, predisposing cells to acquisition of mutations at the TK and PIGA gene loci. This increase in mutation frequency in AML1/ETO-transduced cells is observed both spontaneously and after treatment with genotoxic agents, such as ionising radiation or the chemotherapy agent doxorubicin. Disruption of carefully controlled DNA repair mechanisms is well described to increase propensity to the acquisition of mutations. The effect of AML1/ETO on DNA repair in ectopic AML1/ETO-positive cell line models was investigated revealing dysregulated expression of several DNA repair-associated genes. The DNA base-excision repair pathway was notably affected, including downregulation of the OGGl DNA glycosylase, which is primarily responsible for the repair of 7,8-dihydro-8-oxoguanine lesions in DNA. The role of AML1/ETO in modulating angiogenic regulatory factors, was also investigated in ectopic AML1/ETO-transduced cell lines and t(8;21)-positive patient-derived cell lines. AML1/ETO was found to substantially upregulate the angiogenic regulatory factor ANGPTl. The study of dysregulated angiogenesis in leukaemia is a rapidly expanding field of research, and the investigations presented on AML1/ETO and ANGPT1, suggest that ANGPTl may be a possible therapeutic target in t(8;21) AML. The work presented in this thesis has provided new information as to how the AML1/ETO fusion protein promotes the acquisition of co-operating mutations leading to leukaemic transformation, and identified a 'possible role for AML1/ETO as a regulator of angiogenesis. This information could provide the basis for development of new methods of therapeutic intervention in t(8;21) AML.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available