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The Role of WNT Transcription Factor TCF7L2 in Acute Myeloid Leukaemia

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The Role of WNT Transcription Factor TCF7L2 in Acute Myeloid Leukaemia The Role of WNT Transcription Factor TCF7L2 in Acute Myeloid Leukaemia by Siti Sarah Daud 2014 A thesis presented to Cardiff University in partial fulfilment of the requirement for the degree of Doctor of Philosophy Department of Haematology, Institute of Cancer and Genetics, School of Medicine, Cardiff University, CF14 4XN Cardiff, United Kingdom Supervisors: Dr. Alex Tonks and Dr. Richard Darley 1 DECLARATION This work has not previously been accepted in substance for any degree and is not concurrently submitted in candidature for any degree. Signed …… ………………(candidate) Date ……30-9-2013…… STATEMENT 1 This thesis is being submitted in partial fulfillment of the requirements for the degree of ……PhD………………(insert MCh, MD, MPhil, PhD etc, as appropriate) Signed …… ………………(candidate) Date …30-9-2013……… STATEMENT 2 This thesis is the result of my own independent work/investigation, except where otherwise stated. Other sources are acknowledged by explicit references. Signed …… ………………(candidate) Date …30-9-2013……… STATEMENT 3 I hereby give consent for my thesis, if accepted, to be available for photocopying and for inter-library loan, and for the title and summary to be made available to outside organisations. Signed …… ………………(candidate) Date …30-9-2013………… STATEMENT 4: PREVIOUSLY APPROVED BAR ON ACCESS I hereby give consent for my thesis, if accepted, to be available for photocopying and for inter-library loans after expiry of a bar on access previously approved by the Graduate Development Committee. Signed ……… ……………(candidate) Date …30-9-2013……… I Acknowledgements I would like to express my gratitude and greatest appreciation to my supervisors; Dr. Alex Tonks and Dr. Richard Darley for their generous guidance and support throughout this study. This study has been fully supported by the National Science Fellowship (NSF) from Malaysia. I am very thankful and deeply grateful to Ministry of Science, Technology and Innovation Malaysia (MOSTI) for the financial support they have provided. I would like to thank all staffs of the Department of Haematology; it has been a real pleasure to work with them. Importantly; Professor Alan Burnett for allowing this research to be conducted within Department of Haematology. Amanda Gilkes for her contribution to RNA samples from primary AML cohort and for lending her experience in microarray processing. Sara Pumford for her kind help during the construction of retroviruses constructs. Lorna Pearn and Dr. Marie Gilmour for their endless technical laboratory support. Dr. Nader Omidvar, Dr. Rhys Morgan and Dr. Paul Hole for their scientific insights. Dr. Paul White and the NCRI-MRC AML trials team for providing the primary AML samples. Dr. Robert Hills for his assistance with statistical analyses. Dr. Derrick Bowen for his guidance with the exon-splicing experiment. Dr. Anna Evans for sharing her bioinformatics expertise. I am especially indebted to my truly beloved husband, Mr. Jaime Castillo Garcia, who has constantly encouraged this path. It is again to him that this Ph.D is dedicated. Last but not least, I wish to thank my beloved parents; Mr. Hj. Daud and Mrs. Hjh. Noor Azizan, and my family who has been the fundamental base to every success I have achieved in life. II Foreword Full supplementary materials are provided as electronic documents on the accompanying CD (see back sleeve). The accompanying CD also contains an electronic version of this thesis. III Especially dedicated to my beloved husband, Jaime Castillo Garcia. IV Presentations Conference proceedings: Identification of the Wnt Signalling Protein, TCF7L2 as a Significantly Overexpressed Transcription Factor in AML. Daud SS, Pumford SL, Gilmour MN, Gilkes AF, Burnett AK, Hills R, Tonks A, Darley RL. Blood, Volume 120, (November 2012) pp.1281 (see below *) Large-Scale Integration of Gene Profiling Identifies TCF7L2/TCF4 as the Most Frequently Dysregulated Wnt Signalling Component in AML. Daud SS, Burnett AK, Darley RL, Tonks A. Blood, Volume 116, (November 2010) pp.1029 ( see below **) Poster presentations: * November 2012: American Society of Hematology Abstract Achievement Award for 54th Annual Meeting poster presentation, Atlanta, Georgia, U.S.A. Presenter and award recipient. **December 2010: American Society of Hematology Travel Award for 52nd Annual Meeting poster presentation, Orlando, Florida, U.S.A. Presenter and award recipient. Oral presentations: November 2011: Identification of novel splice variants of TCF7L2, lacking the Groucho repressor domain in Acute Myeloid Leukaemia patients. 26th Annual Postgraduate Research Day, Graduate School of Biomedical and Life Sciences, Cardiff University, U.K. October 2011: Interview with Feinstein Kean Healthcare, New York; for The cancer Biomedical Informatics Grid (caBIG) Milestones newsletter a story on “Identification of Dysregulated Networks in Acute Myeloid Leukemia Using caBIG® Distance Weighted Discrimination”. September 2011: Aberrant gene expression in Acute Myeloid Leukaemia : Dysregulation of T-cell factor 4 (TCF4/TCF7L2). Cancer IRG Ph.D Seminar Day; Medical Genetics. Henry Wellcome Building, Cardiff University, U.K. May 2011: The flow of “Wnt” signals in cancer cells: from Probes to Proteins. Speaking of Science Conference, Graduate Centre,Park Place, Cardiff University, U.K. June 2010: Role of Wnt Signaling in Acute Myeloid Leukemia. Cancer IRG Ph.D Seminar Day; Medical Genetics. Henry Wellcome Building, Cardiff University, U.K. V Abstract Acute myeloid leukaemia (AML) is a heterogeneous clonal disorder that affects the development of haematopoietic cells and has an incidence of 2300 cases / year in the UK. Whilst treatment with conventional cytotoxic agents has significantly increased cure rates in AML, only 35-50% patients under the age of 60 years will be long term survivors. There is a need to develop novel agents targeting molecular lesions or dysregulated pathways to improve clinical responses. This study identified commonly dysregulated pathways and genes using Affymetrix gene expression profiling of AML patients. Analysis of gene expression data using MetacoreTM online gene ontology pathway analysis identified WNT proteins to be one of the most frequently dysregulated processes associated with AML. TCF7L2 was the most significantly dysregulated WNT transcription factor gene and was subsequently examined in greater detail. The expression of TCF7L2 was validated by RQ- PCR. These data significantly correlated with the normalised array expression data (R=0.748; P<0.01) which in turn correlated with overall protein expression determined and quantified by western blotting. TCF7L2 mRNA overexpression was found to be independently prognostic for reduced complete remission rate (P<0.05), OR=5.19 [95% C.I.=1.39 - 19.39]. The TCF7L2 gene undergoes exon splicing which yields multiple isoforms which have been reported to yield functionally distinct proteins. TCF7L2 mRNA isoform expression in AML patients was compared with that in normal human bone marrow and a human cord blood derived from CD34+ haematopoeitic progenitor cells. Extensive variability of TCF7L2 splicing at the 3’ end of the gene (exons 13-18) was identified. AML patients were heterogeneous in the isoform expression pattern, but aberrant exon composition (compared to normal cells) was not observed. At the protein level, expression of the 58 kDa isoform (exons 1-14 and 18) and 56 kDa isoform (exons 1-13 and 18) were detected. In both normal and AML cells, expression of the 56 kDa and 58 kDa isoforms were dominant. To determine the functional significance of TCF7L2 overexpression lentiviral shRNA vectors targeting TCF7L2 was transduced in leukaemic cell lines co- expressing a TCF-GFP reporter which enabled simultaneous analysis of the effect on TCF- dependent transcription. Reporter activity was inhibited by shRNA vectors targeting TCF7L2, and the cells became non-responsive to WNT agonists (WNT3A and BIO) demonstrating that canonical WNT signalling is dependent on TCF7L2 expression in these cells. Phenotypically, shRNA expression was found to strongly inhibit proliferation and to promote apoptosis indicating that TCF7L2 expression is required for the proliferation and survival of myeloid leukaemia cells. Paradoxically, overexpression of individual TCF7L2 isoforms (72 kDa, 58 kDa and 56 kDa) suppressed WNT agonist responses in myeloid leukaemia cell lines but not in epithelial cells. Overexpression of TCF7L2 in normal CD34+ cells was found to promote monocytic differentiation. In summary, this study presents novel data identifying WNT signalling as the most commonly dysregulated process in AML. TCF7L2, a WNT transcription factor was found to be significantly overexpressed in AML and associated with poor clinical outcome. This protein was found to be required to maintain the proliferation and viability of myeloid leukaemia cells suggesting that targeting TCF7L2 maybe a valid approach in AML therapy. VI List of Abbreviations A adenine ABL Abelson ADAPT A Database of Affymetrix Probesets and Transcripts ALL acute lymphoblastic leukaemia AML acute myeloid leukaemia ANOVA analysis of variance APL acute promyelocytic leukaemia APC allophycocyanin Ara-C cytosine arabinoside ATRA all-trans-retinoic acid BIO (2'Z,3'E)-6-Bromoindirubin-3'-oxime BLAST Basic Local Alignment Search Tool BM bone marrow bp base pair C cytosine C-terminus carboxyl (COOH)-terminus C-clamp cysteines-clamp CB cord blood CBP CREB-binding protein cDNA complementary deoxyribonucleic acid CD cluster of differentiation .CDF chip description file CEB cytosolic
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