Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.695386
Title: Criticality of the Hoxa cluster in novel models of leukaemia
Author: Kettyle, Laura Margaret Joy
ISNI:       0000 0004 5989 0888
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2015
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Abstract:
Class I Homeobox genes (Hox) are an evolutionary conserved family of genes that encode master regulators in developmental processes. Hox gene expression has been shown to be high in normal haematopoietic stem/progenitor cells (HSPCs) and decreases during normal differentiation, however elevated Hox expression remains in subtypes of leukaemia. Polycomb repressor complexes (PRCs) and histone modifiers, e.g. Mixed Lineage Leukaemia (MLL), are key regulators of Hox expression. MLL rearrangements, frequent in acute leukaemia, are associated with high HOXA expression. However, the necessity of the Hoxa cluster in MLL-Ieukaemia maintenance is not fully elucidated. Ectopic overexpression of MLL-AF9 in HSPCs in conditional compound transgenic mouse backgrounds MxCre+/Hoxafloxlflox (MAFF) or Hoxafloxlflox (Aflox) models resulted in increased colony formation and growth in liquid culture. Transformed colonies, serially replated in methylcellulose and transplanted into sub-lethally irradiated recipient mice, resulted in primary leukaemia. Direct treatment of MLL-AF9 leukaemias generated in the MAFF background (MAFF-MA9) with interferon-alpha (IFN)resulted in further deletion of the Hoxa cluster and significant reduction in colony formation compared to controls. Although non-leukaemic MAFF HSPCs retained colony forming ability after complete Hoxa cluster deletion (Hoxa-/-), no Hoxa-/- colonies were recovered from the IFN treated MAFF-MA9 cultures. Cre-recombinase induced deletion of the Hoxa cluster from Aflox-MA9 leukaemia cells was confirmed by gDNA-PCR and sequencing. Transplantation of Cre-treated Aflox-MA9 cells resulted in significant increased survival (p
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.695386  DOI: Not available
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