TY  - UNPB
EP  - 214
AV  - public
Y1  - 2009/06//
A1  - Mead, A.J.
M1  - Doctoral
PB  - UCL (University College London)
UR  - https://discovery.ucl.ac.uk/id/eprint/16281/
N2  - 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.
N1  - Unpublished
TI  - The clinical and biological consequences of different FLT3 mutations in patients with AML
ID  - discovery16281
ER  -