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Aberrant Downstream Mechanisms Following Depletion of KMT2C and KMT2D in Pancreatic Ductal Adenocarcinoma

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Aberrant downstream mechanisms following depletion of KMT2C and KMT2D in Pancreatic Ductal Adenocarcinoma Joshua Benjamin Newton Dawkins Thesis submitted in partial fulfilment of the requirements of the degree of Doctor of Philosophy (PhD) at Barts and the London School of Medicine and Dentistry, Queen Mary University of London Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ UK 2016 1 Statement of Originality I, Joshua Benjamin Newton Dawkins, confirm that the research included within this thesis is my own work or that where it has been carried out in collaboration with, or supported by others, that this is duly acknowledged below and my contribution indicated. Previously published material is also acknowledged below. I attest that I have exercised reasonable care to ensure that the work is original, and does not to the best of my knowledge break any UK law, infringe any third party’s copyright or other Intellectual Property Right, or contain any confidential material. I accept that the College has the right to use plagiarism detection software to check the electronic version of the thesis. I confirm that this thesis has not been previously submitted for the award of a degree by this, or any other, university. The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author. Signature: Date: Details of collaboration and publications: - RNA sequencing and was carried out by Source Bioscience, William James House, Cowley Road, Cambridge UK. - Bioinformatic analysis of the clinically annotated patient gene expression datasets, and the RNA sequencing data were carried out by Dr Jun Wang at the Barts Cancer Institute, Queen Mary University of London, London UK. - Generation and maintenance of the compound KC/KPC;Kmt2d genetically engineered mice was carried out alongside Dr Eleni Maniati at the Barts Cancer Institute, Queen Mary University of London, London UK. - Some of the KPC mouse data included was kindly provided by Dr Juliana Candido at the Barts Cancer Institute, Queen Mary University of London, London UK. - Much of the work described has been published in Cancer Research (Appendix I ). 2 Abstract Genomic sequencing of pancreatic ductal adenocarcinoma (PDAC) tumours has highlighted the existence of wide genetic diversity alongside frequent mutations in KRAS, TP53 and SMAD4. Within this heterogeneity many components of the epigenetic machinery are mutated, including the histone H3 lysine 4 methyltransferases KMT2C and KMT2D, which are frequently subject to mutation and can identify patients with a more favorable prognosis. In this thesis low expression of KMT2C and KMT2D were shown to also define better outcome groups, with median survivals of 15.9 vs 9.2 months (p = 0.029), and 19.9 vs 11.8 months (p = 0.001) respectively. Experiments across eight human pancreatic cell lines following their depletion suggest that this improved outcome may be due to attenuated cell proliferation, with decreased progression of cells from G0/G1 observed upon KMT2D loss. Whole transcriptome analysis of PDAC cell lines following KMT2C or KMT2D knockdown identified 31 and 124 differentially expressed genes respectively, with 19 common to both. Gene set enrichment analysis revealed a significant downregulation of genes relating to cell-cycle pathways, confirmed by interrogation of the International Cancer Genome Consortium and The Cancer Genome Atlas PDAC data series. Furthermore, these experiments highlighted a potential role for NCAPD3, a subunit of the condensin II complex, as a PDAC outcome predictor across four patient gene expression series. Alongside this, Kmt2d depletion in cells derived from murine models of pancreatic cancer led to an increase in their response to the antimetabolites 5-fluorouracil and gemcitabine. Taken together, the studies herein suggest that lower levels of this methyltransferase may mediate the sensitivity of PDAC patients to particular treatments. Altogether, these data suggest a potential therapeutic benefit in targeting these methyltransferases within PDAC, especially in those patients that demonstrate higher KTM2C/D expression. 3 Acknowledgements During my time working towards this thesis there have been a great number of people that without whom, I would never have had such a successful and fulfilling experience. First and foremost, I would like to thank both of my supervisors, Professor Jude Fitzgibbon and Dr Richard Grose, who have both been excellent mentors and without their guidance and generosity I have no doubt that I would have been lost after two years. In addition, I would like to acknowledge Professor Frances Balkwill for the role that she played in a period of transition. Another exceptional scientist, mentor and friend crucial for helping to develop both this thesis, and myself as a scientist, is Dr Eleni Maniati, where from the very first day until the last she has given limitless advice and support, and for which I will be always thankful. I am also thankful for the collaborations with many other excellent scientists who have enriched both the work and my experience. I have thoroughly enjoyed working and playing football alongside Dr Jun Wang, whose knowledge and skills in bioinformatics have been key in helping to direct my research. I am also greatly thankful for the input of Dr James Heward, where after each discussion I have always learnt something new. In addition to those mentioned here, countless other brilliant people have made my time truly enjoyable. Specifically, I would like to give a special thanks to Mark Brown, Dr Lily Keane and Dr Laura King for helping to create the many fond memories both in and out of the lab. I am also grateful to Jonas Mackerodt who has helped me to let off steam by joining me in range of sporting activities. Many thanks are also due to Laura Lecker, who through her enthusiasm, and our shared interests and laughter, has always helped to keep me in high spirits. I am also very grateful to Becky Parslow for always being someone who was there to offer unconditional support, understanding and kindness; especially at the times when I needed a reminder to come home for food and rest. In final, I would like to express a great appreciation for my funding body Cancer Research UK who without, this work would have never been possible or indeed reached its full potential. 4 Table of Contents Index of Tables ................................................................................................................ 9 Index of Figures ............................................................................................................. 10 Abbreviations ................................................................................................................ 13 Chapter 1 Introduction ............................................................................................... 17 1.1 Pancreatic ductal adenocarcinoma (PDAC) ....................................................... 18 1.1.1 Prevalence and epidemiology ..................................................................... 18 1.1.2 Disease development ................................................................................... 19 1.1.3 Mutational landscape of PDAC .................................................................. 21 1.1.4 Preclinical models of PDAC ....................................................................... 24 1.1.4.1 Genetically engineered mouse models of PDAC ................................. 24 1.1.5 Current treatments, resistance, and future therapies ................................... 28 1.2 Epigenetics ......................................................................................................... 29 1.2.1 The structure of chromatin .......................................................................... 29 1.2.2 ‘Readers’ ‘Writers’ and ‘Erasers’ ............................................................... 31 1.2.3 Histone modification ................................................................................... 31 1.2.3.1 Histone methylation ............................................................................. 32 1.2.3.1.1 H3K4 methylation ......................................................................... 32 1.3 The KMT2 family of lysine methyltransferases ................................................ 35 1.3.1 Members of the KMT2 family .................................................................... 35 1.3.2 A note on the literature: MLL2 and MLL4 nomenclature inconsistencies .. 36 1.3.3 KMT2 complexes and their roles ................................................................ 38 1.3.3.1 KMT2 proteins implicated in medical conditions ................................ 40 1.4 The KMT2 family in Cancer .............................................................................. 42 1.4.1 Leukaemia and Lymphoma ......................................................................... 42 1.4.2 Solid cancers ............................................................................................... 43 1.4.2.1 KMT2C and KMT2D ........................................................................... 43 1.5 Statement of problem and thesis aims ................................................................ 45 Chapter 2 Materials and Methods ............................................................................. 46 2.1 Materials ............................................................................................................
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