publication . Thesis

Examining telomere dysfunction in multiple myeloma

Hyatt, Sam;
Open Access English
  • Country: United Kingdom
Abstract
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 aspirat...
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2.1 Equipment and Reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 2.2 Patient Samples and Tissue Culture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 2.2.1 Obtaining Patient Bone Marrow Aspirates and DNA Samples . . . . . . . . . 69 3.1 Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86 3.2 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 3.3 Aims of the Chapter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 3.4 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 3.4.1 Characteristics of the MGUS and MM Cohorts . . . . . . . . . . . . . . . . . . . . 93 3.4.2 MGUS and MM Exhibit Heterogeneous Telomere Length Distributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 3.4.3 Telomere Length is Highly Prognostic in MM . . . . . . . . . . . . . . . . . . . . . 101 3.4.4 Incorporating Telomere Length Measurements into the ISS . . . . . . . . . .103 3.4.5 Identifying Chromosomal Fusion Events in the Bone Marrow Aspirates of MM Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105

3.5 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 3.5.1 Telomeric Shortening in MM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 3.5.2 Telomere Length as a Prognostic Indicator in MM . . . . . . . . . . . . . . . . . 113 3.5.3 Chromosomal Fusion in MM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 3.5.4 The Relationship Between Telomere Length and Fusion Frequency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 3.5.5 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120

5.5 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217 5.5.1 PARP Inhibition and the Ability of JJN-3 Cells to Escape from a Telomere-Driven Crisis . . . . . . . . . . . . . . . . . . . . . . . . . . 217 5.5.2 Determining the Efficiency of PARP Inhibition in the JJN-3 Clonal Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221 5.5.3 PARP Inhibition and the Effect on Mean XpYp Telomere Length . . . . . 223 6.1 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 6.2 Comparisons to Current Knowledge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 6.2.1 The Prognostic Value of Telomere Length Measurements in MM . . . . . 232 6.2.2 Telomere-Driven Genomic Instability in MM . . . . . . . . . . . . . . . . . . . . . 234 6.2.3 Preventing the Escape of Cells from a Telomere-Driven Crisis . . . . . . . 237

6.3 Future Directions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239 6.4 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242 Ibrahim, Y. H., C. Garcia-Garcia, V. Serra, L. He, K. Torres-Lockhart, A. Prat, P. Anton, P. Cozar, M. Guzman, J. Grueso, O. Rodriguez, M. T. Calvo, C. Aura, O. Diez, I. T. Rubio, J. Perez, J. Rodon, J. Cortes, L. W. Ellisen, M. Scaltriti, and J. Baselga. 2012. 'PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition', Cancer Discov, 2: 1036-47.

Ihnen, M., C. zu Eulenburg, T. Kolarova, J. W. Qi, K. Manivong, M. Chalukya, J. Dering, L. Anderson, C. Ginther, A. Meuter, B. Winterhoff, S. Jones, V. E. Velculescu, N. Venkatesan, H. M. Rong, S. Dandekar, N. Udar, F. Janicke, G. Los, D. J. Slamon, and G. E. Konecny. 2013. 'Therapeutic potential of the poly(ADP-ribose) polymerase inhibitor rucaparib for the treatment of sporadic human ovarian cancer', Mol Cancer Ther, 12: 1002-15. [OpenAIRE]

Inoue, K., H. Osaka, V. C. Thurston, J. T. Clarke, A. Yoneyama, L. Rosenbarker, T. D. Bird, M. E. Hodes, L. G. Shaffer, and J. R. Lupski. 2002. 'Genomic rearrangements resulting in PLP1 deletion occur by nonhomologous end joining and cause different dysmyelinating phenotypes in males and females', Am J Hum Genet, 71: 838-53.

International Myeloma Working, Group. 2003. 'Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group', Br J Haematol, 121: 749-57.

Ito, S., C. G. Murphy, E. Doubrovina, M. Jasin, and M. E. Moynahan. 2016. 'PARP Inhibitors in Clinical Use Induce Genomic Instability in Normal Human Cells', PLoS One, 11: e0159341.

Iwanaga, M., M. Tagawa, K. Tsukasaki, T. Matsuo, K. Yokota, Y. Miyazaki, T. Fukushima, T. Hata, Y. Imaizumi, D. Imanishi, J. Taguchi, S. Momita, S. Kamihira, and M. Tomonaga. 2009. 'Relationship between monoclonal gammopathy of undetermined significance and radiation exposure in Nagasaki atomic bomb survivors', Blood, 113: 1639-50.

Jacob, J., G. Kelsoe, K. Rajewsky, and U. Weiss. 1991. 'Intraclonal generation of antibody mutants in germinal centres', Nature, 354: 389-92. [OpenAIRE]

Jacobson, J. L., M. A. Hussein, B. Barlogie, B. G. Durie, J. J. Crowley, and Group Southwest Oncology. 2003. 'A new staging system for multiple myeloma patients based on the Southwest Oncology Group (SWOG) experience', Br J Haematol, 122: 441-50.

Janouskova, E., I. Necasova, J. Pavlouskova, M. Zimmermann, M. Hluchy, V. Marini, M. Novakova, and C. Hofr. 2015. 'Human Rap1 modulates TRF2 attraction to telomeric DNA', Nucleic Acids Res, 43: 2691-700.

Javle, M., and N. J. Curtin. 2011. 'The role of PARP in DNA repair and its therapeutic exploitation', Br J Cancer, 105: 1114-22. [OpenAIRE]

Jazayeri, A., J. Falck, C. Lukas, J. Bartek, G. C. Smith, J. Lukas, and S. P. Jackson. 2006. 'ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks', Nat Cell Biol, 8: 37-45.

Jeon, H. S., Y. Y. Choi, J. E. Choi, W. K. Lee, E. Lee, S. S. Yoo, S. Y. Lee, J. Lee, S. I. Cha, C. H. Kim, and J. Y. Park. 2014. 'Telomere length of tumor tissues and survival in patients with early stage non-small cell lung cancer', Mol Carcinog, 53: 272-9.

225 references, page 1 of 15
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