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A Molecular Cytogenetic Investigation of Secondary Abnormalities and Clonal Evolution in ETV6-RUNX1 Positive Acute Lymphoblastic Leukaemia

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A molecular cytogenetic investigation of secondary abnormalities and clonal evolution in ETV6-RUNX1 positive acute lymphoblastic leukaemia Halima Hamdan Abdullah Al-Shehhi Thesis submitted for the degree of Doctor of Philosophy Newcastle University Faculty of Medical Sciences Northern Institute for Cancer Research July 2014 Declaration I certify that no part of the material documented in this thesis has previously been submitted for a degree or other qualification in this or any other university. I declare that this thesis represents my own unaided work, carried out by myself, except where it is acknowledged otherwise in the thesis text. Halima Al-Shehhi July 2014 i Acknowledgements I would like to express my sincere gratitude to my supervisors, Professor Anthony Moorman and Professor Christine Harrison for their unstinting support, encouragement, motivation, enthusiasm, and immense knowledge throughout my PhD study and research. Next, I would like to thank the past and present members of the Leukaemia Research Cytogenetic Group: Dr Amy Erhorn, Dr Alem Gabriel, Claire Schwab, Dr Lucy Chilton, Heather Morrison, Dr Lisa Russell, Dr Sarra Ryan, Dino Mašić, Jake Clayton, Alannah Elliott, Stacey Richardson, Dr Amir Enshaie and Dr Paul Sinclair for all support and help in terms of learning new techniques, comprehensive MLPA screening, review scoring of FISH slides, providing cell lines, SNP array analysis, statistical analysis and sharing knowledge/ ideas. Within the wider NICR, I would like to thank Dr Julie Irving, Elizabeth Matheson, Marian Case and the summer placement student: Alysia Davies for their expertise in helping the establishment of copy number q PCR in the lab and providing a positive control cell line. In addition, I would also thank Stefano Tonin and Martina Finetti who helped me in getting a positive control cell line and q PCR data analysis, respectively. Grateful thanks are also given to the ALL patients and their guardians who had accepted their inclusion in this research work. I would also like to greatly thank my family, friends and neighbours for their support and love throughout my PhD. I could not have done this without any of you. Finally, I extend my sincerest gratitude to Sultanate of Oman Government, in particular Sultan Qaboos University Hospital for providing the funding which made this project possible. ii Dedication This thesis is dedicated to the soul of my father who encouraged me to be the best I can be. I feel he is always with me supporting and guiding. My incredibly wonderful mother has always believed and continues to believe in me. Her prayerful support, encouragement, and constant love have sustained me throughout my life. My husband, Abdullah, his love, understanding, encouragement and unwavering support have been a continuous source of motivation and inspiration throughout the study. I am truly thankful for having you in my life. Words cannot express how grateful I am for all of the sacrifices that you have made during my PhD study. My beloved daughters, Hadeel and Haya, who kept asking “When are you going to be done, Mum?”. Your cute smile, loving eyes and cuddles were a constant source of encouragement and support. You have brought the most joy to my life and I am so proud of each one of you and have a great love for you all. Finally I thank ALLAH, for the showers of blessings that ALLAH has been bestowed upon me throughout my life. I have experienced Your guidance day by day. I will keep on trusting You for my future. iii Abstract The chromosomal translocation, t(12;21)(p13;q22), resulting in ETV6-RUNX1 fusion gene, is the most common chromosomal abnormality in childhood B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). It acts as an initiating factor which arises in utero but is unable to generate clinical leukaemia. Hence considerable research has been devoted to characterising the additional abnormalities that are acquired postnatally for the leukaemogenic transformation. This project investigated the spectrum of secondary abnormalities and clonal evolution in ETV6-RUNX1 ALL using fluorescence in situ hybridization, multiplex ligation- dependent probe amplification, single nucleotide polymorphism arrays and copy number real time polymerase chain reaction. Abnormalities affecting transcriptional co-regulators (ETV6, TBL1XR1 and BTG1) were much more common in ETV6-RUNX1 ALL compared to other ALL cases (52% v 10%; 13% v 0.69%; 15% v 3%, respectively); while alterations affecting the IKZF1 gene, which is involved in B-cell lymphocyte development pathway, were less prevalent (3% v 18%). Interestingly, we have identified and characterised two new abnormalities which both target the der(12)t(12;21) chromosome and the RUNX1-ETV6 fusion gene in 12% of ETV6-RUNX1 cases. The first abnormality was a deletion of der(12)t(12;21) (8%) occurring on either sides of the translocation breakpoint, but never both sides simultaneously, and occurred in 100% of ETV6-RUNX1 positive cells. The second abnormality was the duplication of RUNX1-ETV6 fusion gene (4%) and occurred in an average of 55% of ETV6-RUNX1 positive cells as a result of the formation of der(12) [der(12)(21qter → 21q22.12::12p13.2-12p12.3::12p12.3 → 12qter). Detailed investigation of these abnormalities identified potential tumor suppressor genes (LRP6 and BCL2L14) and a role for the RUNX1-ETV6 fusion protein. Although ETV6-RUNX1 patients respond well to current therapy, some relapses do occur and the identification of prognostic biomarkers is required. No potential relapse driving genes were defined; however, CDKN2A/B losses showed around three fold increase in the relapse cases as compared to non-relapse cases. Analysis of 9 matched diagnostic- relapse samples revealed a high degree of clonal relatedness between the two points but also evidence of low level sub-clones at diagnosis emerging as the major clone at relapse. iv Finally, the spectrum of secondary abnormalities in atypical ETV6-RUNX1 cases (i.e. younger/older patients and Down syndrome) was different with respect to the genetic diversity, nature and frequencies of alterations targeting the following genes – BTG1, RB1 and CDKN2A/B. Hence, considering the eight MLPA genes including ETV6, CDKN2A/B, PAX5, BTG1, RB1, EBF1, IKZF1 and PAR1, infant cases showed fewer alterations compared to non-infant cases (0.67 v 1.3 alterations per case) and CDKN2A/B seemed not to be contributing in their leukaemogenic development. Both BTG1 and RB1 losses are commoner in adolescents and young adults (AYA) group as compared to those under the age of 10 years (33% and 14% v 21% and 7%, respectively). In conclusion, this study has catalogued the frequency of key secondary abnormalities in ETV6-RUNX1 ALL and identified a number of genes whose role in the pathogenesis of this subtype warrants further investigation. v List of abbreviations ABL1 The tyrosine kinase Abelson aCGH Array comparative genomic hybridisation ALL Acute lymphoblastic leukaemia BAC Bacterial artificial chromosomes BCP-ALL Precursor B-cell ALL BM Bone marrow bp Base pairs CNAs Copy number alterations CNN-LOH Copy number neutral loss of heterozygosity CNS Central nervous system CR Complete remission CRD Common region of deletion CT Cycle threshold der(12)t(12;21) Derived chromosome 12 der(21)t(12;21) Derived chromosome 21 DGV Database of Genomic Variants DMC Differentially methylated CpG DS Down syndrome dup(Xq) Duplicated Xq EFS Event-free survival vi ETS E-26 transforming specific ETV6 The ETS- type variant 6 FISH Fluorescent in situ hybridization GC Glucocorticoids HD Heterodimerization domain HeH High hyperdiploidy HLH Helix–loop–helix domain HR High-risk HSC Haematopoietic stem cells IGH The immunoglobulin heavy chain IR Intermediate risk MLL Mixed lineage leukaemia MLPA Multiplex ligation dependent probe amplification MRD Minimal residual disease O/N Overnight PAR1 The pseudo-autosomal region PCR Polymerase chain reaction Ph Philadelphia chromosome RT Room temperature RUNX1 Runt- related transcription factor 1 SNP Single Nucleotide Polymorphism SR Standard risk vii T-ALL T cell acute lymphoblatic leukaemia TSG Tumour suppressor genes ΔCT CT difference ΔΔCT Comparative CT viii Table of Contents Chapter 1. Introduction ............................................................................................ 1 1.1 Cancer ................................................................................................................. 2 1.1.1 Overview ..................................................................................................... 2 1.1.2 Incidence ..................................................................................................... 2 1.1.3 Multistep development of cancer............................................................... 2 1.1.4 Genetic determinants of cancer ................................................................. 3 1.2 Leukaemia development .................................................................................... 4 1.2.1 Epidemiology ............................................................................................... 6 1.2.2 Classification and Diagnosis ........................................................................ 7 1.2.3 Clinical overview ......................................................................................... 8 1.3 Acute lymphoblastic leukaemia ......................................................................... 8 1.3.1 Aetiology ....................................................................................................
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