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The prognostic significance of the mixed lineage leukaemia partial tandem duplication in acute myeloid leukaemia

Austin, Steve 2010. The prognostic significance of the mixed lineage leukaemia partial tandem duplication in acute myeloid leukaemia. PhD Thesis, Cardiff University.

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Abstract

This study concerns a specific molecular genetic mutation, the mixed lineage leukaemia partial tandem duplication ( MLL PTD). MLL is a transcriptional regulator that known to be instrumental in both normal haematopoiesis and in leukaemogenesis. This study aimed to evaluate the prognostic importance of this abnormality through investigation of its influence on clinical outcome, its utility as a marker of minimal residual disease (MRD) and the downstream effects of its expression. A qualitative PCR assay was established and determined the frequency of MLL PTD to be 5.2% in de novo AML. MLL PTD was found to be a useful independent marker being associated with a greater risk of relapse and a reduction of relapse free survival and overall survival. A quantitative PCR (QPCR) assay was developed that reliably distinguished AML-related MLL PTDs from the low level of background MLL PTDs occurring normally. Despite a high rate of cytogenetic clonal evolution MLL PTD expression remained stabled between diagnosis and relapse, making it a suitable marker for MRD. Results also suggested the QPCR assay could determine onset of remission and prediction of relapse. Gene expression profiling was used to identify a gene signature unique to the MLL PTD and was found to be distinct from that associated with MLL translocation. Analysis of the gene signature also identified three candidate chemotherapy compounds predicted to antagonise the effects of the MLL PTD. The results of this study could prove instrumental in improving the treatment of MLL PTD patients.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Date of First Compliant Deposit: 30 March 2016
Last Modified: 14 Oct 2019 13:19
URI: http://orca-mwe.cf.ac.uk/id/eprint/54154

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