An investigation into cellular stress pathways in Hodgkin lymphoma

Dean, Robert T. G. (2014) An investigation into cellular stress pathways in Hodgkin lymphoma. PhD thesis, University of Glasgow.

Abstract

Hodgkin lymphoma (HL) is one of the most common haematological malignancies in the Western world. Although HL responds favourably to cytotoxic therapy in the majority of cases, late side-effects such as secondary malignancies and cardiovascular disease are becoming of great concern, particularly in younger patients. The current challenges are to maintain treatment efficacy whilst reducing side-effects and to develop biomarkers to predict response to treatment(s). Protein degradation pathways in HL cells have remained largely unstudied in this malignancy and represent an opportunity for more targeted therapy. This thesis describes the activities of protein degradation pathways in HL-derived cell lines and their sensitivities to inhibition. The results suggest that the use of proteasome and HDAC6 inhibitors, alone or in combination, may be of clinical benefit in the treatment of HL in the future. The presence of p62 was used to monitor protein handling stress; however, its diverse expression patterns in HL-derived cell lines and in paraffin-embedded HL biopsy material preclude its use as an informative biomarker in HL. p62 was found to traffic between the cytoplasm and nucleus in HL-derived cell lines and its association with a DNA damage marker in both cellular compartments implicate it as a chaperone for the cytoplasmic degradation of nuclear proteins. A previously unreported nuclear expression of the lysosomal enzyme cathepsin B in HL-derived cell lines was identified, and this may have implications for the aberrant transcriptional profile of these cells given the regulatory activities of other members of this family of cysteine proteases. The non-lymphoid origin of the HD-MyZ cell line, a putative HL-derived cell line, was corroborated by phenotypic differences in protein handling pathways in comparison to accepted HL-derived cell lines. The activities and insensitivity to inhibition of protein handling pathways in this cell line suggest that it will be an interesting model for studying alternative protein degradation pathways. The presence of a number of small cell populations with cancer stem cell (CSC)-like characteristics was confirmed in HL-derived cell lines and, although these populations require further characterisation, this has implications for HL patients who suffer relapse.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: Q Science > QH Natural history > QH426 Genetics; Q Science > QR Microbiology > QR355 Virology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Supervisor's Name: Rich, Dr Tina and Jarrett, Professor Ruth
• Date of Award: 2014
• Depositing User: Mr Robert T G Dean
• Unique ID: glathesis:2014-5225
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 25 Jun 2014 11:01
• Last Modified: 26 Jun 2017 10:51
• URI: https://theses.gla.ac.uk/id/eprint/5225