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Please use this identifier to cite or link to this item: http://hdl.handle.net/1807/30545

Title: Analysis of Signalling Network Consequent to FLT3 in AML Patients
Authors: Chen, Hsiao-Wei Tina
Advisor: Hedley, David
Department: Medical Biophysics
Keywords: Leukemia
AML
FLT3
ITD
Flow Cytometry
Sorafenib
Resistance
TKI
Issue Date: 6-Dec-2011
Abstract: The FMS-like tyrosine kinase 3- internal tandem duplication (FLT3/ITD) aberration is common in acute myeloid leukemia (AML) and associated with poor patient outcome. Inhibitors targeting FLT3/ITD are in development, but clinical responses are transient. This project focussed on elucidating molecular signalling consequences of FLT3/ITD inhibition, to identify rational drug combinations for future development. A Multicolour Phospho Flow Cytometry (MPFC) assay was developed to assess signalling events downstream of FLT3/ITD in primary patient samples, focusing on alterations in ERK, STAT5, Akt, and S6. STAT5 signalling appeared to be important exclusively in FLT3/ITD samples. MPFC accurately predicted the presence of FLT3/ITD, inhibitor sensitivity and the initial positive clinical response of a trial patient receiving a FLT3/ITD inhibitor. PI3K pathway upregulation was observed in a Sorafenib-resistant FLT3/ITD cell line established to study resistance mechanisms of FLT3 inhibition. Further, combination FLT3 and PI3K inhibition demonstrated synergy, suggesting potential clinical relevance to this therapeutic strategy.
URI: http://hdl.handle.net/1807/30545
Appears in Collections:Master

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