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FLT3 Mutations (flt3 + mutation)
Selected AbstractsD324N single-nucleotide polymorphism in the FLT3 gene is associated with higher risk of myeloid leukemiasGENES, CHROMOSOMES AND CANCER, Issue 4 2006Susanne Schnittger Mutations within the FLT3 gene are of growing importance for classification, risk assessment, and therapeutic targeting of acute myeloid leukemia (AML). We analyzed 656 AML patients for a recently described single-nucleotide polymorphism (SNP) in the third immunoglobulin-like domain of the extracellular region of FLT3. The FLT3 D324N variant was present in 42 cases (6.4%), but it was not associated with a specific AML subtype and did not show an elevated leukocyte count, as do other FLT3 mutations. In remission samples, a 50% ratio of the normal to the D324N variant was detectable. Stably expressed in IL-3 dependent Ba/F3 cells, the D324N variant did not confer receptor autophosphorylation, factor independent growth, or increased resistance to apoptotic cell death in response to varying doses of FLT3 ligand. In 400 healthy donors, the FLT3 D324N variant was detected in 6 cases (1.5%) and segregated in a family. Thus, it was shown to be a polymorphism with a lower frequency in healthy controls than in patients with AML (P < 0.001). In addition, 21 of 234 CML (9.0%) and 7 of 155 ALL (4.5%) cases carried the FLT3 D324N. Our data suggest that the FLT3 D324N variant might be associated with a predisposition to different subtypes of leukemia. © 2005 Wiley-Liss, Inc. [source] Comparative analysis of MLL partial tandem duplication and FLT3 internal tandem duplication mutations in 956 adult patients with acute myeloid leukemiaGENES, CHROMOSOMES AND CANCER, Issue 3 2003Christine Steudel Partial tandem duplication (PTD) of the MLL gene and internal tandem duplication (ITD) of the juxtamembrane region of the FLT3 receptor tyrosine kinase gene have been described in acute myeloid leukemia (AML) patients, preferentially in those with normal cytogenetics. These alterations have been associated with a poor prognosis. In our study, we analyzed the prevalence and the potential prognostic impact of these aberrations in a large unselected and well-defined cohort of 956 patients with AML. Results were correlated with cytogenetic data and clinical outcome. MLL PTD was detected by RT-PCR, subsequent nucleotide sequencing, and Southern blotting. The overall incidence was found to be 5.0% (48/956), whereas FLT3 ITD was detected in 19.2% (184/956). Sixteen cases were positive for both alterations. The rate of MLL PTD in FLT3 ITD positive patients was significantly higher than that in FLT3 ITD negative patients [16/184 (8.7%); 32/772 (4.1%); P = 0.025]. However, both aberrations were highly increased in patients with normal karyotype (MLL PTD 35/431, P = 0.004; FLT3 ITD 132/334, P < 0.001). When restricted to this subgroup, the rate of MLL PTD in patients with FLT3 mutations was not significantly increased. No statistically significant differences were detected between patients positive for MLL PTD and patients negative for MLL PTD in the rate of complete remissions or the overall survival, although we did see a significantly shorter disease-free survival in patients age 60 or younger. In conclusion, although there is an overlap in the mutational spectrum in AML with FLT3 ITD and MLL PTD mutations, our data do not support a common mechanistic basis. Although associated with inferior disease-free survival, the results of this study do not unequivocally support the notion that MLL PTD mutations represent an independent prognostic factor. © 2003 Wiley-Liss, Inc. [source] A celecoxib derivative inhibits focal adhesion signaling and induces caspase-8-dependent apoptosis in human acute myeloid leukemia cellsINTERNATIONAL JOURNAL OF CANCER, Issue 1 2008Isolda Casanova Abstract Most acute myeloid leukemias (AMLs), including those with c-Kit or FLT3 mutations, show enhanced anchorage independent growth associated with constitutive activation of focal adhesion proteins. Moreover, these alterations increase cell survival, inhibit apoptosis and are associated with poor prognosis and resistance to chemotherapy. Therefore, the induction of apoptosis by selective inhibition of focal adhesion signaling may represent a novel anti-AML therapy. Here, we have evaluated the antitumor effect and the mechanism of action of celecoxib and E7123, a non-Cox-2 inhibitor derivative, in a panel of human AML cell lines and bone marrow mononuclear cells from AML patients. Both compounds induce cell death by inhibiting focal adhesion signaling through p130Cas, FAK and c-Src, leading to caspase-8 dependent apoptosis. This mechanism of action differs from that of classical cytotoxic drugs or of other targeted therapies, and is amenable to rational drug development. Therefore, both drugs could be developed as AML therapeutics; nevertheless, E7123 shows more activity than celecoxib against AML cells, and may not present its Cox-2 dependent cardiovascular toxicity. Finally, our results support the evaluation of celecoxib in AML patients, and the preclinical evaluation of E7123, before its possible clinical testing. © 2008 Wiley-Liss, Inc. [source] FLT3 mutations have no prognostic impact in elderly patients with acute myeloid leukemia and normal karyotype,AMERICAN JOURNAL OF HEMATOLOGY, Issue 8 2009Felicetto Ferrara No abstract is available for this article. [source] Identification of additional cytogenetic and molecular genetic abnormalities in acute myeloid leukaemia with t(8;21)/AML1-ETOBRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2006F. Kuchenbauer Abstract AML1-ETO collaborates with further genetic abnormalities to induce acute myeloid leukaemia (AML). We analysed 99 patients with an AML1-ETO rearrangement for additional aberrations. Frequent genetic abnormalities were, loss of a sex chromosome (56/99, 56·5%) and del(9)(q22) (24/99, 24·2%). The most frequent molecular aberrations were mutations of KITD816 (3/23, 13%) and NRAS (8/89, 8·9%). Further molecular abnormalities were FLT3 mutations (3/87, 3·4%), AML1 (1/26, 3·8%) and PU1 (1/14, 7·1%). MLL-PTD, KRAS and CEBPA mutations were not found. These clinical findings support the model that AML1-ETO collaborates with other genetic alterations, such as mutations of receptor tyrosine kinases, to induce AML. [source] | ||||||||||||||||||||||