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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 haematopoi

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 haematopoi