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