Mutant FLT3 signaling contributes to a block in myeloid differentiation

@article{Zheng2005MutantFS,
  title={Mutant FLT3 signaling contributes to a block in myeloid differentiation},
  author={Rui Zheng and Donald M. Small},
  journal={Leukemia \& Lymphoma},
  year={2005},
  volume={46},
  pages={1679 - 1687}
}
FLT3 is a member of the class III receptor tyrosine kinase family and is primarily expressed on hematopoietic stem/progenitor cells. Somatic mutations of FLT3 involving internal tandem duplication (ITD) of the juxtamembrane domain or point mutations in the activation loop have been identified in ∼17 – 34% and 7 – 9% of acute myeloid leukemia (AML) patients, respectively. The ITD mutations appear to activate the tyrosine kinase domain through receptor dimerization in a FLT3 ligand-independent… 
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References

SHOWING 1-10 OF 94 REFERENCES
Inhibition of the transforming activity of FLT3 internal tandem duplication mutants from AML patients by a tyrosine kinase inhibitor
TLDR
Investigation of the inhibitory effects of AG1296 on FLT3/ITDs isolated from AML patients in the IL-3-dependent cell line, Ba/F3, as well as in primary leukemia samples fromAML patients, suggest that inhibiting the activity ofFLT3 may have a therapeutic value in some leukemias expressing FLT 3/ ITDs.
Inhibition of FLT3-mediated transformation by use of a tyrosine kinase inhibitor
TLDR
In transfected Ba/F3 cells, AG1296 selectively and potently inhibited autophosphorylation of FL-stimulated wild-type and constitutively activated FLT3, demonstrating that the inhibition is specific to theFLT3 pathway in that it leaves the kinases of the IL-3 pathway and other kinases further downstream involved in proliferation intact.
A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo.
TLDR
It is demonstrated that CEP-701 induces a cytotoxic effect on cells in a dose-responsive fashion that parallels the inhibition of FLT3, and form the basis for a planned clinical trial of the indolocarbazole derivative Cep-701 in patients with AML harboringFLT3- activating mutations.
Internal tandem duplication mutation of FLT3 blocks myeloid differentiation through suppression of C/EBPalpha expression.
TLDR
Investigation of the mechanism by which internal tandem duplication (ITD) mutation of FLT3 signaling blocks differentiation finds that forced expression of C/EBPalpha was able to overcomeFLT3/ITD-mediated differentiation block, further proving the importance of C- EBPalpha in this process.
SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo.
TLDR
The in vivo efficacy of SU11248 (20 mg/kg/d) dramatically regresses FLT3-ITD tumors in the subcutaneous tumor xenograft model and prolongs survival in the bone marrow engraftment model, suggesting that further exploration of SU 11248 activity in AML patients is warranted.
Constitutive activation of FLT3 stimulates multiple intracellular signal transducers and results in transformation
TLDR
The mimicking of naturally occurring TEL fusions provides an approach to assess aspects of the biology of activated FLT3, or other receptor-type tyrosine kinases (RTKs) in leukemic transformation.
Identifying and characterizing a novel activating mutation of the FLT3 tyrosine kinase in AML.
TLDR
Results suggest that mutations at N841 represent a significant new activating mutation in patients with AML and that patients with such mutations may respond to small-molecule FLT3 inhibitors such as PKC412.
Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations.
TLDR
Interestingly, other parts of the transcriptional program involve novel, IL-3-independent pathways that antagonize differentiation-inducing effects of wild-type Flt3, which should ease the development of specific therapies.
FLT3-ITD and tyrosine kinase domain mutants induce 2 distinct phenotypes in a murine bone marrow transplantation model.
TLDR
The lymphoid manifestation and longer latency of FLT 3-TKD compared with FLT3-ITD mutants together with the lack of influence of FLt3- TKD mutations on the clinical outcome of patients with AML suggest differences in cell signaling between FLT2-TkD mutants and FLT1-ITDs.
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