Hockings, Catherine Ann;
(2020)
Secondary driver mutations in CEBPA-mutated Acute Myeloid Leukaemia.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
In this thesis I explored the role of the transcription factor CEBPA in leukaemogeneis by creating novel cebpa mutant zebrafish lines modelling mutations found in sporadic AML. These recapitulated the two well-described categories of CEBPA mutation: CEBPA Nterm, mutations in the N terminus of full length CEBPA inducing a frameshift mutation prior to the internal reading frame, and Cterm, encoding an in-frame defect in the bZIP DNA binding domain coded in the C terminus. Primitive and definitive haematopoiesis were studied during embryonic development in both biallelic and heterozygous mutants. This revealed marked defects in production of mature granulocytes and monocytes in all biallelic mutants. Myeloid progenitor cell numbers in all biallelic mutants and N term heterozygotes were also markedly reduced. Distinct phenotypes were also seen between the two mutations highlighting their functional differences. Biallelic mutants with cebpaNterm showed an increase in HSPCs expressing myb, presumed to have undergone myeloid priming. However, early HSPC numbers expressing cd41 and runx1 showed no alteration in number. Haematopoiesis was also studied in juvenile and adult zebrafish. Survival was poor in biallelic mutants, with leukaemia developing in the presence of cebpaNterm before eight weeks of age. This was not seen in cebpaCterm/Cterm, where expansion in HSPCs and myeloid progenitors was observed without subsequent leukaemic transformation.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Secondary driver mutations in CEBPA-mutated Acute Myeloid Leukaemia |
| 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/10113744 |
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