jeudi 22 mars 2012

Mutated genes in cancer (61) – FLT3


In databases:

● Entrez ( 2322 or FLT3
● Ensembl ( ENSG00000122025
● UniProt ( P36888
● GeneCards ( FLT3
● HGNC ( 3765 or FLT3
● Enzyme Number (IUBMB): EC 2.7.10 ; EC

Gene locus:


Protein name :

Fms-related tyrosine kinase 3

Protein Size :

993 amino acids; about 113 kDa

Function :

The protein encoded by the gene, FLT3, is a protein tyrosine kinase receptor for the FL cytokine. 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 phosphorylation 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.

Cancer-related alterations:

Somatic mutations in the FLT3 gene are the most frequent genetic aberration that have been described in acute myeloid leukemia (AML). Mutations have also been observed in bile duct tumors. These somatic mutations are highly frequent in two regions corresponding to amino acids 550-650 and 831-842. In this latter region, corresponding to the second tyrosine kinase kinase domain of FLT3, alterations are mostly point mutations related to codon 835 or deletions related to codon 836. These mutations lead to constitutive autoactivation of the receptor.

FLT3-length mutations (FLT3-LM), in which internal tandem duplications and/or insertions and, rarely, deletions in the FLT3-gene occur, are implicated in 20-25% of all acute myeloid leukemias (AML). They were 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) In FLT3-LM, mutations lead to constitutive ligand independent autophosphorylation of the receptor. The duplicated sequence belongs to exon 11 but sometimes involves intron 11 and exon 12. Prognosis            FLT3-LM are highly correlated with a) normal karyotype, b) t(15;17)(q25;q21) translocation.

References (open access):

Downstream molecular pathways of FLT3 in the pathogenesis of acute myeloid leukemia: biology and therapeutic implications. Takahashi S. J Hematol Oncol. 2011 Apr 1;4:13.

Will newer tyrosine kinase inhibitors have an impact in AML? Levis MJ. Best Pract Res Clin Haematol. 2010 Dec;23(4):489-94.

Bench to bedside targeting of FLT3 in acute leukemia. Pratz KW, Levis MJ. Curr Drug Targets. 2010 Jul;11(7):781-9.

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