Genomic structure of human <i>FLT3</i>: implications for mutational analysis

Abuduhier, Faisel M.; Goodeve, Anne; Wilson, Gill; Care, Rory; Peake, I. R.; Reilly, John T.

doi:10.1046/j.1365-2141.2001.02821.x

Cited by 75 publications

(63 citation statements)

References 6 publications

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“…18 ) A schematic of the FLT3 receptor and sample of the assay is shown in Figure 1. Patients with this abnormality were found to have an increased incidence of leukocytosis and a decreased overall survival (OS) when compared with patients without FLT3/ITD mutations.…”

Section: Flt3/itd Mutationsmentioning

confidence: 99%

“…Human FLT3 maps to chromosome 13 (13q12) and is comprised of 24 exons extending over more than 100 kilobases (kb). [16][17][18] FLT3 is a member of the PDGF-R subfamily (the socalled class III) of receptor tyrosine kinases, characterized by an interrupted kinase domain. 19 It has closest homology to FMS, KIT, and the two PDGF receptors, and lesser homology to the vascular endothelial growth factor and nerve growth factor receptor subfamilies.…”

Section: Flt3 Receptor and Ligandmentioning

confidence: 99%

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FLT3: ITDoes matter in leukemia

2003

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FMS-like tyrosine kinase-3 (FLT3), a receptor tyrosine kinase, is important for the development of the hematopoietic and immune systems. Activating mutations of FLT3 are now recognized as the most common molecular abnormality in acute myeloid leukemia, and FLT3 mutations may play a role in other hematologic malignancies as well. The poor prognosis of patients harboring these mutations renders FLT3 an obvious target of therapy. This review summarizes the data on the molecular biology and clinical impact of FLT3 mutations, as well as the therapeutic potential of several small-molecule FLT3 inhibitors currently in development.

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Section: Flt3/itd Mutationsmentioning

confidence: 99%

Section: Flt3 Receptor and Ligandmentioning

confidence: 99%

FLT3: ITDoes matter in leukemia

2003

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“…Flt3 exons 14 and 15 (27) were amplified with 35 PCR cycles (94jC for 30 seconds, 60jC for 1 minute, and 72jC for 1 minute) using 500 ng of genomic DNA, 0.3 Amol/L each of primers S (TggTgTTTgTCTCTTCTTCATTgT) and AS (gTTgCgTTCATCACTTTTCCAA), 750 Amol/L of deoxynucleotide triphosphate, 5 mmol/L of MgCl 2 , 1.25 units of Taq GOLD polymerase, and 1Â buffer GOLD I (PerkinElmer, Norwalk, CT) in a total volume of 50 AL.…”

Section: Flt3/itd Detectionmentioning

confidence: 99%

Flt3 Internal Tandem Duplication and P-Glycoprotein Functionality in 171 Patients with Acute Myeloid Leukemia

Marzac

Teyssandier²,

Calendini³

et al. 2006

Clinical Cancer Research

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Purpose: Patients with adult acute myeloid leukemia (AML) with intermediate cytogenetics remain a heterogeneous group with highly variable individual prognoses. New molecular markers could help to refine cytogenetic stratification. Experimental Design: We assessed P-glycoprotein (Pgp) activity and Flt3 internal tandem duplication (ITD+) because of their known prognostic value and because they might lead to targeted therapy. We did a multivariate analysis on 171 patients with adult AML treated in the European Organization for Research and Treatment of Cancer protocols. Results: ITD+ and high Pgp activity (Pgp+) were found in 26 of 171 (15%) and 55 of 171 (32%) of all patients, respectively. ITD and Pgp activities were negative in 94 of 171 (55%, PgpÀITDÀ group), mutually exclusive in 73 of 171 (43%, PgpÀITD+ and Pgp+ITDÀ groups), and only 4 of 171 (2%, Pgp+ITD+ group) patients were positive for both. In multivariate analyses, Pgp+ITD+ (P < 0.0001) and age (P = 0.0022) were independent prognostic factors for the achievement of complete remission (CR). Overall survival (OS), CR achievement (P < 0.0001),WHO performance status (P = 0.0007), and Pgp+ITD+ status (P = 0.0014) were also independent prognostic factors. In 95 patients with intermediate cytogenetics, the CR rates of ITD+ patients were 40% versus 62% for ITDÀ (P = 0.099) and 41% versus 67% (P = 0.014) for Pgp+ versus PgpÀ patients. In the PgpÀITDÀ group (41 of 95), CR rates were 70 % versus 44% for others (P = 0.012), OS achieved 48% versus 16% (P < 0.0001) and disease-free survival was 56% versus 27% (P = 0.024), respectively. Furthermore, the OS curves of the intermediate cytogenetics-PgpÀITDÀ group were not significantly different from the favorable cytogenetic group. Conclusion: Flt3/ITD and Pgp activity are independent and additive prognostic factors which provide a powerful risk classification that can be routinely used to stratify the treatment of patients with intermediate cytogenetic AML. ITD+ and Pgp+ patients should be considered for targeted therapy.

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“…[1][2][3] Mutations of the FLT3 gene have been reported in 25% of adult acute myeloid leukemia (AML), in 3-15% of myelodysplastic syndrome (MDS), and occasionally in chronic myeloid leukemia and lymphoproliferative disorders. [4][5][6][7] Usually, the mutated gene presents an internal tandem duplication (ITD) of the juxtamembrane (JM) domain-coding sequence, which frequently involves exon 14 and more rarely intron 14 or exon 15,5,8 according to the recently description of the FLT3 locus by Abu-Duhier et al 9 Duplicated sequences of the JM domains have variable lengths but can always be read inframe. The role of FLT3-ITDs in leukemogenesis is still unclear.…”

Section: Introductionmentioning

confidence: 99%

Prognostic significance of FLT3 internal tandem repeat in patients with de novo acute myeloid leukemia treated with reinforced courses of chemotherapy

et al. 2002

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FLT3 internal tandem duplications (FLT3-ITDs) are present in nearly 25% of patients with AML and have been associated with poor response to conventional therapy and poor outcome. We retrospectively evaluated the effect of reinforced courses of chemotherapy on the prognostic value of FLT3-ITDs in 159 AML patients prospectively enrolled in the ALFA-9000 trial, which randomly compared three reinforced induction regimens (standard 3+7 including high-dose daunorubicin, double induction, and timed-sequential therapy). FLT3-ITD was present in 40/159 (25%) blast samples and associated with high WBC (P = 0.002) and cytogenetics (P Ͻ 0.001) with a higher incidence (35%) in patients with a normal karyotype. There was no difference in CR rate between FLT3-wt and FLT3-ITD patients (80% vs 78%). Relapse-free survival (RFS) was similar in both groups (5-year RFS, 33% vs 32%; P = 0.41), even after adjustment for age, sex, WBC, cytogenetics, and treatment arm. A trend to a worse survival was observed in the FLT3-ITD group (estimated 5-year OS, 23% vs 37%; P = 0.09), mainly in patients with a normal karyotype. This was associated with a dramatic outcome in relapsing FLT3-ITD patients (estimated 3-year postrelapse survival, 0% vs 27%; P = 0.04). These results suggest that the bad prognosis associated with FLT3-ITDs in AML might be partly overcome using reinforced chemotherapy. Early detection of FLT3 mutations might thus be useful to intensify induction as well as post-remission therapy in FLT3-ITD patients.

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Genomic structure of human FLT3: implications for mutational analysis

Cited by 75 publications

References 6 publications

FLT3: ITDoes matter in leukemia

FLT3: ITDoes matter in leukemia

Flt3 Internal Tandem Duplication and P-Glycoprotein Functionality in 171 Patients with Acute Myeloid Leukemia

Prognostic significance of FLT3 internal tandem repeat in patients with de novo acute myeloid leukemia treated with reinforced courses of chemotherapy

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