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Hypercholesteremia as a regulator in haematopoiesis and leukaemic stem cells in acute myeloid leukaemia

Taha, Sarab 2023. Hypercholesteremia as a regulator in haematopoiesis and leukaemic stem cells in acute myeloid leukaemia. PhD Thesis, Cardiff University.
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Accumulating evidence suggests an emerging association between perturbed haematopoiesis, development of leukaemia and cardiovascular disease in the context of a high-fat western diet. To explore this subject, I investigated the role of atherosclerosis prone low-density lipid receptor (Ldlr) in normal and leukaemic haematopoiesis and the impact of a high-fat diet (HFD) or normal chow diet (ND) in this setting. In steady-state, under normal dietary conditions, mice engineered to be deficient in the LDL receptor (Ldlr-/-) had increased numbers of haematopoietic stem cells (HSCs), which was associated with increased cell cycling and an increase in inflammatory cytokines and chemokines. In Ldlr-/- mice bone marrow differentiation, as assessed by the CFC assay, was decreased while paradoxically white blood cells were increased which mapped to CD4+ T cell and monocyte increases in the peripheral blood. To induce hypercholesteremia and atherosclerosis, Ldlr-/- mice were fed a HFD and the attendant impact on haematopoiesis was evaluated. A significant increase in HSCs and associated early progenitor compartments (HSPCs) was noted in Ldlr-/- mice fed HFD alongside an increase in committed progenitor cells of both the myeloid and lymphoid lineage. As expected, inflammatory immune cell subsets were increased together with increases in platelets and alterations in regulatory immune cells in Ldlr-/- mice fed HFD. HSCs from Ldlr-/- mice fed HFD performed poorly in functional analysis, as judged by competitive transplantation, displaying significant multi-lineage differentiation defects. Underpinning these defects, RNA-seq analysis revealed altered apoptosis, inflammation, lipid metabolism pathways, RNA biology, and AML enriched gene pathways in HSCs from Ldlr-/- mice fed a HFD. These molecular pathways mapped not only to haematological disease, like AML, and cardiovascular disease, but also nephrotoxicity and hepatoxicity, highlighting the widespread impact of perturbed haematopoiesis induced by HFD and atherosclerosis. Unexpectedly, we found that MLL-AF9 transformed HSPCs from Ldlr-/- mice fed a HFD developed AML later than their ND counterparts, but this was likely reflected by a delayed migration of leukaemic blast cells from BM to PB. This argument was supported by altered adhesion protein expression in human MLL-AF9 AML cell lines exposed to atherogenic lipoproteins in vitro. Decreased markers of immune recognition were also observed in human MLL-AF9 AML cell lines exposed to atherogenic lipoproteins in vitro. The data provided in this thesis provide mechanistic vi insights into how HFD epigenetically disrupts HSC function and haematopoiesis in the setting of atherosclerosis, and it provides a starting point to further explore relationship between HFD, atherosclerosis and how perturbed haematopoiesis can lead to AML.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Biosciences
Subjects: Q Science > Q Science (General)
Date of First Compliant Deposit: 16 May 2023
Last Modified: 16 May 2023 14:51

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