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A genotypic, phenotypic and functional exploration of multiple myeloma sub-clones

Murray, James William 2019. A genotypic, phenotypic and functional exploration of multiple myeloma sub-clones. PhD Thesis, Cardiff University.
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The concept of genetic clonal tiding is well established in Multiple myeloma. Immunophenotypic analysis as a means of sub-clone distinction is less well recognised. In this thesis, a ST-colour panel was designed that showed examples of distinct CDUV, CDSUV, CXCRX, MMP-Y, IL-Z and CDXYd sub-populations in both primary MM samples and cell lines. The huge variation in CDUV expression amongst the samples and its positive correlation with Ki-Z\, CXCRX and CD]Z expression was of particular interest, culminating in the previously undescribed discovery of a bimodal CDUV expression in the well-known cell line, MM.SS. In terms of function, I showed that CDUV expression was a predictor of myeloma cell migration; high expression was associated with increased cell migration. Furthermore, I developed a novel migratory model in MM, that had been previously used in our research group for CLL. In this dynamic circulatory model, I showed that pharmacological inhibition of CXCRX and CDXYd inhibited MM migration. To further explore the functional difference in CDUV expressing sub-populations, the MM.SS CDUV populations were cell sorted and the distinct subsets were examined in terms of phenotype, function and genotype. The weakly expressing CDUV population, termed MM.SSdim, was shown to contain a mutation in the gene MKI$%, providing a rationale for the observed decrease in cell growth. Through further genetic analysis, sub-clonality between the U populations were proven, ultimately showing that both of the MM.SS CDUV sub-clones were manifest in the MM.SR cell line. The exome analysis also identified that the CDUV sub-clones harboured distinct genetic mutations, which conferred differential sensitivity to molecular targeted inhibitors such as PIUK. This, combined with my migratory work, showed the potential for developing bespoke treatment plans based on the identification of cell signalling pathway mutations via genomic sequencing and immunophenotypic analysis. By selective targeting of these genetic lesions it may be possible to remove multiple sub-clones thereby diminishing the potential for clonal tiding and the development of drug resistance.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 4 March 2020
Last Modified: 04 Mar 2020 10:58

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