FLT3

Primary Author(s)*

Kay Weng Choy MBBS, BMedSci, FAACB, Monash Health

Synonyms

Fms Related Tyrosine Kinase 3, Fms-like Tyrosine Kinase 3

Genomic Location

Cytoband: 13q12.2

Genomic Coordinates:

chr13:28,577,411-28,674,729 (GRCh37/hg19)

chr13:28,003,274-28,100,592 (GRCh38/hg38)

Cancer Category/Type

Acute Myeloid Leukemia (AML) and Related Precursor Neoplasms

Acute Myeloid Leukemia (AML) with Mutated FLT3

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.

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].

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) [3,7]; 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].

Copy Number Loss	Copy Number Gain	LOH	Loss-of-Function Mutation	Gain-of-Function Mutation	Translocation/Fusion
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Internal Pages

Acute Myeloid Leukemia (AML) with Mutated FLT3

External Links

FLT3 by Atlas of Genetics and Cytogenetics in Oncology and Haematology - detailed gene information

FLT3 by COSMIC - sequence information, expression, catalogue of mutations

FLT3 by CIViC - general knowledge and evidence-based variant specific information

FLT3 by Precision Medicine Knowledgebase (Weill Cornell) - manually vetted interpretations of variants and CNVs

FLT3 by Cancer Genetics Web - gene, pathway, publication information matched to cancer type

FLT3 by OncoKB - mutational landscape, mutation effect, variant classification

FLT3 by My Cancer Genome - brief gene overview

FLT3 by UniProt - protein and molecular structure and function

FLT3 by Pfam - gene and protein structure and function information

FLT3 by GeneCards - general gene information and summaries

References

1. Rosnet O, et al., (1996). Human FLT3/FLK2 receptor tyrosine kinase is expressed at the surface of normal and malignant hematopoietic cells. Leukemia 10(2):238-248. PMID 8637232.

2. Liu, S, et al., (2014). MUC1-C oncoprotein promotes FLT3 receptor activation in acute myeloid leukemia cells. Blood 123(5):734-742. PMID 24282218.

3. Patnaik MM, (2017). The importance of FLT3 mutational analysis in acute myeloid leukemia. Leuk Lymphoma 22:1-14. PMID 29164965.

4. Kayser S, et al., (2009). Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome. Blood 114(12):2386-2392. PMID 19602710.

5. Papaemmanuil E, et al, (2016). Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med 374:2209-2221. PMID 27276561.

6. Patel JP, et al., (2012). Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 366(12):1079-1089. PMID 22417203.

7. Smith CC, et al., (2012). Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature 485:260-263. PMID 22504184.

Notes

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