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Exploring the role of Apolipoprotein E in normal and malignant Haematopoiesis

Alotaibi, Badi 2021. Exploring the role of Apolipoprotein E in normal and malignant Haematopoiesis. PhD Thesis, Cardiff University.
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Apolipoprotein E (ApoE) is a gene known for its role in lipid metabolism and has an anti-atherogenic role. Consequently, the deficiency of ApoE in mice results in the development of atherosclerosis and, conversely, re-expression of the gene reduces the development of the disease. Atherosclerosis is known to involve haematopoietic cell subsets and deregulated haematopoiesis drives both clonal haematopoiesis (a pre-leukaemia syndrome) and atherosclerosis. In this thesis, I investigated the broad requirement of ApoE signalling in normal haematopoiesis and the role of ApoE signalling in haematopoiesis and the development of leukaemia in the context of a high fat diet (HFD) that drives atherosclerosis. ApoE-/- mice fed a normal chow diet (NCD) displayed normal abundance of most haematopoietic stem/progenitor (HSPC) subsets and lineage specific myeloid and lymphoid progenitors, with the exception of a marginal reduction in B cells in the bone marrow and spleen, and a decrease in Mac-1+ cells and platelets in the peripheral blood. Functionally, as assessed by colony forming cell (CFC) assays, haematopoietic progenitor formation from ApoE-/- mice was unperturbed. When ApoE-/- mice were fed an HFD, a select expansion of immunophenotypic HSPCs was observed, including expansion of the LSK compartment reflecting ApoE mediated increases in haematopoietic stem cells (HSCs), multipotent progenitors (MPPs) and committed myeloid progenitors. ApoE-/- mice fed an HFD have a HPSC late survival advantage. Unexpectedly, ApoE signalling in the context an HFD appeared, with some exceptions, to be largely unneeded for HSC functioning, as assessed by transplantation, and for HSC self-renewal, judged by secondary transplantation. To test the impact of an HFD on ApoE signalling in leukaemia, an MLL-AF9 driven model of acute myeloid leukaemia (AML) was employed. MLL-AF9 transformed HSPCs from ApoE-/- mice fed an HFD showed no differences in pre-LSC formation in vitro and when pre-LSCs were transplanted allowing the development of AML in vivo, no impact was seen on the development of leukaemia, indicating that HFD has no influence on ApoE signalling in the initiation and development of leukaemia. In conclusion, these data suggest an association between the requirement for ApoE and the regulation of steady state haematopoiesis in select mature blood cell lineages, which requires further investigation in functional in vivo experiments. ApoE signalling in HFD expands select HSPC subsets, but functionally these cells behave normally. Further experimentation will be needed to resolve the ApoE mediated transcriptional signature underlying the immunophenotypic changes in HSPCs observed in an HFD. However, ApoE signalling in HFD has no impact on leukaemogenesis in an MLL-AF9 driven model of acute myeloid leukaemia.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Biosciences
Subjects: Q Science > Q Science (General)
Date of First Compliant Deposit: 18 June 2021
Last Modified: 18 Jun 2022 01:30

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