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Examining telomere dysfunction in multiple myeloma

Hyatt, Sam 2017. Examining telomere dysfunction in multiple myeloma. PhD Thesis, Cardiff University.
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Telomeres are repetitive nucleotide sequences of TTAGGG that cap the ends of linear eukaryotic chromosomes. Short dysfunctional telomeres have previously been identified as a driving force in cancer, resulting in chromosomal fusion and rearrangement that acts to facilitate progression of the malignancy. As it has recently been demonstrated that telomere length is an accurate predictor of clinical outcome in patients with chronic lymphocytic leukaemia (CLL), we aimed to determine whether a similar relationship existed in multiple myeloma (MM). Having used single telomere length analysis (STELA) to measure the mean XpYp telomere length of whole bone marrow aspirates from 141 MM patients, a telomere length threshold of 3.92kb was identified which could be used to stratify patients as either low- or high-risk. Incorporation of this threshold into the international staging system (ISS) for MM increased its prognostic resolution, allowing each prognostic subset to be further risk-stratified. Having demonstrated that a shorter mean XpYp telomere length (<3.92kb) was associated with inferior patient outcome in MM, we next sought to identify a potential cause for this observation. Using clonal populations of the JJN-3 cell line, each expressing DN-hTERT, we observed that telomeric shortening resulted in a greater frequency of fusion and the initiation of a telomere-driven crisis. Cells were eventually able to escape crisis, driven by the spontaneous reactivation of telomerase which led to increasing telomere length and decreasing fusion frequency. Finally, we sought use the PARP inhibitors Rucaparib and Olaparib to prevent the escape of these clonal JJN-3 populations from a telomere-driven crisis. It was thought that PARP inhibition would interfere with the DNA repair pathways that are known to be responsible for processing telomere-deficient chromosomes. It was established that treating JJN-3 cells with either 7.50μM Rucaparib or 3.75μM Olaparib prevented their escape from a telomere-driven crisis.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 8 November 2017
Last Modified: 11 Dec 2020 03:20

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