The Myelodysplastic syndromes (MDSs) are comprised of a heterogeneous group of clonal disorders characterised by ineffective haematopoiesis. Although 30 to 35% of MDS cases progress to Acute Myeloid Leukaemia (AML), the majority of patients die from blood related ailments caused by progressive bone marrow failure. Large-scale genomic rearrangements are a key feature of MDS, with different aberrations conferring specific risks of progression. Telomere erosion, dysfunction and fusion, creating cycles of anaphase bridging breakage and fusion is a mechanism that has the potential to drive genomic instability in many tumour types including MDS. The key aim of this project was to examine the role that telomere dysfunction may play in the generation of genomic rearrangements observed in MDS/AML. High resolution Single Telomere Length Analysis (STELA) revealed telomere shortening when compared to age-matched individuals in two cohorts of MDS and AML patients; this included large-scale telomeric deletion events observed within the MDS cohort. A PCR based telomere fusion assay detected telomere-telomere fusion events at a frequency that was consistent with sporadic fusion arising as a consequence of large-scale deletion. Telomerase activity was up-regulated in AML which may contribute to the reduction of deletion and fusion events in these cells. Sequence analysis revealed that telomere fusion was associated with microhomology and sub-telomeric deletion; this profile was consistent with error-prone Ku-independent alternative end joining processes. Telomere length at diagnosis irrespective of conventional markers appeared to influence the overall survival of MDS patients, but this was not apparent in AML. More importantly, telomere length was able to refine favourable prognostic markers, specifically good risk cytogenetics, uni-lineage cytopenia and low-risk IPSS (International Prognostic Scoring System) scores of which MDS patients bearing shorter telomeres for their respective age displayed reduced overall survival. This may be a particularly important finding given the heterogeneous clinical outcomes observed within low-risk MDS patients.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:590379 |
| Date | January 2014 |
| Creators | Williams, Jenna |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/56965/ |
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