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ETV6-RUNX1 Translocation in Pluripotent Stem Cells

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ETV6-RUNX1 Translocation in Pluripotent Stem Cells Modelling first-hit functions of the t(12;21) ETV6-RUNX1 translocation in pluripotent stem cells Emma Victoria Laycock UCL Cancer Institute University College London A thesis submitted for the degree of Doctor of Philosophy 1 DECLARATION I, Emma Victoria Laycock, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 2 ABSTRACT Childhood acute lymphoblastic leukaemia (cALL) has a higher incidence, better prognosis and distinct mutational spectrum from its adult counterpart. Within B-cell precursor ALL, the ETV6-RUNX1 fusion gene accounts for 25% of paediatric cases but is rarely seen in adults. The childhood association of ETV6-RUNX1 ALL may reflect its origins in a progenitor unique to fetal life. Functioning as a first-hit mutation, ETV6-RUNX1 initiates an asymptomatic pre-leukaemia in utero, until further mutations cause progression to overt leukaemia. To understand how ETV6-RUNX1 contributes to leukemogenesis, we need to study the oncogene in the cellular framework in which it arises and functions. In vitro B-cell differentiation of human induced pluripotent stem cells (hiPSC) recapitulates early embryonic lymphoid development, providing a relevant model to study ETV6-RUNX1 cALL initiation. Here I show, genome-engineered hiPSCs which constitutively express ETV6-RUNX1 exhibit a relative expansion of a developmentally-restricted CD19−IL7R+ lymphomyeloid progenitor compartment and a partial block in B-lineage commitment. ETV6-RUNX1 proB cells that emerge downregulate genes encoding cell cycle-related targets of E2F transcription factors, with preliminary results suggesting ETV6-RUNX1 proB cells progress more slowly through the cell cycle. In addition, the ETV6-RUNX1 IL7R+ lymphomyeloid progenitor compartment has an increased myeloid transcriptome. ETV6-RUNX1 proB cells aberrantly retain this myeloid programming – expressing myeloid genes and markers and the ability to differentiate into actively phagocytic macrophages. To delineate the stage specific impact of ETV6-RUNX1 activity, I designed a RUNX1 FLEx switch construct targeted into the ETV6 locus to develop an inducible ETV6- RUNX1 hiPSC line – this work is ongoing. Overall, this data could suggest a model in which ETV6-RUNX1 impacts fetal lymphopoiesis within a vulnerable developmental window, potentially at the level of the transient lymphomyeloid IL7R+ progenitor, restricting lymphoid specification. This could result in arrested myeloid-primed B-cells with altered self-renewal properties which can aberrantly survive postnatally, allowing acquisition of secondary hits. 3 IMPACT STATEMENT Acute lymphoblastic leukaemia (ALL) is the commonest malignancy of childhood. Childhood ALL is distinct from adult ALL, associated with a different set of cancer- causing mutations. The mutation ETV6-RUNX1 causes 25% of B cell precursor ALL in children but is rarely seen in adult ALL. This has led to the question – why is ETV6- RUNX1 ALL a childhood disease? Many new-born babies have cells containing ETV6-RUNX1, but only a small fraction will go on to develop leukaemia. The childhood association of ETV6-RUNX1 may be due to its origins in cells uniquely susceptible to the mutation within early fetal development. The current models of ETV6-RUNX1 leukaemia have provided some conflicting results. There is a need for a model that recapitulates the developmental landscape in which the mutation arises and impacts. The differentiation of human induced pluripotent stem cells (hiPSC) has been shown to mimic this early blood development. The findings in this thesis provide further insights into the pre-leukaemic impact of ETV6-RUNX1 in hiPSC. The hiPSC model of ETV6-RUNX1 pre-leukaemia demonstrates a lineage dysregulation and cell cycle deceleration impact of the oncogene on fetal lymphopoiesis. The fetal IL7R progenitor compartment, with a developmentally restricted myeloid to lymphoid transition offers a potential explanation as to why ETV6-RUNX1 ALL is a disease of childhood and why ETV6- RUNX1 ALL frequently co-expresses B and myeloid surface markers. In the future, these findings could aid in the development of therapies targeted against ETV6-RUNX1 – potentially identifying fetal-specific vulnerabilities in ETV6-RUNX1 ALL, informing new therapeutic targets, which could be tested within this platform. The cellular hierarchy which ETV6-RUNX1 impacts may offer insights into non-ETV6- RUNX1-associated ALL. Further work on the inducible ETV6-RUNX1 hiPSC line could help to identify the cell of origin and cell of impact for ETV6-RUNX1 pre- leukaemia. Some of the work described in chapter three and chapter four has recently been published in the journal Developmental Cell (Boiers, C.,* Richardson, S.,* Laycock, E., et al., (2018). A Human IPS Model Implicates Embryonic B-Myeloid Fate Restriction as Developmental Susceptibility to B Acute Lymphoblastic Leukemia- Associated ETV6-RUNX1. Developmental Cell. 44, (3): 362-377). 4 TABLE OF CONTENTS DECLARATION ................................................................................................................................ 2 ABSTRACT ....................................................................................................................................... 3 IMPACT STATEMENT ................................................................................................................... 4 TABLE OF CONTENTS ................................................................................................................... 5 TABLE OF FIGURES ....................................................................................................................... 9 LIST OF TABLES ............................................................................................................................ 11 ABBREVIATIONS .......................................................................................................................... 12 ACKNOWLEDGEMENTS ............................................................................................................. 17 1. CHAPTER ONE: INTRODUCTION ................................................................ 19 1.1. ONTOGENY OF HAEMATOPOIESIS ......................................................................................... 20 1.1.1. ON THE ORIGIN OF HAEMATOPOIETIC STEM CELLS ...................................................................... 20 1.1.2. DEFINING THE HAEMATOPOIETIC STEM CELL ............................................................................... 21 1.1.3. WAVES OF HAEMATOPOIESIS ........................................................................................................... 23 1.1.4. HAEMATOPOIESIS IN THE EMBRYO ................................................................................................. 24 1.2. LINEAGE COMMITMENT AND REGULATION .......................................................................... 28 1.2.1. MODELS OF THE HAEMATOPOIETIC HIERARCHY .......................................................................... 28 1.2.2. MOLECULAR HAEMATOPOIESIS ....................................................................................................... 31 1.3. B CELL FUNCTION AND DEVELOPMENT ................................................................................ 34 1.3.1. B CELL FUNCTION ............................................................................................................................... 35 1.3.2. B CELL DEVELOPMENT IN ADULTS .................................................................................................. 36 1.3.3. B CELL DEVELOPMENT IN THE EMBRYO ......................................................................................... 39 1.3.4. EXTRINSIC REGULATION OF B CELL DEVELOPMENT .................................................................... 41 1.3.5. TRANSCRIPTIONAL REGULATION OF B CELL DEVELOPMENT ..................................................... 42 1.4. MODELLING HAEMATOPOIESIS IN HEALTH AND DISEASE ................................................... 46 1.4.1. CLINICAL RESEARCH AND MATERIAL .............................................................................................. 46 1.4.2. ANIMAL MODELS ................................................................................................................................ 48 1.4.3. HUMAN PLURIPOTENT STEM CELL MODELS .................................................................................. 49 1.5. GENOME ENGINEERING ......................................................................................................... 58 1.5.1. DNA REPAIR MECHANISMS .............................................................................................................. 58 1.5.2. GENOME ENGINEERING SYSTEMS .................................................................................................... 59 1.6. CHILDHOOD ACUTE LYMPHOBLASTIC LEUKAEMIA .............................................................. 63 5 1.6.1. GENETIC LANDSCAPE OF ALL .......................................................................................................... 64 1.6.2. INHERITED SUSCEPTIBILITY ............................................................................................................. 67 1.6.3. INITIATION OF CHILDHOOD ALL ..................................................................................................... 68 1.6.4. INFECTION HYPOTHESIS
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