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

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