Medicine (St Vincent's) - Theses
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ItemThe roles of retinoic acid receptors and target gene HOXA1 in regulating haematopoiesis and myelodysplastic syndromes( 2022)Haematopoietic stem cells (HSCs) are multipotent cells responsible for the maintenance of the haematopoietic system throughout life. Dysregulation of the balance between HSC self-renewal, death and differentiation can have serious consequences such as myelodysplastic syndromes (MDS) or leukaemia. All-trans retinoic acid (ATRA), the biologically active metabolite of retinoic acid (RA) has pleiotropic effects on haematopoietic cells, maintaining haematopoiesis via complex intrinsic and extrinsic mechanisms involving retinoic acid receptor-alpha (RARalpha) and RARgamma signalling. Conditional murine Rar knockout models were utilised to determine the intrinsic and extrinsic impacts of Rara and/or Rarg deletion on HSCs and their progeny in vivo via global, postnatal deletion, haematopoietic cell-specific deletion (whole bone marrow transplants (WBMTs)) and HSC and progenitor-specific deletion (Lineage-c-Kit+Sca-1+ (LKS+) WBMTs). These data revealed novel roles of Rara in haematopoiesis, with postnatal deletion resulting in intrinsically-mediated myeloid-biased haematopoiesis, reduced numbers of CD8+ T cells and altered HSC reconstitution capacity, in addition to extrinsically-mediated aberrant BM erythropoiesis and B lymphopoiesis. Loss of either Rara and/or Rarg resulted in myeloid-biased haematopoiesis and concurrent deletion (expression of Rarb only) enhanced HSC exhaustion. Contrary to germline Rarg-/- studies, postnatal Rarg deletion had a limited impact on haematopoiesis. The observed phenotypical differences between germline and global, postnatal Rar deletions may be due to a combination of developmental and microenvironmental interactions, interactions between Rara and Rarg and their differential target genes and compensatory effects. Whilst the relative contribution of RA signalling to its haematopoietic regulation is unknown, homeoboxa1 (HOXA1) is an RARgamma target gene and its full-length isoform (HOXA1-FL) is frequently upregulated in human MDS. A series of studies utilising conditional murine haematopoietic Hoxa1 knockin mice revealed that whilst recipient mice developed MDS during serial transplantation, consistent with previous studies, the levels of Hoxa1-FL overexpression were insufficient to result in progression to secondary acute myeloid leukaemia (sAML). Additionally, Hoxa1 overexpression resulted in profound, persistent and serially transplantable macrothrombocytopenia despite a depleted yet highly megakaryocyte-primed HSC and progenitor compartment. The macrothrombocytopenia resulted from ineffective thrombopoiesis by dysfunctional, low ploidy megakaryocytes, potentially due to inflammation-mediated lineage skewing and/or late-stage developmental defect(s). Dysregulated BM erythropoiesis and granulopoiesis were also observed. These phenotypes were consistently evident early, persisted in non-transplanted pre-malignant mice and became more profound during serial transplantation and after MDS progression. Phenotypic severity also depended on Hoxa1 gene-dosage and isoform expression. Furthermore, the megakaryocyte-priming correlated to increased DNA damage and/or deficient DNA damage responses (DDR), increased expression of inflammatory markers and altered programmed cell death, suggesting that an altered inflammatory microenvironment and associated haematopoietic lineage skewing may have contributed to the Hoxa1-FL-mediated haematopoietic defects, although this remains under investigation. Whilst the precise mechanisms underlying these phenotypes therefore remain to elucidated, it is evident that Rara, Rarg and Hoxa1-FL have pleiotropic impacts on haematopoiesis that are both cell-type and maturation-stage dependent. Elucidation of these effects in murine models are critical steps in the development of targeted therapies for MDS patients with increased Hoxa1-FL expression and for other haematopoietic malignancies to which dysregulated Hoxa1 and/or RA signalling may contribute.