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Title: Investigation of molecular heterogeneity and new prognostic biomarkers in chronic myeloid leukaemia
Author: Daghistani, Mustafa
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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In Chronic Myeloid Leukaemia (CML) tyrosine kinase inhibitor (TKI) therapy has greatly prolonged survival for patients in the chronic phase of CML and is effective also in patients in the accelerated blast phase. However, primary and secondary resistance to TKI remains a significant clinical challenge. Similarly, while a number of additional genetic lesions accompany transformation to the advanced phase, no change provides a method of prospectively distinguishing those patients who will progress rapidly to blast crisis from those whose disease pursues a relatively indolent course. The precise genomic mechanisms of transformation are elusive. It is therefore important to identify new prognostic markers and new molecular alterations that, alone or combined, can predict a patient’s clinical course or provide additional therapeutic targets. The first part of this thesis describes the prognostic relevance of MECOM oncogene expression in imatinib resistance and post-stem cell transplantation in CML patients. Expression of MECOM, a gene previously shown to be commonly transcribed in CML blast crisis and to a lesser extent, in the chronic phase, predicted an adverse response to second line TKI therapy, but not following stem cell transplantation. The second part of this thesis details the use of high-resolution comparative genomic hybridization (CGH) on diagnostic samples from CML patients in an attempt to identify additional prognostic indicators or recurrent co-operating lesions. A number of regions of apparent genomic enrichment were identified that were recurrently targeted to specific genes. An extensive range of confirmatory molecular assays, however, failed to support a true change in gene copy number. Interestingly, the majority of these genes were differentially expressed in the CML samples, raising the possibility that changes in chromatin conformation had given rise to the aberrant CGH results. Nevertheless, many of the under-expressed genes were attractive candidate genes for a role in BCR-ABL1-induced oncogenesis, therefore two further lines of investigation were taken: 1) An analysis of the prognostic impact of differential expression of these genes at diagnosis in CML, which revealed four genes in particular whose expression was significantly associated with outcome; and 2) Functional analysis of one of these genes, STK17B, in which an increase in apoptosis in the CML cell line K562 was observed in association with forced expression of this gene mediated by inhibition of COX-2. Thus this work has identified novel prognostic indicators with a potential role in CML patient management that are also worthy of further investigation as rational targets for therapy.
Supervisor: Reid, Alistair ; Foroni, Letizia Sponsor: King Abdul Aziz Medical City
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available