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Title: Characterisation of genetic complexity in chronic lymphocytic leukaemia
Author: Timbs, Adele T.
ISNI:       0000 0004 7430 826X
Awarding Body: Oxford Brookes University
Current Institution: Oxford Brookes University
Date of Award: 2017
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Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia in the Western world, characterised by the accumulation of mature B-cells. The disease has a heterogeneous course whereby some patients do not require treatment for several years while others follow a more aggressive disease progression and require early therapeutic action. Although several prognostic markers have been described, it is still difficult to predict the prognosis of the disease at diagnosis or to explain the diversity associated with the disease. The goal of this thesis was therefore, to characterise the genomic complexity and molecular drivers of clonal expansion and maintenance of CLL using targeted next generation sequencing (NGS) and high resolution single nucleotide polymorphism (SNP) array. NGS analysis of the immunoglobulin variable heavy-chain (IgHV) in 497 pre-treatment CLL patients found IgHV subclones in 18.5%, far higher than previously reported. SNP array analysis in 411 CLL patients refined the minimally overlapping regions (MOR) on del(6q) to the ATG5 and PRDM1 genes. Further autophagy related genes were also found to be present in other MORs. Analysis of the autophagy pathway at the protein level showed higher autophagy activity in primary CLL cells compared with age-matched controls. NGS-IgHV enabled the existing Sanger-sequencing based prognostic system to be refined. Correlation to the clinical outcome data showed that this new classification was prognostically significant. Furthermore, the identification of IgHV subclones imply that the leukaemia initiating event in CLL takes place prior to recombination. Concurrently, the detection of altered autophagy levels suggests a role for autophagy in CLL. Collectively these data provide new insights into the pathogenesis of CLL.
Supervisor: Schuh, Anna ; Brooks, Susan Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral