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Title: Id proteins as determinants of drug-induced cell death in B-cell chronic lymphocytic leukaemia
Author: Weiler, Sarah
Awarding Body: University of Essex
Current Institution: University of Essex
Date of Award: 2012
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Inhibitor of differentiation (Id) proteins function as transcriptional regulators by modulating the activities of several transcription factors through protein-protein interactions. Recent studies have shown that, in addition to their regulatory function in cell cycle, differentiation, tumourigenesis and survival, Id proteins mediate drug-induced apoptosis in a variety of solid tumours. Chronic lymphocytic leukaemia (Cll) is characterised by an increased resistance to apoptosis, owing to impaired cell death pathways. This project aimed to investigate the role and mechanism of Id proteins in drug-induced cell death in Cll. No direct correlation between endogenous Id2 and Id3 protein levels and in vitro drug sensitivity could be established. Id2 and Id3 displayed rather heterogeneous expression patterns following in vivo and in vitro drug treatment. However, fludarabine treatment induced distinctly different Id3 expression patterns in drug-sensitive and -resistant Cll samples, implying a role for Id3 in mediating drug sensitivity. Further, information-theoretic methods were used to reverse engineer gene regulatory networks and identify candidate target genes through which Id3 mediates fludarabine sensitivity in Cll. Functional inhibition of Id2 and Id3 by small interfering RNA induced cell death in most primary Cll samples, suggesting that these proteins are essential for survival. Finally, culture in the presence of endothelial cells conferred fludarabine resistance and was associated with increased Id2 and/or Id3 protein levels. This upregulation of Id expression and correlated drug resistance was abolished by the use of a glutathione (GSH) inhibitor and was mimicked by GSH treatment in some Cll samples, suggesting that it is partially mediated through increased intracellular GSH levels. Collectively, this data suggests that a subgroup of Clls rely on Id2 and Id3 to promote survival and drug resistance, although the underlying cause for this heterogeneity remains to be identified.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available