| 總結: | <p>Myelodysplastic Syndromes (MDS) are a heterogeneous group of haematological malignancies characterised by ineffective haematopoiesis and dysplastic bone marrow changes. Patients frequently progress to Acute Myeloid Leukaemia and this is associated with very poor clinical outcomes. This thesis focusses on a subtype of MDS, <em>Del(5q)</em> MDS.</p> <p>Sequencing analysis revealed that <em>Del(5q)</em> is frequently the initiating lesion in low risk isolated <em>Del(5q)</em> MDS and tracking patients over time demonstrated progressive disease is associated with the acquisition of new mutations (including <em>Tp53</em> mutations). Early in disease, MDS appears to be sustained by the Lin-CD34+CD38-CD90+CD45RA- MDS stem cells. In one patient, however, at the point of disease progression and after the acquisition of a <em>Tp53</em> mutation, self-renewal activity could be detected in a progenitor cell population outside the stem cell compartment.</p> <p>On the basis of these findings and previous evidence linking <em>Tp53</em> mutations with progression of <em>Del(5q)</em> MDS, mouse models were used to investigate if and how <em>Del(5q)</em> and mutant <em>Tp53</em> collaborate to perturb haematopoiesis. An established model of <em>Del(5q)</em> (heterozygous deletion of Cd74-Nid67) was combined with a <em>Tp53</em> knockout model and conditional knockin models of <em>Tp53</em> mutations found in MDS patients. This work showed <em>Tp53</em> loss and mutations collaborate with <em>Del(5q)</em> to alter haematopoietic stem/ progenitor cell number, function and differentiation ability. <em>Del(5q)</em><sup>+/-</sup><em>Tp53</em><sup>-/-</sup> cells also uniquely develop long-term self-renewal potential in vitro which can be associated with chromosomal instability. Preliminary evidence also suggests a possible role for <em>Del(5q)</em> itself in the development of chromosomal instability.</p>
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