Constitutively activating internal tandem duplication (ITD) mutations of the receptor tyrosine kinase FLT3 (Fms-like tyrosine kinase 3) play an important role in leukemogenesis, and their presence is associated with poor prognosis in acute myeloid leukemia (AML). To better understand FLT3 signaling in leukemogenesis, we have examined the changes in gene expression induced by FLT3/ITD or constit...

Mutations in the isocitrate dehydrogenase gene (IDH1) were recently described in patients with acute myeloid leukemia (AML). To investigate their prognostic significance we determined IDH1 status in 1333 young adult patients, excluding acute promyelocytic leukemia, treated in the United Kingdom MRC AML10 and 12 trials. A mutation was detected in 107 patients (8%). Most IDH1(+) patients (91%) ha...

BACKGROUND Internal tandem duplications of the FLT3 gene (FLT3-ITDs) are frequent in patients with acute promyelocytic leukemia (APL), however its clinical impact remains controversial. DESIGN AND METHODS We analyzed the prognostic significance of FLT3-ITD mutant level and size, as well as FLT3-D835 point mutations, PML-RARalpha expression and other predictive factors in 129 APL patients at d...

Our previous observation of a higher incidence of FLT3-ITD in DR(-) M1/M2 AML than in DR(+) M1/M2 led to an investigation of NPM1 mutation in the same samples, since DR(-) AML and AML with NPM1 mutation share such characteristics as normal karyotype, the absence of CD34, and FLT3-ITD. NPM1 mutation was found in 18 of 26 (69.2%) of DR(-) cases, but not in any of 28 DR(+) cases. FLT3-ITD was note...

Recently, treatment with bromodomain and extraterminal protein antagonist (BA) such as JQ1 has been shown to inhibit growth and induce apoptosis of human acute myelogenous leukemia (AML) cells, including those expressing FLT3-ITD. Here, we demonstrate that cotreatment with JQ1 and the FLT3 tyrosine kinase inhibitor (TKI) ponatinib or AC220 synergistically induce apoptosis of cultured and primar...

Mice deficient in c-fms-like tyrosine kinase 3 (FLT3) signaling have reductions in early multipotent and lymphoid progenitors, whereas no evident myeloid phenotype has been reported. However, activating mutations of Flt3 are among the most common genetic events in acute myeloid leukemia and mice harboring internal tandem duplications within Flt3 (Flt3-ITD) develop myeloproliferative disease, wi...

Internal tandem duplication (ITD) mutations of the receptor tyrosine kinase FLT3 have been found in 20% to 30% of patients with acute myeloid leukemia (AML). These mutations constitutively activate the receptor and appear to be associated with a poor prognosis. Recent evidence that this constitutive activation is leukemogenic renders this receptor a potential target for specific therapy. In thi...

In acute myeloid leukaemia (AML), further prognostic determinants are required in addition to cytogenetics to predict patients at increased risk of relapse. Recent studies have indicated an internal tandem duplication (ITD) in the FLT3 gene may adversely affect clinical outcome. The studies reported in this thesis evaluated the impact of a FLT3/ITD on outcome in 854 patients treated in UK MRC A...

Up to 30% of patients with acute myeloid leukemia (AML) harbor internal tandem duplications (ITD) within the FLT3 gene, encoding a receptor tyrosine kinase. These mutations induce constitutive tyrosine kinase activity in the absence of the natural Flt3 ligand and confer growth factor independence, increased proliferation, and survival to myeloid precursor cells. The signaling pathways and downs...

BACKGROUND FLT3 is mutated in about 1/3 of acute myelogenous leukemia (AML) patients. The aim of the present study was to report the prevalence of FLT3 mutations and comparison with prognostic factors in AML patients in the Northeastern of Iran. MATERIALS AND METHODS This cross-sectional study concerned 100 AML cases diagnosed based on bone marrow aspiration and peripheral blood. DNA for ever...