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Title: The clinical and biological consequences of different FLT3 mutations in patients with AML
Author: Mead, A. J.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2009
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Characterisation of pathogenic markers in acute myeloid leukaemia (AML) may benefit patients through refinement of risk stratification, application of molecularly targeted therapy and improved understanding of AML biology. Whilst the presence of an internal tandem duplication (ITD) within the fms-like tyrosine kinase-3 (FLT3) gene is known to predict adverse outcome in young adults with AML, the clinical significance of activating mutations in the tyrosine kinase domain (TKD) of FLT3 is unclear. Therefore, a highly sensitive and specific denaturing-HPLC technique was developed to screen for FLT3/TKDs in 1339 young adult patients with AML. Mutations were detected in 161 (12%) cases, with a high incidence in patients with inv(16) (24%; P=.009), a group in which FLT3/ITDs are uncommon. Unlike FLT3/ITDs, FLT3/TKDs were associated with a favourable long-term outcome with a 10-year overall survival (OS) of 36% for FLT3 WT, 51% for FLT3/ITD-TKD+ and 24% for FLT3/ITD+TKDpatients (P<.001). The relative FLT3/TKD mutant level was highly variable with the favourable prognosis residing in those patients with greater than 25% mutant alleles (10-year OS of 59%), possibly reflecting the stage at which the mutation is acquired. The mechanism of FLT3 activation also influenced sensitivity to FLT3-inhibitor induced cytotoxicity, with FLT3/ITD+ blast cells more sensitive than FLT3/TKD+ cells. Following lentiviral transduction, FLT3/ITD-transduced 32Dcl3 and Ba/F3 cells demonstrated more rapid proliferation than FLT3/TKD-transduced cells. In an NB4 cell line model of ATRA-induced myeloid differentiation, the presence of a FLT3/ITD inhibited differentiation unlike a FLT3/TKD mutation which increased differentiation. Furthermore, FLT3/ITD-transduced CD34 positive haematopoietic stem cells showed greater cytokine-free survival of colony forming cells than FLT3/TKD-transduced cells. Signalling studies also revealed that a FLT3/ITD induced stronger STAT5 activation than a FLT3/TKD mutation. This unexpected genotype-phenotype relationship is of direct relevance to current clinical decision making in AML, and may also provide insights into mechanisms of chemoresistance.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available