Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.689453
Title: Elucidating molecular mechanisms of leukaemogenesis in normal karyotype AML
Author: Smith, S. L.-L.
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2008
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Abstract:
The aim of this thesis was to examine the role that gene specific mutations play in leukaemogenesis of normal karyotype (NK) acute myeloid leukaemias (AMLs), by studying the number of genes involved, types of mutations, order by which they arise and their function. AML is a stem cell disease in which the bulk of the disease is perpetuated by a rare population of leukaemic stem cells (LSCs), which arise due to an accumulation of genetic events within the target cell. Eight genes known to be mutated in AML were screened from a panel of 88 NK AML patients. One hundred and twenty-seven mutations were detected multiple mutations were common and 44% of the AMLs contained mutations that affect both differentiation and proliferation, indicating a requirement for cooperating mutations. Regions of acquired uniparental disomy (aUPD) detected by SNP arrays were found to contain homozygous mutations in genes implicated in AML, such as homozygous FLT3-ITDs on 13q, indicating that mitotic recombination can act as a second genetic event in leukaemogenesis. Semi-quantitative real-time PCR mutation specific assays, were designed against mutations in the transcription factor CEBPA. These assays were used to test AML samples which had been sorted into populations corresponding to stem cell and early progenitors in normal haematopoiesis. CEBPA mutation was detected in all compartments tested, indicating it is an early event in leukaemogenesis, which is supported by their occurrence in familial AML. Functional studies of mutations in CEBPA indicated that the 30kDa isoform of the protein was able to direct differentiation of lineage depleted cord blood mononuclear cells towards the myeloid pathway, where the addition of an ITD within the C-terminal region promoted erythroid differentiation. The work presented here demonstrates that gene specific mutations play a key role in leukaemogenesis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.689453  DOI: Not available
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