FLT3 (FMS-like tyrosine kinase 3)

2005-06-01   Susanne Schnittger 

MLL Münchner Leukümielabor GmbH, Max-Lebsche-Platz 31, 81377 München, Germany





the FLT3 gene contains 24 exons and spans 96,982 bases (start:27,475,753 bp to end 27,572,735 from 13pter) oriented at the minus strand.


3.7 kb; 2979 bp open reading frame



Size: 993 amino acids; 112804 Da;
FLT3 is a class III receptor tyrosine kinase (RTK) structurally related to the receptors for platelet derived growth factor (PDGF), colony stimulating factor 1 (CSF1), and KIT ligand (KL).; these RTK contain five immunoglobulin-like domains in the extracellular region and an intracelular tyrosine kinase domain splitted in two by a specific hydrophilic insertion (kinase insert); immunoprecipitation of the human FLT3 protein results in the appearance of a minor band of Mr 130 000 and a major band of Mr 155 000/160 000; the high-molecular-weight band corresponds to the mature, N-glycosylated form, and the low-molecular-weight band to the immature, high mannose-containing form; N-linked glycosylations account for 50 000 daltons.


FLT3 expression was described on bone marrow CD34-positive cells, corresponding to multipotential, myeloid and B-lymphoid progenitor cells, and on monocytic cells; FLT3 expression is restricted to cells of the fetal liver expressing high levels of CD34; in addition, the FLT3 protein is expressed on blast cells from most AML and B-ALL.


Subcellular location: Type I membrane protein. 3D structure: PDB id 1RJB (3D).


FLT3 receptor function can be defined by the activity of its ligand (FL); FL is an early acting factor and supports the survival, proliferation and differentiation of primitive hemopoietic progenitor cells. Ligand binding to FLT3 promotes receptor dimerization and subsequent signalling through posphorylation of multiple cytoplasmatic proteins, including SHC, SHP-2, SHIP, Cbl, Cbl-b, Gab1 and Gab2, as well as the activation of several downstream signalling pathways, such as the Ras/Raf/MAPK and PI3 kinase cascades.
Function: Receptor for the FL cytokine. Has a tyrosine-protein kinase activity. Catalytic activity: ATP + a protein tyrosine = ADP + protein tyrosine phosphate.
Similarity: Belongs to the Tyr protein kinase family. CSF-1/PDGF receptor subfamily. Contains 1 immunoglobulin-like C2-type domain.


Other tyrosine kinases: KIT, PDGFRA, PDGFRB, VEGFR



Mutations in the FLT3 gene are the most frequent genetic aberration that have been described in acute myeloid leukemia. With 20-25% length mutations in the juxtamembrane domain are the most frequent, followed by 7-8% mutations in the second tyrosine kinase kinase domain, mostly point mutations in codon 835 or deletions of codon 836. Also point mutations in the juxta membrane domain have been described and the number of new mutations all over the total gene is still growing.

Implicated in

Entity name
FLT3-length mutation (FLT3-LM)
Internal tandem duplications and/or insertions and, rarely, deletions in the FLT3-gene are implicated in 20-25% of all acute myeloid leukemias (AML). It was also described to be involved in 5-10 % myelodysplastic syndromes (MDS) refractory anaemia with excess of blasts (RAEB 1 and RAEB 2) and rare cases with acute lymphoblastic leukemia (ALL) The duplicated sequence belongs to exon 11 but sometimes involves intron 11 and exon 12. The most frequently used nomenclature is FLT3-ITD (internal tandem duplication). Because of the very heterogenous molecular structure the term FLT3-LM (length mutation) seems to be more adequate.
An unfavourable impact on prognosis especially a high relapse rate of the FLT3-LM has been shown by many study groups. Patients with loss of the wildtype allele have an even worse prognosis than the mutated with retention of the wildtype allele. Perspective : It is of special interest that this mutation allows to perform PCR-based minimal residual disease detection in a high number of these high risk AML patients.
FLT3-LM are highly correlated with a) normal karyotype, b) t(15;17)(q25;q21) c) t(6;9)(p23;q34)
Perspective: It is of special interest that this mutation allows to perform PCR-based minimal residual disease detection in a high number of these high risk AML patients.
This mutation leads to constitutive ligand independent autophosphorylation of the receptor. The FLT3-LM vary in size and position in a nearly patient specific manner. Overall the aberrant structure of the juxtamembrane domain disrupts a negative regulatory domain, which leads to the constitutive receptor activation. Several Groups have reported qualitative differences in the intracellular signals provided by wild type and mutated receptors.Mutated receptor weakly works through MAP kinase and Akt but instead through strong and constitutively activated STAT5.
Entity name
FLT3 Tyrosine Kinase Domain Mutation (FLT3-TKD)
In the second tyrosine kinase domain point mutations and small deletions mostly of codons 835 and 836, respectively, can be found in 7-8% of all AML.
No independent impact on prognosis shown yet.
In contrast to the FLT3-LM they do not seem to be specifically correlated to a certain AML type.
These mutations also lead to constitutive autoactivation of the receptor. It has been suggested that TKD mutation may both trigger the activation loop and stabilize it in the active state.


Pubmed IDLast YearTitleAuthors
13847911992Expression of the FMS/KIT-like gene FLT3 in human acute leukemias of the myeloid and lymphoid lineages.Birg F et al
81458511994Ligand for FLT3/FLK2 receptor tyrosine kinase regulates growth of haematopoietic stem cells and is encoded by variant RNAs.Hannum C et al
102161041999Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia.Kiyoi H et al
94547401998c-kit ligand and Flt3 ligand: stem/progenitor cell factors with overlapping yet distinct activities.Lyman SD et al
91764881997Flt3 ligand induces tumor regression and antitumor immune responses in vivo.Lynch DH et al
76210741995Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors.Mackarehtschian K et al
16484481991A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell-enriched populations.Matthews W et al
92074451997Functional and phenotypic characterization of cord blood and bone marrow subsets expressing FLT3 (CD135) receptor tyrosine kinase.Rappold I et al
86372321996Human FLT3/FLK2 receptor tyrosine kinase is expressed at the surface of normal and malignant hematopoietic cells.Rosnet O et al
16563681991Murine Flt3, a gene encoding a novel tyrosine kinase receptor of the PDGFR/CSF1R family.Rosnet O et al
83947511993Human FLT3/FLK2 gene: cDNA cloning and expression in hematopoietic cells.Rosnet O et al
79193611994Cellular and molecular characterization of the role of the flk-2/flt-3 receptor tyrosine kinase in hematopoietic stem cells.Zeigler FC et al

Other Information

Locus ID:

NCBI: 2322
MIM: 136351
HGNC: 3765
Ensembl: ENSG00000122025


dbSNP: 2322
ClinVar: 2322
TCGA: ENSG00000122025


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Cytokine-cytokine receptor interactionKEGGko04060
Hematopoietic cell lineageKEGGko04640
Acute myeloid leukemiaKEGGko05221
Cytokine-cytokine receptor interactionKEGGhsa04060
Hematopoietic cell lineageKEGGhsa04640
Pathways in cancerKEGGhsa05200
Acute myeloid leukemiaKEGGhsa05221
Transcriptional misregulation in cancerKEGGko05202
Transcriptional misregulation in cancerKEGGhsa05202
Central carbon metabolism in cancerKEGGhsa05230
Central carbon metabolism in cancerKEGGko05230
Immune SystemREACTOMER-HSA-168256
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147


Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA162372840sunitinibChemicalClinicalAnnotation, MultilinkAnnotationassociatedPD19248971, 19667267, 20683446, 24013576, 26244574
PA443624Carcinoma, Renal CellDiseaseClinicalAnnotationassociatedPD19667267, 20683446, 24013576, 26244574
PA444773LeukopeniaDiseaseClinicalAnnotationassociatedPD19667267, 20683446, 24013576, 26244574


Pubmed IDYearTitleCitations
210673772010DNMT3A mutations in acute myeloid leukemia.596
184506022008Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia.422
112906082001Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies.244
120700092002Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease.178
179570272008The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia.163
179570272008The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia.163
160768672005Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype.143
202122542010Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia.127
147593632004The structural basis for autoinhibition of FLT3 by the juxtamembrane domain.113
181925052008Internal tandem duplication of FLT3 (FLT3/ITD) induces increased ROS production, DNA damage, and misrepair: implications for poor prognosis in AML.102


Susanne Schnittger

FLT3 (FMS-like tyrosine kinase 3)

Atlas Genet Cytogenet Oncol Haematol. 2005-06-01

Online version: http://atlasgeneticsoncology.org/gene/144/flt3

Historical Card

1999-05-01 FLT3 (FMS-like tyrosine kinase 3) by  Olivier Rosnet 

Centre dImmunologie INSERM-CNRS de Marseille-Luminy Case 906, 13288 Marseille Cedex 9, France