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Dissecting the Role of Trisomy 21 in Childhood Acute Lymphoblastic Leukaemia

Holohan, Sean David; (2022) Dissecting the Role of Trisomy 21 in Childhood Acute Lymphoblastic Leukaemia. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Children with Down’s Syndrome (DS) have a twenty fold increased risk of developing acute lymphoblastic leukaemia (ALL) and a five hundred fold increased chance of developing acute megakaryoblastic leukaemia (AMKL). This suggests a role for trisomy 21 as a ‘first hit’ event, predisposing these children to leukaemogenesis. Childhood leukaemias differ from adult leukaemias in that they have an increased incidence, improved prognosis and have a distinct mutational spectrum. I hypothesized that T21 distorts DS foetal hematopoiesis inducing a predisposition to B-ALL and that DS iPSCs could recapitulate these effects providing an in- vitro approach to identify likely target cells for 2nd hits. The objective of this project is to utilise human DS induced pluripotent stem cells (DS-iPSCs) to model B-cell development in children with DS and to elucidate the effects of trisomy 21 on B-cell differentiation in-vitro and relate this to the characteristics of DS-ALL. In-vitro B-cell differentiation of isogenic DS iPSCs produced both pro and preB cells and an immature cellular compartment termed the LM cell immunophenotypically identified as CD34+ CD38- CD33hi CD45Rahi that displayed misexpression of the immature myeloid marker CD33. I hypothesised misexpression of CD33 induced a failure in lineage resolution and a partial block in B cell commitment at the LM cell. Transcriptomic analysis of LM, pro and preB compartments revealed enhanced stem, myeloid, cell cycle and protein synthesis gene expression pathways in the T21 LM progenitor suggestive of pre-leukaemic development. This suggests a DS hematopoietic hierarchical model in which a failure of lineage resolution in the T21 LM progenitor results in impaired B-cell commitment and conflicting lympho-myeloid signature observed in the B- cell compartment. I propose the LM cell is a potential in-utero target cell for DS pre- leukaemic initiation and that this DS-iPSC system offers a platform for targeting potential therapeutic candidates of DS-ALL.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Dissecting the Role of Trisomy 21 in Childhood Acute Lymphoblastic Leukaemia
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/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 > 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
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10143095
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