FLT3


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FLT3

A gene on chromosome 13q12 that encodes a class-III receptor tyrosine kinase, which regulates haematopoiesis. FLT3 is activated by binding the fms-related tyrosine kinase 3 ligand to the extracellular domain, which induces homodimer formation in the plasma membrane leading to autophosphorylation of the receptor. The activated receptor kinase in turn phosphorylates and activates multiple cytoplasmic effectors involved in apoptosis, proliferation and differentiation of haematopoietic cells in bone marrow.

Molecular pathology
FLT3 mutations that activate the receptor are thought to induce acute (myeloid or lymphocytic) leukaemia.
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Results from QuANTUM-R, which was the first randomized phase 3 study to show that a FLT3 inhibitor prolonged overall survival as an oral, single agent compared to chemotherapy in patients with relapsed/refractory FLT3-ITD AML, were recently published in The Lancet Oncology.
Mutations of FLT3, DNMT3A, and NPM1 are often present concurrently, while other mutations of NPM1, RUNX1, CEBPA, and TP53 are almost always mutually exclusive both at diagnosis and during disease transformation (11-19).
Studies have shown that DNMT3A mutations are often accompanied by other mutations, including FLT3, NPM1, and IDH1 and IDH2 mutations (24) and confer an unfavorable prognosis in both younger and older patients (17).
In FLT3, wild-type DNA (E) is easily distinguished from samples containing ITDs of 38 bp (A), 57 bp (B), 108 bp (C) and 201 bp (D).
Given that both Flt3 and Myc regulate HSCs' self-renewal and differentiation, evaluating the interplay between Flt3-ITD signaling and Myc molecules may represent therapeutic targets for AML therapy.
Phosphorylated Flt3 levels were assessed in mouse retina specimens obtained at P13, P15, P18, and P21 by ELISA with a specific kit as previously described [38].
The dBMA Treg [greater than or equal to] 21/[micro]L correlation with integrated molecular-cytogenetic risk; the NPM mutation; the FLT3 ITD or D835 mutation; and de novo versus secondary AML and WBC are summarized in Table 4: the molecularcytogenetic risk association (p = 0.020) was demonstrated.
Mutations in genes involved in epigenetics (DNMT3A, IDH, TET2, ASXL1) are considered as early events in leukemogenesis, in contrast to activating mutations (FLT3, RAS) which are late events and are frequently lost during disease progression [7].
In normal karyotype AML, overexpression of WT1 at diagnosis has been associated with decreased CR, DFS and OS in both Flt3 negative and Flt3 positive AML patients.35 Additionally higher blood and marrow WT1 levels at diagnosis and post consolidation correlates with higher risk of relapse.36
Novartis received approval from the FDA for Rydapt (midostaurin) for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who have a specific genetic mutation called FLT3, in combination with chemotherapy.
Mutation of other epigenetic regulators, such as TET2 [14], MLL [15], IDH1/2 [16], FLT3 [11], NPM1 [11], RUNX1 [17], and ASXL1 [18], has been associated with unfavourable clinical outcomes for AML patients [7].