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Title: Modelling Down Syndrome leukaemia using transchromosomic ES cell lines
Author: De Vita, Serena
ISNI:       0000 0004 2678 1968
Awarding Body: Queen Mary, University of London
Current Institution: Queen Mary, University of London
Date of Award: 2009
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AMKL (acute megakaryoblastic leukaemia) accounts for at least 50% of all cases of acute myeloid leukaemia (AML) associated with Down Syndrome (DS). Every tenth neonate with DS develops Transient Myeloproliferative Disorder (TMD), a self-regressing neoplasia with features that closely resemble AMKL. Despite the vast majority of TMD cases self-regressing within a few weeks, approximately 30% of DS infants with TMD develop by the age of 2-4 years a more aggressive, full-blown AMKL. Both DS-TMD and DS-AMKL are associated with trisomy of human chromosome 21 (HSA21) and with acquired mutations of GATA-1 (a transcription factor essential for erythroid/megakaryocytic lineage specification) leading to the exclusive production of a short form of the protein known as GATA-1s. Additional molecular events involved in the progression from TMD to AMKL remain largely unknown. The aim of this project was to shed new light on the critical events involved in the pathogenesis of DS-TMD and AMKL utilizing an innovative in vitro model that mimics Down syndrome, a murine embryonic stem cell line carrying an extra copy of human chromosome 21 (HSA21). Using this transchromosomic ES cell system, I explored the effect of trisomy 21 (t21) on the generation of megakaryocytes in vitro, and showed that trisomic megakaryocyte precursors display increased levels of GATA-1 compared to euploid controls and exhibit the tendency of forming macroscopic colonies without overt GATA1 mutations. Furthermore, I genetically manipulated the transchromosomic ES cell system by retrovirally 4 overexpressing GATA1s and demonstrated that trisomy 21 is required for GATA-1s to exert its full hyperproliferative potential. The influence of the supernumerary HSA21 on the ontogenesis of haematopoietic stem cells (HSCs) from mesodermal precursors was also studied in the transchromosomic system. In this thesis, I present evidence that mesodermal colonies derived from transchromosomic ES cells give rise to an increased number of immature haematopoietic progenitors compared to euploid controls. I demonstrate that at least two independent genes on HSA21 contribute to this effect, and that trisomy of RUNX-1 (a master regulator of primitive haematopoiesis encoded on chromosome 21) is required for an increased haematopoietic commitment from the mesodemal precursors. This thesis shows that t21 influences haematopoiesis (in general) and the megakaryocytic lineage (in particular) at several levels and that it is responsible for an overall increase in levels of immature cells that are targets for acquisition of further leukaemogenic mutations. Finally, in this study I clarify the role of JAK3, a gene whose mutations have been reported in AMKL, in the progression from TMD to AMKL.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Medicine