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FLT3 (FMS-like tyrosine kinase 3)

Written1999-05Olivier Rosnet
Centre d'Immunologie INSERM-CNRS de Marseille-Luminy Case 906, 13288 Marseille Cedex 9, France
Updated2005-06Susanne Schnittger
MLL Münchner Leukümielabor GmbH, Max-Lebsche-Platz 31, 81377 München, Germany

(Note : for Links provided by Atlas : click)

Identity

Other aliasCD135
FLK2 (Fetal liver kinase 2)
STK1 (Stem cell kinase 1)
LocusID (NCBI) 2322
Atlas_Id 144
Location 13q12.2  [Link to chromosome band 13q12]
Location_base_pair Starts at and ends at bp from pter
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
ETV6 (12p13.2) / FLT3 (13q12.2)FLT3 (13q12.2) / ETV6 (12p13.2)SPTBN1 (2p16.2) / FLT3 (13q12.2)
ZMYM2 (13q12.11) / FLT3 (13q12.2)

DNA/RNA

Description 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.
Transcription 3.7 kb; 2979 bp open reading frame

Protein

Description 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.
Expression 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.
Localisation Subcellular location: Type I membrane protein. 3D structure: PDB id 1RJB (3D).
Function 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.
Homology Other tyrosine kinases: KIT, PDGFRA, PDGFRB, VEGFR

Mutations

Somatic 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

Note
  
Entity FLT3-length mutation (FLT3-LM)
Disease 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.
Prognosis 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.
Cytogenetics 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.
Oncogenesis 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 FLT3 Tyrosine Kinase Domain Mutation (FLT3-TKD)
Disease 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.
Prognosis No independent impact on prognosis shown yet.
Cytogenetics In contrast to the FLT3-LM they do not seem to be specifically correlated to a certain AML type.
Oncogenesis 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.
  

Bibliography

Expression of the FMS/KIT-like gene FLT3 in human acute leukemias of the myeloid and lymphoid lineages.
Birg F, Courcoul M, Rosnet O, Bardin F, Pébusque MJ, Marchetto S, Tabilio A, Mannoni P, Birnbaum D
Blood. 1992 ; 80 (10) : 2584-2593.
PMID 1384791
 
Ligand for FLT3/FLK2 receptor tyrosine kinase regulates growth of haematopoietic stem cells and is encoded by variant RNAs.
Hannum C, Culpepper J, Campbell D, McClanahan T, Zurawski S, Bazan JF, Kastelein R, Hudak S, Wagner J, Mattson J
Nature. 1994 ; 368 (6472) : 643-648.
PMID 8145851
 
Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia.
Kiyoi H, Naoe T, Nakano Y, Yokota S, Minami S, Miyawaki S, Asou N, Kuriyama K, Jinnai I, Shimazaki C, Akiyama H, Saito K, Oh H, Motoji T, Omoto E, Saito H, Ohno R, Ueda R
Blood. 1999 ; 93 (9) : 3074-3080.
PMID 10216104
 
c-kit ligand and Flt3 ligand: stem/progenitor cell factors with overlapping yet distinct activities.
Lyman SD, Jacobsen SE
Blood. 1998 ; 91 (4) : 1101-1134.
PMID 9454740
 
Flt3 ligand induces tumor regression and antitumor immune responses in vivo.
Lynch DH, Andreasen A, Maraskovsky E, Whitmore J, Miller RE, Schuh JC
Nature medicine. 1997 ; 3 (6) : 625-631.
PMID 9176488
 
Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors.
Mackarehtschian K, Hardin JD, Moore KA, Boast S, Goff SP, Lemischka IR
Immunity. 1995 ; 3 (1) : 147-161.
PMID 7621074
 
A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell-enriched populations.
Matthews W, Jordan CT, Wiegand GW, Pardoll D, Lemischka IR
Cell. 1991 ; 65 (7) : 1143-1152.
PMID 1648448
 
Functional and phenotypic characterization of cord blood and bone marrow subsets expressing FLT3 (CD135) receptor tyrosine kinase.
Rappold I, Ziegler BL, Köhler I, Marchetto S, Rosnet O, Birnbaum D, Simmons PJ, Zannettino AC, Hill B, Neu S, Knapp W, Alitalo R, Alitalo K, Ullrich A, Kanz L, Bühring HJ
Blood. 1997 ; 90 (1) : 111-125.
PMID 9207445
 
Human FLT3/FLK2 receptor tyrosine kinase is expressed at the surface of normal and malignant hematopoietic cells.
Rosnet O, Bühring HJ, Marchetto S, Rappold I, Lavagna C, Sainty D, Arnoulet C, Chabannon C, Kanz L, Hannum C, Birnbaum D
Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1996 ; 10 (2) : 238-248.
PMID 8637232
 
Murine Flt3, a gene encoding a novel tyrosine kinase receptor of the PDGFR/CSF1R family.
Rosnet O, Marchetto S, deLapeyriere O, Birnbaum D
Oncogene. 1991 ; 6 (9) : 1641-1650.
PMID 1656368
 
Human FLT3/FLK2 gene: cDNA cloning and expression in hematopoietic cells.
Rosnet O, Schiff C, Pébusque MJ, Marchetto S, Tonnelle C, Toiron Y, Birg F, Birnbaum D
Blood. 1993 ; 82 (4) : 1110-1119.
PMID 8394751
 
Cellular and molecular characterization of the role of the flk-2/flt-3 receptor tyrosine kinase in hematopoietic stem cells.
Zeigler FC, Bennett BD, Jordan CT, Spencer SD, Baumhueter S, Carroll KJ, Hooley J, Bauer K, Matthews W
Blood. 1994 ; 84 (8) : 2422-2430.
PMID 7919361
 

Citation

This paper should be referenced as such :
Schnittger, S
FLT3 (FMS-like tyrosine kinase 3)
Atlas Genet Cytogenet Oncol Haematol. 2005;9(4):275-277.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/FLT3ID144.html
History of this paper:
Rosnet, O. FLT3 (FMS-like tyrosine kinase 3). Atlas Genet Cytogenet Oncol Haematol. 1999;3(2):73-74.
http://documents.irevues.inist.fr/bitstream/handle/2042/37508/05-1999-FLT3ID144.pdf


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 53 ]
  Pediatric T-Cell Acute Lymphoblastic Leukemia
t(2;13)(p16;q12) SPTBN1/FLT3
t(12;13)(p13;q12) ETV6/FLT3
t(3;13)(q13;q12) GOLGB1/FLT3
t(12;13)(p13;q12) FLT3/ETV6
t(13;13)(q12;q12) FLT3/FLT3
t(13;13)(q12;q12) ZMYM2/FLT3
t(13;14)(q12;q32) TRIP11/FLT3
11q23 rearrangements (KMT2A) in childhood acute lymphoblastic leukemia
11q23 rearrangements (KMT2A) in de novo childhood acute myeloid leukemia
Acute myeloid leukemia with myelodysplasia related changes
Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)
Chronic Myelomonocytic Leukemia (CMML)
dic(3;9)(p14;p13) PAX5/FOXP1
dic(7;9)(p11-12;p12-13) PAX5/LOC392027
dic(9;12)(p13;p12) PAX5/SLCO1B3
dic(9;16)(p13;q11) PAX5/?
dic(9;17)(p13;q11) PAX5/TAOK1
dic(9;18)(p13;q11) PAX5/ZNF521
dic(9;20)(p11-13;q11) PAX5/Various
Early T-cell precursor acute lymphoblastic leukemia
i(17q) solely in myeloid malignancies
i(4p) in myeloid malignancies
M3/M3v acute myeloid leukemia (AML M3/M3v)
::Acute promyelocytic leukemia (APL)
::Acute promyelocytic leukemia (APL) PML/RARA

Mixed phenotype acute leukemia (MPAL)
t(1;9)(p13;p12) PAX5/HIPK1
t(2;2)(p22;p22) LTBP1/BIRC6::del(2)(p22p22) LTBP1/BIRC6
t(2;3)(p16;q26) BCL11A/MECOM
t(2;8)(p15;q24) BCL11A/MYC
t(2;13)(p16;q12) SPTBN1/FLT3
t(3;11)(p11;p15) NUP98/POU1F1
t(3;21)(q26;q22) RUNX1/MECOM
t(4;22)(q12;q11) BCR/PDGFRA
t(6;9)(p22;q34) DEK/NUP214
t(6;9)(p22;q34) DEK/NUP214 in Childhood
t(7;9)(q11;p12) PAX5/POM121
t(8;9)(q24;p13) ?/MYC
t(9;9)(p13;p24) PAX5/JAK2::del(9)(p13p24) PAX5/JAK2::inv(9)(p13p24) PAX5/JAK2
t(9;13)(p12;q21) PAX5/DACH1
t(9;15)(p13;q24) PAX5/PML
t(9;15)(p13;q24) PAX5/GOLGA6A
t(9;17)(p13;p12) PAX5/NCOR1
t(9;22)(p13;q13) PAX5/BRD1
t(12;13)(p13;q12) ETV6/FLT3
t(15;17)(q24;q21) PML/RARA
t(20;21)(q13.2;q22.12) ZFP64/RUNX1
t(3;13)(q13;q12) GOLGB1/FLT3
t(12;13)(p13;q12) FLT3/ETV6
t(13;13)(q12;q12) FLT3/FLT3
t(13;13)(q12;q12) ZMYM2/FLT3
t(13;14)(q12;q32) TRIP11/FLT3
+13 or trisomy 13
t(X;9)(q21;p13) PAX5/DACH2


External links

Nomenclature
Cards
AtlasFLT3ID144.txt
Aliases
Genomic and cartography
Gene and transcription
RefSeq transcript (Entrez)
RefSeq genomic (Entrez)
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)2322
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Protein Interaction databases
Ontologies - Pathways
Clinical trials, drugs, therapy
Miscellaneous
canSAR (ICR) (select the gene name)
Other databasehttp://cancergenome.broadinstitute.org/index.php?tgene=FLT3
Probes
Litterature
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed


© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Thu Oct 18 17:36:42 CEST 2018

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