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.
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. PrognosisFLT3-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.