Mutant FLT3 signaling contributes to a block in myeloid differentiation

  title={Mutant FLT3 signaling contributes to a block in myeloid differentiation},
  author={Rui Zheng and Donald M. Small},
  journal={Leukemia \& Lymphoma},
  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… 
Inhibition of the receptor tyrosine kinase Axl impedes activation of the FLT3 internal tandem duplication in human acute myeloid leukemia: implications for Axl as a potential therapeutic target.
The data suggest that Axl contributes to the pathogenesis of FLT3-ITD(+) AML through, at least in part, positive regulation of constitutiveFLT3 activation.
RUNX1 cooperates with FLT3-ITD to induce leukemia
It is predicted that blocking RunX1 activity will greatly enhance current therapeutic approaches using FLT3 inhibitors and establish and elucidate the unanticipated oncogenic function of RUNX1 in AML.
Mechanisms of resistance to FLT3 inhibitors.
  • S. H. Chu, D. Small
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Mechanisms of resistance to FLT 3 inhibitors
The mechanisms of resistance to FLT3 inhibitors and possible strategies to overcome resistance are discussed through closer examination of the events of leukemogenesis and design of combination therapy.
NF-κB/STAT5/miR-155 network targets PU.1 in FLT3-ITD-driven acute myeloid leukemia
A novel network in which FLT3-ITD signaling induces oncogenic miR-155 by p65 and STAT5 in AML, thereby targeting transcription factor PU.1.1, which blocks proliferation and induces apoptosis of FLT 3- ITD-associated leukemic cells.
A Robust Error Model for iTRAQ Quantification Reveals Divergent Signaling between Oncogenic FLT3 Mutants in Acute Myeloid Leukemia*
A robust experimental framework and associated error model for iTRAQ-based quantification on an Orbitrap mass spectrometer that relates variance of peptide ratios to mass spectral peak height and provides for assignment of p value, q value, and confidence interval to every peptide identification, obviating the need for detailed characterization of individual ion peaks is described.
Prognostic relevance of FLT3-TKD mutations in AML: the combination matters--an analysis of 3082 patients.
An additional favorable impact of FLT3-TKD on EFS in prognostically favorable AML with NPM1- or CEBPA mutations is found and is associated with inferior survival in MLL-PTD/TkD double-mutated cases.
Frequency of FLT3 Internal Tandem Duplications in Adult Syrian Patients with Acute Myeloid Leukemia and Normal Karyotype
The results support that FLT3-ITD are independent adverse prognostic factors for elderly AML-CN patients and are associated with low overall survival (OS), low rate of CR, high relapse rate (RR), and high percentage of BM blast at diagnosis.
Very late antigen-4 function of myeloblasts correlates with improved overall survival for patients with acute myeloid leukemia.
Adhesion and migratory properties of AML blasts thus appear to influence chemosensitivity and therefore may be therapeutic targets.


Inhibition of the transforming activity of FLT3 internal tandem duplication mutants from AML patients by a tyrosine kinase inhibitor
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
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.
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.
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.
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
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.
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.
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.
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.