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==Primary Author(s)*==
==Primary Author(s)*==
Dr Kay Weng Choy PhD, FRACP, Monash Health
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==Synonyms==
==Synonyms==
Fms Related Tyrosine Kinase 3, Fms-like Tyrosine Kinase 3
==Genomic Location==
==Genomic Location==
'''Cytoband:''' Put your text here. EXAMPLE: 17p13.1
'''Cytoband:''' 13q12.2
'''Genomic Coordinates:'''
'''Genomic Coordinates:'''
chr13:28,577,411-28,674,729 (GRCh37/hg19)
chr13:28,003,274-28,100,592 (GRCh38/hg38)
==Cancer Category/Type==
==Cancer Category/Type==
Acute myeloid leukemia (AML)
==Gene Overview==
==Gene Overview==
''FLT3'' is a member of the type III receptor tyrosine kinase family that regulates hematopoiesis [1]. The receptor is activated by binding of the FLT3 ligand to the extracellular domain, which leads to homodimer formation in the plasma membrane and consequently autophosphorylation of tyrosine residues in the receptor; the activated receptor kinase then phosphorylates and activates multiple cytoplasmic effector molecules involved in proliferation and differentiation of hematopoietic cells in the bone marrow [2]. ''FLT3'' contains five functional domains: an immunoglobulin-like extracellular domain, a transmembrane domain, a juxtamembrane domain (JMD), an interrupted tyrosine kinase domain (TKD), and a small C-terminal domain [3].
''FLT3'' mutations occur in about one-third of patients with AML [3]. In-frame duplications of 3 to >400 base pairs, also known as internal tandem duplications (ITDs), are the most common mutations in ''FLT3'' and they occur in up to 30% of adult patients with ''de novo'' AML [3,4,5,6]. About 70% of ''FLT3''-ITDs occur in the JMD and about 30% in the TKD [3]. The JMD inhibits activation of the receptor by steric hindrance, preventing the TKD from assuming an active conformation; presence of an ITD causes loss of this inhibitory effect, resulting in activation of the TKD.
Differences in expression levels [measured using the FLT3-ITD-to-wild-type (WT) allelic ratio] have prognostic implications [3,7,8,9]. It is commonly agreed that a high FLT3-ITD-to-wild-type allelic ratio is a negative prognostic factor (regardless of cytogenetics); the 2017 European Leukemia Net (ELN) guidelines defined 0.5 as the cut-off between low and high allelic ratios [10]. ''FLT3''-ITD remains relevant as a prognostic factor even after intensive chemotherapy and/or stem cell transplant [3]. ''FLT3'' testing was historically viewed as being purely prognostic; however, with the advent of ''FLT3'' inhibitors, it will likely be considered as both prognostic (clinical outcome) and predictive (treatment benefit) [3].
The second most common type of ''FLT3'' mutations in AML are those within the TKD (occurring in up to 14% of adult patients with AML) [3]. The majority are point mutations within the activation loop (e.g., residues D835, I836, Y842) of the TKD2, and within the TKD1 (e.g., residues N676, F691) [3,11]. As a result of amino acid substitutions, changes in the activation loop favor the active kinase confirmation. The prognostic significance of ''FLT3''-TKD mutations is controversial and may depend on additional mutations and cytogenetics [3].
''FLT3''-ITD and ''FLT3''-TKD mutations are common in patients with AML with normal karyotype but they can also be associated with abnormal karyotype, such as t(15;17)/PML-RARA and core binding factor (''CBF'') AML. ''FLT3''-ITD is frequently associated with t(6;9)(p23;q34.1) abnormalities [12]. The prognosis for patients with ''FLT3'' mutations can be affected by the presence or absence of additional mutations. Patients who are ''FLT3''-ITD negative (''FLT3''-ITD-) or ''FLT3''-ITD low and positive for nucleophosmin 1 mutations (NPM1+) have a “favorable” prognosis; patients who are FLT3-ITD- (or FLT3-ITDlow) with NPM1-WT have an intermediate prognosis [10]. On the other hand, patients who are FLT3-ITDhigh with NPM1-WT have a “poor” prognosis and are less likely to achieve complete remission (CR) with induction chemotherapy than patients with other ''FLT3''/''NPM1'' combinations [3,13].
Allogeneic hematopoietic stem cell transplant (alloHSCT) is generally recommended for patients with ''FLT3''-ITD mutations in first complete remission (CR1), provided they are eligible for transplant therapy and have a suitable donor. Among patients with ''FL3''-ITD mutations in ''CR1'', those who undergo alloHSCT have significantly better outcomes (e.g., prolonged survival and decreased risk of relapse) than those who receive chemotherapy alone. Despite this, ''FLT3''-ITD remains a poor prognostic factor (high relapse rate and short relapse-free and overall survival) after alloHSCT and chemotherapy. Patients with ''FLT3''-ITD AML may benefit from the use of ''FLT3'' tyrosine kinase inhibitors as maintenance therapy to prevent relapse following alloHSCT.
Given its prognostic and predictive values, it is argued that ''FLT3'' testing should be performed in all AMLs regardless of cytogenetics [3]. If the ''FLT3''-ITD-to-WT allelic ratio is used for risk stratification, harmonisation of ''FLT3'' testing is essential to ensure that comparable results are achieved [3].
==Common Alteration Types==
==Common Alteration Types==
In-frame duplications of 3 to >400 base pairs, also known as internal tandem duplications (ITDs), are the most common mutations in ''FLT3'' and they occur in up to 30% of adult patients with ''de novo'' AML [3,4,5,6]. About 70% of ''FLT3''-ITDs occur in the JMD and about 30% in the TKD. See Figure in [3].
The second most common type of ''FLT3'' mutations in AML are those within the TKD (occurring in up to 14% of adult patients with AML) [3]. The majority are point mutations within the activation loop (e.g., residues D835, I836, Y842) of the TKD2, and within the TKD1 (e.g., residues N676, F691) [3,11]; activating mutations caused by insertions (e.g., insertion of glycine and serine between residues S840 and N841) and deletions have also been found in TKD [3].
Additional ''FLT3'' point mutations that have been found in patients with AML include mutations within the extracellular domain (e.g. T167, V194, D324, Y364, and V491), transmembrane domain (e.g., I548, V557), JMD (e.g., V579, E598), TKD1 (e.g., A680, M737), and TKD2 (e.g., V816, A814, T784). See Figure in [3].
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==Internal Pages==
==Internal Pages==
Not applicable.
==External Links==
==External Links==
EXAMPLES
EXAMPLES
'''[http://atlasgeneticsoncology.org/Genes/P53ID88.html ''TP53'' by Atlas of Genetics and Cytogenetics in Oncology and Haematology]''' - detailed gene information
'''[http://atlasgeneticsoncology.org/Genes/FLT3ID144.html ''FLT3'' by Atlas of Genetics and Cytogenetics in Oncology and Haematology]''' - detailed gene information
'''[https://pecan.stjude.cloud/proteinpaint/tp53 ''TP53'' by St. Jude ProteinPaint]''' mutational landscape and matched expression data.
'''[https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=FLT3 ''FLT3'' by COSMIC]''' - sequence information, expression, catalogue of mutations
'''[https://pmkb.weill.cornell.edu/search?utf8=%E2%9C%93&search=tp53 ''TP53'' by Precision Medicine Knowledgebase (Weill Cornell)]''' - manually vetted interpretations of variants and CNVs
'''[https://civicdb.org/events/genes/24/summary/variants/519/summary ''FLT3'' by CIViC]''' - general knowledge and evidence-based variant specific information
'''[http://www.cancerindex.org/geneweb/TP53.htm ''TP53'' by Cancer Index]''' - gene, pathway, publication information matched to cancer type
'''[https://pmkb.weill.cornell.edu/search?utf8=%E2%9C%93&search=FLT3 ''FLT3'' by Precision Medicine Knowledgebase (Weill Cornell)]''' - manually vetted interpretations of variants and CNVs
'''[http://oncokb.org/#/gene/TP53 ''TP53'' by OncoKB]''' - mutational landscape, mutation effect, variant classification
'''[http://www.cancer-genetics.org/FLT3.htm ''FLT3'' by Cancer Genetics Web]''' - gene, pathway, publication information matched to cancer type
'''[https://www.mycancergenome.org/content/gene/tp53/ ''TP53'' by My Cancer Genome]''' - brief gene overview
'''[http://oncokb.org/#/gene/FLT3 ''FLT3'' by OncoKB]''' - mutational landscape, mutation effect, variant classification
'''[http://www.uniprot.org/uniprot/P04637 ''TP53'' by UniProt]''' - protein and molecular structure and function
'''[https://www.mycancergenome.org/content/gene/FLT3 ''FLT3'' by My Cancer Genome]''' - brief gene overview
'''[https://pfam.xfam.org/family/p53 ''TP53'' by Pfam]''' - gene and protein structure and function information
'''[https://www.uniprot.org/uniprot/P36888 ''FLT3'' by UniProt]''' - protein and molecular structure and function
'''[http://www.genecards.org/cgi-bin/carddisp.pl?gene=tp53 ''TP53'' by GeneCards]''' - general gene information and summaries
'''[https://pfam.xfam.org/search/keyword?query=FLT3 ''FLT3'' by Pfam]''' - gene and protein structure and function information
'''[https://www.ncbi.nlm.nih.gov/books/NBK1311/ GeneReviews]''' - information on Li Fraumeni Syndrome
'''[https://www.genecards.org/cgi-bin/carddisp.pl?gene=FLT3&keywords=FLT3 ''FLT3'' by GeneCards]''' - general gene information and summaries
==References==
==References==