Identification of novel <i>FLT‐3</i> Asp835 mutations in adult acute myeloid leukaemia

Abu-Duhier, FM; Goodeve, Anne; Ga, Wilson; Rs, Care; Ir, Peake; Jt, Reilly

doi:10.1046/j.1365-2141.2001.02850.x

Cited by 340 publications

(318 citation statements)

References 37 publications

Supporting

Mentioning

298

Contrasting

Unclassified

Order By: Relevance

“…Some studies have shown that FLT3-D835 is associated with shorter disease-free and overall survival. 7,14,17,18 Other studies did not identify differences in these parameters. 8,14 Conflicting data may be due to small patient numbers, different treatment regimens, and patient selection.…”

mentioning

confidence: 91%

Clinical impact of change of FLT3 mutation status in acute myeloid leukemia patients

et al. 2012

View full text Add to dashboard Cite

FMS-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in acute myeloid leukemia and is associated with worse clinical outcome. Changes in FLT3 mutation status can occur during the course of disease, but the clinical impact of a change is unclear. We retrospectively reviewed 3555 acute myeloid leukemia patients, who have been assessed for FLT3 mutation at our institution between May 2002 and January 2011. We found that 42 (6.2%) out of 680 patients with FLT3 mutation experienced a change of FLT3 mutation status. In all, 36 patients with wild-type FLT3 at the time of initial diagnosis gained mutation (Negative/Positive) and six initially FLT3-mutated patients became wild type during their following relapses (Positive/Negative). The 5-year survival of these patients was similar to that of patients with persistently wild-type FLT3 (Negative/ Negative; P ¼ 0.464), and significantly better than patients who had stable FLT3 mutation during their disease course (Positive/Positive; Po0.001). However, after mutations became detectable in the Negative/Positive group, the forward survival of these patients tracked that of the Positive/Positive group after relapse (P ¼ 0.761). In addition, we did not find a significant difference in survival between patients with internal tandem duplications and those with point mutations in the tyrosine kinase domain of the FLT3 gene. These results suggest that FLT3 mutations are unstable and that there is potential clinical value in continuously monitoring FLT3 mutation status.

show abstract

mentioning

confidence: 91%

Clinical impact of change of FLT3 mutation status in acute myeloid leukemia patients

et al. 2012

View full text Add to dashboard Cite

show abstract

“…These alterations are missense mutations that alter the wild-type aspartic acid residue at position 835 (D835) within the activation loop of the FLT3 protein. 7,12 Alteration of D835 also appears to result in constitutive activation of the FLT3 receptor and portends a worse disease-free survival in at least some studies. 7 D835 mutations have been reported to occur in ϳ7% of patients with AML, 3% of patients with myelodysplastic syndrome (MDS), and 3% of patients with acute lymphocytic leukemia.…”

Section: Flt3 Is a Receptor Tyrosine Kinase That Is Expressed On Earlmentioning

confidence: 99%

Detection of FLT3 Internal Tandem Duplication and D835 Mutations by a Multiplex Polymerase Chain Reaction and Capillary Electrophoresis Assay

Murphy¹,

Levis²,

Hafez³

et al. 2003

The Journal of Molecular Diagnostics

188

141

View full text Add to dashboard Cite

FLT3 is a receptor tyrosine kinase that is expressed on early hematopoietic progenitor cells and plays an important role in stem cell survival and differentiation. Two different types of functionally important FLT3 mutations have been identified. Internal tandem duplication mutations arise from duplications of the juxtamembrane portion of the gene and result in constitutive activation of the FLT3 protein. This alteration has been identified in ϳ20% to 30% of patients with acute myelogenous leukemia and appears to be associated with a worse prognosis. The second type of FLT3 mutation, missense mutations at aspartic acid residue 835, occurs in ϳ7.0% of acute myelogenous leukemia cases. These mutations also appear to be activating and to portend a worse prognosis. Identification of FLT3 mutations is important because it provides prognostic information and may play a pivotal role in determining appropriate treatment options. We have developed an assay to identify both internal tandem duplication and D835 FLT3 mutations in a single multiplex polymerase chain reaction. After amplification, the polymerase chain reaction products are analyzed by capillary electrophoresis for length mutations and resistance to EcoRV digestion. Here we describe the performance characteristics of the assay, FMS-like tyrosine kinase 3 (FLT3 also known as STK1 and flk2) is a member of the class III receptor tyrosine kinase family that also includes PDGF-R, KIT, and FMS. 1 The FLT3 protein is normally expressed on hematopoietic stem progenitor cells and appears to play an important role in stem cell survival, and the development of dendritic and natural killer cells. 2,3 FLT3 is overexpressed in most cases of acute myeloid leukemia (AML). 4,5 In addition, analysis of leukemic blasts from AML patients has identified two specific somatic mutations of the FLT3 gene. 6,7 Identification of these mutations in AML patients provides independent prognostic information that may also prove important for treatment optimization.The first and best-studied FLT3 mutation is an internal tandem duplication (ITD) mutation. ITD mutations typically result from the duplication and tandem insertion of a portion of the juxtamembrane (JM) region (exons 11 to 12) of the FLT3 wild-type gene. 6 The lengths of the duplicated segments have been reported to range in size from 6 to 180 bases and are always in frame. 8,9 ITD mutations result in the constitutive autophosphorylation of the FLT3 receptor and are thus gain-of-function mutations of the FLT3 proto-oncogene. 10 FLT3 ITD mutations have been reported to occur in 20 to 30% of patients with AML and have been associated with an increased relapse risk, decreased disease-free survival, decreased event-free survival, and decreased overall survival. 8,9,11 In a multivariate analysis of FLT3 ITD mutations, cytogenetic risk group, presentation white blood cell count, percentage BM blasts at diagnosis, age, gender, and FAB type in 854 AML patients, the presence of a FLT3 ITD mutation was the most significant factor adversely a...

show abstract

“…Internal tandem duplication (ITD) mutations of the FLT3 juxtamembrane (JM) occur in approximately 24% of patients with AML and in 15% of patients with secondary AML 1,2 and are associated with shortened disease-free survival. 3 Mutations in the activation loop (AL), typically D835Y, occur in approximately 7% of patients with AML and 3% of patients with myelodysplastic syndromes (MDS) 4,5 and in patients with T-cell ALL (T-ALL). 6 An increased frequency of FLT3 mutations has also been associated with mutations involving the mixed-lineage leukemia (MLL) gene.…”

mentioning

confidence: 99%

Identifying and characterizing a novel activating mutation of the FLT3 tyrosine kinase in AML

Jiang

Páez

Lee

et al. 2004

Blood

View full text Add to dashboard Cite

The FLT3 receptor is activated by juxtamembrane insertion mutations and by activation loop point mutations in patients with acute myeloid leukemia (AML). In a systematic tyrosine kinase gene exon resequencing study, 21 of 24 FLT3 exons were sequenced in samples from 53 patients with AML, 9 patients with acute lymphoblastic leukemia (ALL), and 3 patients with myelodysplasia samples. Three patients had novel point mutations at residue N841 that resulted in a change to isoleucine in 2 samples and to tyrosine in 1 sample. Introduction of FLT3-N841I cDNA into Ba/F3 cells led to interleukin-3 (IL-3)-independent proliferation, receptor phosphorylation, and constitutive activation of signal transducer and activator of transcription 5 (STAT5) and extracellular regulatory kinase (ERK), suggesting that the N841I mutation confers constitutive activity to the receptor. An FLT3 inhibitor (PKC412) inhibited the growth of Ba/F3-FLT3N841I cells (IC 50 10 nM), but not of wild-type Ba/F3 cells cultured with IL-3. PKC412 also reduced tyrosine phosphorylation of the mutant receptor and inhibited STAT5 phosphorylation. Examination of the FLT3 autoinhibited structure showed that N841 is the key residue in a hydrogen-bonding network that likely stabilizes the activation loop. These 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 smallmolecule FLT3 inhibitors such as PKC412. IntroductionFLT3, a class 3 receptor tyrosine kinase, is targeted and activated by somatic mutation in acute myeloid leukemia (AML). Internal tandem duplication (ITD) mutations of the FLT3 juxtamembrane (JM) occur in approximately 24% of patients with AML and in 15% of patients with secondary AML 1,2 and are associated with shortened disease-free survival. 3 Mutations in the activation loop (AL), typically D835Y, occur in approximately 7% of patients with AML and 3% of patients with myelodysplastic syndromes (MDS) 4,5 and in patients with T-cell ALL (T-ALL). 6 An increased frequency of FLT3 mutations has also been associated with mutations involving the mixed-lineage leukemia (MLL) gene. 7 ITD and AL mutations result in constitutive FLT3 kinase activity. When FLT3 receptors harboring such mutations are introduced into mammalian cells, downstream signaling pathways are activated that lead to factor-independent growth in vitro and to leukemogenesis in vivo. 8,9 For example, the production of FLT3-ITD mutant proteins in primary murine bone marrow cells results in a lethal myeloproliferative phenotype. 10 Thus, FLT3 is a leukemia oncogene, and activating FLT3 mutations likely contribute significantly to the development of leukemia in humans.Several small-molecule inhibitors block the kinase activity of FLT3 with high potency 10-13 (eg, PKC412, MLN518, SU11248) and can prolong the lifespans of mice harboring leukemias expressing mutant FLT3 receptors. 10,14 In phase-1 and -2 clinical trials, FLT3 inhibitors have reduced FLT3 phosphorylation 15-17 and leukemia...

show abstract

Identification of novel FLT‐3 Asp835 mutations in adult acute myeloid leukaemia

Cited by 340 publications

References 37 publications

Clinical impact of change of FLT3 mutation status in acute myeloid leukemia patients

Clinical impact of change of FLT3 mutation status in acute myeloid leukemia patients

Detection of FLT3 Internal Tandem Duplication and D835 Mutations by a Multiplex Polymerase Chain Reaction and Capillary Electrophoresis Assay

Identifying and characterizing a novel activating mutation of the FLT3 tyrosine kinase in AML

Contact Info

Product

Resources

About