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Title: Investigation of the 'HOX code' in haematopoiesis and leukaemia
Author: Ramsey, Joanne Margaret
ISNI:       0000 0004 2722 7627
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2011
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The Homeobox (Hox) gene network in conjunction with their Tale cofactors act as master regulators of embryogenesis and haematopoiesis. Co-ordinated and overlapping expression of the genes has been reported in several developmental processes including malignant haematopoiesis, indicative of a 'Hox code.' Hox codes may have value as prognostic indicators in disease conditions, particularly in leukaemia subtypes. Gene expression profiling in normal embryonic stem (ES) cells and a Tel- PDGFRbeta conditional leukaemic ES model indicated a core subset of Hox-Tale members involved in normal and malignant haematopoiesis. The combination of Hox genes a7, a9, and b2-b4, along with Meisl were identified as a candidate 'Hox code' based on their differential expression at key stages of development. Investigations of two of these genes, Hoxa9 and Meisl, in factor- dependent BaF3 cells revealed cytokine independent growth consistent with cellular transformation. Altered expression of the HOX-MEIS axis is associated with leukaemia, where it plays a role in increased proliferation and impaired differentiation. A re- transplantable murine model using co-overexpression of Hoxa9-Meisl was developed to evaluate downstream targets and potential therapeutic intervention. The immature myeloid progenitor phenotype leukaemia showed highly infiltrative pathology with observable splenomegaly. Genes profiled within transcription factor, immune and pluripotency signature platforms showed decreased expression between leukaemic and normal bone marrow samples. miRNAs also showed measurable changes in expression with many showing increased expression in the leukaemic setting. predictive target analysis demonstrated potential overlap with candidate genes identified as being down- regulated in the same setting. Protein arrays indicated enhanced angiogenesis related expression with reduced phospho-receptor tyrosine kinase protein levels in the leukaemia. Connectivity mapping of the deregulated gene expression profiles compared to human leukaemia profiles identified potential drug therapies. Disruption of colony growth was observed following candidate drug treatment of the leukaemic cells, suggesting potential clinical application of these compounds in HOXA9 and MEISl associated leukaemia. The data confirm this mouse leukaemia as an appropriate and relevant model of human disease, and its usefulness for profiling downstream events and the identification of candidate drugs for future investigations.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available