Regulation of flt3 gene expression in haematopoietic and leukaemic stem cells

Volpe, Giacomo (2010). Regulation of flt3 gene expression in haematopoietic and leukaemic stem cells. University of Birmingham. Ph.D.

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Abstract

The interaction between the tyrosine kinase receptor Flt3 and its ligand leads to signalling during the commitment of haematopoietic stem cells (HSCs). Constitutive activation of the Flt3/FL pathway is a key factor in enhanced survival and expansion in acute myeloid leukaemia (AML). Although there is extensive knowledge regarding mutations leading to the constitutive activation of Flt3 receptor activity, the molecular mechanisms underlying the regulation of the \(flt3\) gene in HSCs, and how such mechanisms might be altered in leukaemia, are still poorly understood. Here, by using HSC and leukaemic cell lines, I locate several regulatory elements in the \(flt3\) locus by DNaseI mapping and have characterized their epigenetic environment. Analysis of the methylation and acetylation status of histones H3 and H4 around \(flt3 cis\)-regulatory regions highlights a distinct combination of epigenetic modifications specific to AML cells in a region that distinguishes the Flt3\(^-\) and Flt3\(^+\) stages of HSC differentiation. Moreover, I show the link between the \(in vivo\) binding of C/EBP and c-Myb on regulatory elements and epigenetic remodelling in the differential regulation of \(flt3\) in leukaemic cells. Finally, I identify the histone modifiers TIP60 and CBP as potential mediators of the epigenetic regulation of \(flt3\) in AML cells.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):