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Modelling first-hit functions of the t(12;21) ETV6-RUNX1 translocation in pluripotent stem cells

Laycock, Emma Victoria; (2020) Modelling first-hit functions of the t(12;21) ETV6-RUNX1 translocation in pluripotent stem cells. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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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.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Modelling first-hit functions of the t(12;21) ETV6-RUNX1 translocation in pluripotent stem cells
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
URI: https://discovery.ucl.ac.uk/id/eprint/10096731
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