Garcia Belém, Cláudia;
(2025)
Developing developmental models to study paediatric
glioma.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Diffuse midline glioma (DMG) is a fatal paediatric brain cancer currently lacking effective treatments. Recent studies revealed that approximately 80% of these midline glial tumours harbour a pLys > Met mutation in histone H3 (H3K27M) and 20% of DMG cases encompass recurrent activating mutations in the Activin A Receptor Type 1 (ACVR1) gene alongside H3K27M, specifically in histone variant 3.1. The co-segregation of these genetic lesions seems to be regionally restricted to tumours located in the pons. However, the identity of the cell of origin and the mechanisms through which these genetic alterations synergise to drive oncogenesis remain unclear. I hypothesise that in the developing hindbrain the mutant histone arrests glial progenitor cells in an undifferentiated state, whilst mutation of ACVR1 drives proliferation. To address these hypotheses, I have established human embryonic stem cell (hESC) lines harbouring inducible ACVR1G328V and inducible-Histone 3.1K27M both individually, and in combination. In parallel, I developed and optimised a reproducible protocol to differentiate hESCs into rostral hindbrain neural progenitor cells (NPCs) corresponding to ventral rhombomere segments r2–r4, which are thought to be the anlage of the pons. Furthermore, I have extended this protocol to differentiate NPCs into 90% GFAP-positive astrocytes. I have also attempted to differentiate NPCs into oligodendrocyte precursor cells (OPCs) but have not yet succeeded. Finally, I briefly explored the consequences of inducing the expression of the mutant histone during neural differentiation. qPCR data suggested that induction of H3.1K27M during regionalisation results in increased expression of posterior markers. The identification of the cell of origin and the molecular mechanisms behind this malignancy may contribute to the development of targeted therapies for DMG patients.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Developing developmental models to study paediatric glioma |
| Language: | English |
| Additional information: | Copyright © The Author 2025. 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 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 Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10217206 |
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