FLT3 and its Role in the Pathogenesis of Acute Myeloid Leukaemia

@article{Reilly2003FLT3AI,
  title={FLT3 and its Role in the Pathogenesis of Acute Myeloid Leukaemia},
  author={John T. Reilly},
  journal={Leukemia \& Lymphoma},
  year={2003},
  volume={44},
  pages={1 - 7}
}
  • J. Reilly
  • Published 1 January 2003
  • Biology, Medicine
  • Leukemia & Lymphoma
FLT3, a tyrosine kinase receptor class III (RTK), and its ligand (FL) are important for normal haematopoiesis and the development of the immune system. Recently, internal tandem duplications (FLT3 ITDs) in exons 14 and/or 15 that lead to constitutive receptor activation, have been described in 20-25% of adults with acute myeloid leukaemia (AML). The FLT ITD mutations, which are thought to disrupt a repressor sequence in the juxta-membrane region, confer a poor prognosis in AML, especially in… 
FLT3 inhibitors in the treatment of Acute Myeloid Leukemia: current status and future perspectives.
TLDR
This review focuses on the role of FLT3 mutations in AML, pharmacological features ofFLT3 inhibitors, known mechanisms of drug resistance and accumulated evidence for the use of FLt3 inhibitors in different clinical settings.
Therapeutic intervention in leukemias that express the activated fms-like tyrosine kinase 3 (FLT3): opportunities and challenges
TLDR
Recent efforts to disrupt FLT3 signaling in acute myelogenous leukemia and to identify potential therapeutic challenges posed by the acquisition of resistance mutations in these malignancies are reviewed.
Fluvastatin inhibits FLT 3 glycosylation in human and murine cells and prolongs survival of mice with FLT 3 / ITD leukemia
TLDR
It is demonstrated that statins, a class of drugs already approved by the US Food and Drug Administration, might be repurposed for the management of FLT3 mutant acute myeloid leukemia cases either alone or in conjunction withFLT3 TKI.
Fluvastatin inhibits FLT3 glycosylation in human and murine cells and prolongs survival of mice with FLT3/ITD leukemia.
TLDR
It is demonstrated that statins, a class of drugs already approved by the US Food and Drug Administration, might be repurposed for the management of FLT3 mutant acute myeloid leukemia cases either alone or in conjunction withFLT3 TKI.
Prevalence of FMS-like tyrosine kinase 3/internal tandem duplication (FLT3/ITD+) in de novo acute myeloid leukemia patients categorized according to cytogenetic risk.
TLDR
It is found that 2 patients were still alive more than 24 months later, FLT3/ITD+ did not influence the patients' survival rate, and the prognostic advantage of favorable cytogenetics among patients with FLT 3/ ITD+ remains to be elucidated, for it to be better understood.
Expression of pSTAT5 predicts FLT3 internal tandem duplications in acute myeloid leukemia
TLDR
It is concluded that p STAT5 expression can precisely be assessed by immunohistochemistry in routinely processed bone marrow trephines, STAT5 is highly likely the preferred second messenger of FLT3-mediated signaling in AML, and expression of pSTAT5 is predictive of FLt3-ITD.
Nucleophosmin gene mutations in acute myeloid leukemia.
TLDR
D detection of NPM1 gene mutations may allow dissection of the heterogeneous group of AML with normal karyotype into prognostically different subgroups, thereby providing insights for the development of new chemotherapeutic agents.
Normal and Oncogenic Forms of the Receptor Tyrosine Kinase Kit
TLDR
The objective of this review is to summarize what is known about normal and oncogenic forms of Kit and to place particular emphasis on recent developments in understanding the mechanisms of action of normal and activated forms of this RTK and its association with human disease.
...
...

References

SHOWING 1-10 OF 100 REFERENCES
Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies.
TLDR
Analysis of the mutation of D835 of FLT3, which corresponds to D816 of c-KIT, in a large series of human hematologic malignancies demonstrates that the FLT 3 gene is the target most frequently mutated to become constitutively active in AML.
Internal tandem duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia
TLDR
Clinically, the presence of FLT3/ITD was related to high peripheral white blood cell counts as well as peripheral leukemia cell counts, and high ldh level, and low fibrinogen concentration, suggesting that FLT 3/ ITD plays a significant role in progression of APL.
Genomic structure of human FLT3: implications for mutational analysis
TLDR
The findings indicate that FLT3 ITD mutations are located in exons 14 and 15, and not 11 and 12 as previously reported, which indicates that the availability of the complete genomic structure ofFLT3 will facilitate mutational screening of the entire coding and promoter regions.
Constitutive activation of FLT3 in acute myeloid leukaemia and its consequences for growth of 32D cells
TLDR
It is concluded that, in some AML samples, Flt3 is constitutively activated and that this does not correlate with ITR mutations in the juxtamembrane domain.
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.
Biological characteristics and prognosis of adult acute myeloid leukemia with internal tandem duplications in the Flt3 gene
TLDR
Data show that the Flt3/ITD represents an important diagnostic marker for patient prognosis, and that the presence of these mutations is associated with altered proliferative ability of progenitors in vivo and in vitro.
Internal tandem duplication of the FLT3 gene and clinical evaluation in childhood acute myeloid leukemia
TLDR
The results suggest that the tandem duplication in the jm domain of the FLT3 gene is not a frequent phenomenon but might be a factor of poor prognosis in childhood patients with AML.
Prognostic significance of FLT3 ITD and D835 mutations in AML patients.
TLDR
It is concluded that FLT3/ITD mutations may be an important prognostic marker in AML, especially in the standard/good risk karyotype groups, where it may allow risk-directed therapy.
Tandem duplications of the FLT3 receptor gene are associated with leukemic transformation of myelodysplasia
TLDR
The fact that the accumulation of genetic events, including FLT3 duplication, correlates with leukemic transformation from antecedent myelodysplasia and with subsequent disease progression is uncovered.
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.
...
...