The role of apoptosis and ineffective haematopoiesis in the myelodysplastic syndromes (MDS)
thesisposted on 01.03.2017 by Guirguis, Andrew Adel
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The myelodysplastic syndromes (MDS) are defined as clonal haematopoietic stem cell disorders whose key features are those of ineffective haematopoiesis, bone marrow dysplasia and an increased likelihood of transformation to acute leukaemia. From a clinical perspective, although these disorders are notable for their heterogeneity, the presence of recurrent cytopenias and leukaemic progression remains a common theme. With an ever-ageing Australian population, the incidence of MDS is predicted to rise exponentially in years to come. In spite of this, research in MDS has been hampered over the years by a lack of adequately representative cell lines or useful xenograft models that accurately recapitulate features of the disease. Additionally, the mechanism of action of the limited armamentarium of therapies such as azacitidine and lenalidomide has not been fully elucidated at the present moment. Although this is likely to change as our understanding of the heterogeneous molecular basis of human MDS is further refined, there are still some significant deficiencies in our current knowledge and approach. Early-stage MDS has long been characterized by an increase in apoptosis or ‘programmed cell death’. This is thought to contribute to the disparity between marrow hypercellularity and peripheral blood cytopenias – a phenomenon referred to as ‘ineffective haematopoiesis’. However, the mechanism of apoptosis has been a contentious one with some groups supporting a cell extrinsic model and others postulating a cell intrinsic one. Additionally, the majority of this data remains observational. In this body of work, we have used the Nup98-HoxD13 (NHD13) murine model as a tool for studying apoptosis in MDS. We have specifically sought to determine how apoptosis contributes to the MDS phenotype, which proteins might be involved and the functional benefit and significance of abrogating apoptosis on the associated cytopenias and on leukaemic progression.