The role of telomere dysfunction in modulating disease progression and response to treatment in chronic lymphocytic leukaemia.

Jones, Ceri Hopcyn 2018. The role of telomere dysfunction in modulating disease progression and response to treatment in chronic lymphocytic leukaemia. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

In Chronic lymphocytic leukaemia (CLL), short telomere length (TL) and dysfunction and is a powerful predictor of patient survival. The aim of this project was to understand the dynamics of TL in CLL and the relationship between TL in CLL B-cells and autologous T-cells. Normal B-cells from CLL patients showed TL erosion that was indistinguishable from normal ageing. In contrast, T-cells showed rapid TL shortening. Using serial sampling and longterm follow-up, the change in CLL B-cell TL correlated strongly with starting TL. Patients with CLL B-cell TL above the fusogenic threshold displayed TL erosion, whereas patients below the threshold showed no change. There was no lower limit to the mean TL in CLL B-cells suggesting a dysfunctional DNA-damage response allowing on-going cell division and stabilisation of TL. T-cell TL demonstrated marked erosion over the same timescale and the degree of erosion correlated with longevity of diagnosis. Mean T-cell TL did not reach the same degree of shortening as CLL B-cells, consistent with the induction of replicative senescence. T-cell TL was associated with immunophenotypic changes indicating T-cell exhaustion. Furthermore, TCR repertoires showed evidence of clonality and a skewed reliance on certain V gene segments. Longterm co-culture of PBMC from CLL patients, showed survival and proliferation for up to 154 days in-vitro. Despite proliferation, little change in CLL B-cell TL was observed. Surprisingly T-cell TL increased probably due to the selective loss of shorter TL T-cells during the culture. This study shows that the telomeres of CLL B-cells show distinct dynamics over the course of the disease, suggesting that the TL may be pre-determined at the initiation of disease. In contrast, the TL of T-cells showed significant erosion, evidence of replicative senescence, and a phenotype that, together with the associated T-cell exhaustion, may have consequences for the therapeutic use of autologous T-cells.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	30 March 2021
Last Modified:	04 Aug 2022 02:04
URI:	https://orca.cardiff.ac.uk/id/eprint/121606

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