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Title: Studies of glucocorticord resistance in chronic lymphocytic leukaemia
Author: Melarangi, Tony
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2012
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Glucocorticoids represent an important component of modern treatment regimens for patients with fludarabine-refractory or TP53-defective chronic lymphocytic leukaemia. However, not all patients respond to GC therapy. This in-vitro study / investigated-the molecular mechanisms responsible for GC resistance in a cohort / / of 46 primary CLL samples. As expected, dexamethasone-induced killing was more pronounced in cases with UM-IGHV genes. Cross resistance was observed between dexamethasone and other GCs but not fludarabine, implying distinct resistance mechanisms. GC resistance was not associated with GC receptor defects, altered NF-KB signalling or impaired Bim up-regulation. siRNA knockdown experiments confirmed that Bim plays a crucial role in the GC- induced killing of CLL cells, while immunoprecipation experiments showed that GC resistance was associated with impaired Bax/Bak activation and that Bim was bound to Bcl-2. Levels of Bcl-2 were found to be higher in GC-resistant samples, and disruption of the Bim/Bcl-2 interaction by ABT -737 sensitised GC-resistant CLL cells to GC-induced killing. Taken together, these findings provide compelling evidence that GC resistance in CLL cells results from the sequestration of up-regulated Bim by high levels of Bcl-2 with consequent failure of Bax/Bak activation and apoptosis induction.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral