Fms-Related Tyrosine Kinase 3

Alternative Names

  • FLT3
  • Stem Cell Tyrosine Kinase 1
  • STK1
  • FLK2
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OMIM Number

136351

NCBI Gene ID

2322

Uniprot ID

P36888

Length

97,314 bases

No. of Exons

27

No. of isoforms

2

Protein Name

Receptor-type tyrosine-protein kinase FLT3

Molecular Mass

112903 Da

Amino Acid Count

993

Genomic Location

chr13:28,003,273-28,100,586

Gene Map Locus
13q12.2

Description

This gene encodes a class III receptor tyrosine kinase that regulates hematopoiesis. This receptor is activated by binding of 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 subsequently phosphorylates and activates multiple cytoplasmic effector molecules in pathways involved in apoptosis, proliferation, and differentiation of hematopoietic cells in bone marrow. Mutations that result in the constitutive activation of this receptor result in acute myeloid leukemia and acute lymphoblastic leukemia. [From RefSeq]

Molecular Genetics

Somatic mutations of the FLT3 gene are the most frequent genetic aberrations that have been described in patients with acute myelogenous leukemia (AML).  These mutations lead to constitutive activation of the FLT3 receptor and they fall into two classes.  The most common mutations involve small tandem duplications of amino acids within the juxtamembrane domain of the receptor and result in constitutive tyrosine kinase activity.  The second category of mutations includes point mutations, usually involving the kinase domain (KD) and resulting in a constitutively activated kinase.  These mutations cause constant signaling leading to uncontrolled proliferation of abnormal, immature white blood cells, a hallmark of acute myeloid leukemia.

Epidemiology in the Arab World

View Map
Variant NameCountryGenomic LocationClinvar Clinical SignificanceCTGA Clinical Significance Condition(s)HGVS ExpressionsdbSNPClinvar
NM_004119.2:c.2504A>TLebanonNC_000013.11:g.28018504T>APathogenicPathogenicLeukemia, Acute MyeloidNG_007066.1:g.87065A>T; NM_004119.2:c.2504A>T; NP_004110.2:p.Asp835Val12190964616272

Other Reports

Iraq

Al-Husseinawi (2014) evaluated the frequency of FLT3-ITD mutation in acute lymphoid leukemia (ALL) patients using conventional polymerase chain reaction (PCR) in Iraq.  The study included 25 individuals (16 children with ALL and nine adults with ALL), attending two teaching hospitals in Baghdad.  FLT3-ITD mutation was detected in two patients.  These cases were an 8-year-old girl and a 7-year-old boy, L2 subtype, who had achieved complete hematological remission throughout the study.  All the other ALL cases showed absence of the mutation.

Lebanon

Salem et al. 2017a reported on two patients with AML that deveoped John Cunningham virus reactivation following cyclophosphamide and rituximab treatment after haploidentical stem cell transplantation. Molecular studies were negative for one patient, however were positive for NPM1 and FLT3 genes in the other patient who developed progressive multifocal leukodystrophy. To understand the molecular response of predictive markers to treatment, Salem et al. 2017b studied 12 adult patients with acute myeloid leukemia (AML) who were positive for both NPM1 and FLT3 mutations at the time of diagnosis. Molecular testing on bone marrow samples were carried out: at diagnosis; within regular intervals before and during chemotherapy and allo-SCT (allogeneic stem cell transplantation); and every three months after allo-SCT. All patients were positive for NPM1 frameshift mutations at diagnosis. Ten of them had FLT3 internal tandem duplications, whereas two patients were positive for FLT3 D835V mutation. All patients had tested negative for FLT3 mutation after induction and apart from two patients who had early deaths, the others remained negative. Only two out of 10 patients became negative for NPM1 mutations after induction and eight additional patients tested negative for NPM1 mutations after allo-SCT. Salem et al. noted that patients with a < 4-log reduction in peripheral blood minimal residual disease (PB-MRD) had better disease free survival and overall survival, supporting the prognostic significance of early NPM1 mutation PB-MRD.

Saudi Arabia

Gari et al. (2008) carried out direct DNA sequencing analysis for 129 patients with acute myeloid leukemia (AML) in Saudi Arabia.  Internal tandem duplication (ITD) mutations with lengths varying between 24-60 bp were identified within exons 14 and 15 of the FLT3 gene in 15 AML patients.  The FLT3-ITD mutations were either a part or whole stretch of tyrosine-rich sequence of the FLT3 gene located between codons 589-599.  Also a G>C point mutation of exon 20, resulting in p.Asp835Tyr substitution, was identified in 11 AML patients.  These mutations lead to constitutive activation of the FLT3 receptor.

Elyamany et al. (2014a) analyzed the prevalence of activating ITD and point mutations in the FLT3 gene in a sample of 77 patients with ALL in Saudi Arabia and tried to assess their prognostic significance.  Only two of the 77 patients examined showed FLT3 mutations, giving an overall prevalence of 3%.  One of these was a 14-year old male patient with an ITD mutation, who was diagnosed as acute mixed-lineage leukemia.  The second patient was a 4-year old female who was found to have the D835 mutation.  Cytogenetic studies showed no association with balanced translocations or MLL rearrangement.  Both patients responded well to treatment and achieved complete remission.  Elyamany et al. (2014a) concluded that there was no prognostic significance of FLT3 mutations in ALL patients.  Elyamany et al. (2014b) also did a similar study in 97 Saudi patients with AML, and found 18 cases positive for FLT3 mutations, giving an increased prevalence of 19%.  Of these, 14 had FLT3-ITD mutations, while the remaining had the D835 mutation.  Interestingly, these FLT3 mutations were found more in males (72%) than that in females (28%) in this study.

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