Alternative titles; symbols
HGNC Approved Gene Symbol: FLT3
Cytogenetic location: 13q12.2 Genomic coordinates (GRCh38): 13:28,003,274-28,100,576 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q12.2 | Leukemia, acute lymphoblastic, somatic | 613065 | 3 | |
| Leukemia, acute myeloid, reduced survival in, somatic | 601626 | 3 | ||
| Leukemia, acute myeloid, somatic | 601626 | 3 |
The growth factor receptor tyrosine kinase family comprises several classes with distinct structural features. Ullrich and Schlessinger (1990) distinguished 4 classes. One class is represented by the ERBB family (164870). A second class includes dimeric receptors such as the insulin receptor as well as several protooncogenes such as MET (164860) and ROS (165020). A third class is characterized by the presence of 5 immunoglobulin-like domains in the extracellular region and by the interruption of the catalytic domain in 2 parts by a specific hydrophilic 'interkinase' sequence of variable length. This class includes the protooncogene FMS, which encodes the CSF1 receptor (164770), and KIT (164920), which corresponds to the 'white spotting' locus in the mouse, as well as 2 PDGF receptor genes (173490, 173410) and FLT1 (165070). A fourth class is represented by the fibroblast growth factor receptors encoded by FLG (FLT2; 136350) and BEK (176943). These receptors have strong sequence similarities to the products of the third class but possess only 3 immunoglobulin-like domains in the extracellular region and a short kinase insert in the intracellular domain. By screening human and mouse testis cDNA libraries with an FMS probe, Rosnet et al. (1991) obtained a partial cDNAs encoding human and mouse FLT3, a novel member of the class 3 receptors. FLT3 belongs to the tyrosine kinase family and has strong sequence similarities with other members of the group.
Lymphohematopoietic stem cells serve as a reservoir for virtually all blood cells but make up only approximately 0.01% of human or murine marrow cells. The ability to isolate and expand this population has clinical applications in bone marrow transplantations for cancer and genetic diseases. Small et al. (1994) cloned a cDNA for FLT3, which they called STK1, from a CD34+ hematopoietic stem cell-enriched library. The cDNA encodes a protein of 993 amino acids with 85% identity to the murine homolog. STK1 is a member of the type III receptor tyrosine kinase family that includes KIT (164920), FMS (164770), and platelet-derived growth factor receptor (173410, 173490). STK1 expression in human blood and marrow was restricted to CD34+ (142230) cells, a population greatly enriched by stem/progenitor cells.
Small et al. (1994) found that antisense oligonucleotides directed against STK1 sequences inhibited hematopoietic colony formation, most strongly in long-term bone marrow cultures. The data suggested that STK1 may function as a growth factor receptor on hematopoietic stem and/or progenitor cells.
Christensen and Weissman (2001) showed that FlK2 is a marker in hematopoietic stem cell differentiation. They showed, furthermore, that the addition of Flk2 to a lineage mix allowed isolation of highly purified hematopoietic stem cells from many mouse strains using 3-color fluorescence-activated cell sorting.
Wolf and Rohrschneider (1999) determined that Fiz1 (609133) binds to the catalytic domain of Flt3 but not to the structurally related receptor tyrosine kinases Kit, Fms, or platelet-derived growth factor receptor. This association is independent of kinase activity.
Mitton et al. (2003) determined that mRNA and protein for both Fiz1 and Flt3 are expressed in retina. Using a purified polyclonal antibody to the extracellular domain, Flt3 immunoreactivity was primarily detected in the photoreceptor inner segments and the plexiform layers of the mouse retina.
In mouse pro-B cells, Holmes et al. (2006) found that repression of Flt3 by Pax5 (167414) was crucial for B-cell lineage commitment.
By in situ hybridization, Rosnet et al. (1991) assigned the FLT3 gene to human chromosome 13q12 and mouse chromosome 5. Thus, in the mouse, Kit and Flt3 are syntenic. Rosnet et al. (1993) demonstrated close physical linkage of the murine equivalents of FLT1 and FLT3 within a 350-kb MluI fragment on mouse chromosome 5. They are also closely linked to the murine equivalents of the PDGFRA (173490) and KIT (164920) genes, being in the same 630-kb DNA segment. Carow et al. (1995) used PCR screening of a human/rodent somatic cell hybrid panel and fluorescence in situ hybridization (FISH) to map FLT3 to 13q12-q13.
Acute Myeloid Leukemia
Abu-Duhier et al. (2000) reviewed data from a number of sources suggesting a pathogenic role for FLT3 in acute myeloid leukemia. Internal tandem duplication mutations causing constitutive activation of the receptor, the latter being phosphorylated independently of the ligand, had been identified and the FLT3 mutations found to be the strongest prognostic factor for overall survival in patients under the age of 60 years. Abu-Duhier et al. (2000) screened genomic DNA from 106 cases of adult de novo acute myeloid leukemia for FLT3 internal tandem duplication mutations within the juxtamembrane domain. Such mutations were detected in 14 cases (13.2%) and occurred in 4 different FAB types. Patients lacking the mutation survived significantly longer from diagnosis (mean, 29.1 months) than those with the internal tandem duplication (mean, 12.8 months).
Kelly et al. (2002) noted that acute promyelocytic leukemia (APL; 612376) cells invariably express aberrant fusion proteins involving the retinoic acid receptor alpha (RARA; 180240). The most common fusion partner is promyelocytic leukemia protein (PML; 102578), which is fused to RARA in the balanced reciprocal chromosomal translocation, t(15;17)(q22;q11). Expression of PML/RARA from the cathepsin G promoter (CTSG; 116830) in transgenic mice causes a nonfatal myeloproliferative syndrome in all mice; about 15% go on to develop APL after a long latent period, suggesting that additional mutations are required for the development of APL. A candidate target gene for a second mutation is FLT3, because it is mutated in approximately 40% of human APL cases. Activating mutations in FLT3, including internal tandem duplication in the juxtamembrane domain, transform hematopoietic cell lines to factor independent growth. FLT3 internal tandem duplications also induce a myeloproliferative disease in a murine bone marrow transplant model, but are not sufficient to cause acute myeloid leukemia (AML; 601626). Kelly et al. (2002) tested the hypothesis that PML/RARA can cooperate with FLT3 internal tandem duplications to induce an APL-like disease in the mouse. Retroviral transduction of FLT3 internal tandem duplications into bone marrow cells obtained from PML/RARA transgenic mice resulted in a slow latency APL-like disease with complete penetrance. This disease resembled the APL-like disease that occurs with long latency in the PML-RARA transgenics, suggesting that activating mutations in FLT3 can functionally substitute for the additional mutations that occur during mouse APL progression. The leukemia is transplantable to secondary recipients and is responsive to ATRA (all-trans-retinoic acid). These observations documented cooperation between PML/RARA and FLT3 internal tandem duplications in development of the murine APL phenotype.
Activation of the FLT3 receptor tyrosine kinase due to length mutations in the juxtamembrane domain is found in 20 to 25% of AML patients (Nakao et al., 1996; Kottaridis et al., 2001; Meshinchi et al., 2001). Length mutation is usually an internal duplication (136351.0001). Point mutations and deletions of codons 835-836 of FLT3, which are located in the activation loop of the protein tyrosine kinase domain, were described in approximately 7% of all AML cases (Yamamoto et al., 2001; Abu-Duhier et al., 2001); see 136351.0003.
Yamamoto et al. (2001) and Abu-Duhier et al. (2001) described mutations in the asp835 (D835) codon located within the activation loop of the FLT3 gene in cases of acute myeloid leukemia. D816 mutations have been described in the activation loop of the KIT oncogene (e.g., 164920.0009, 164920.0018, 164920.0021); this suggests that the activation loop represents a hotspot region for activating mutations in class III receptor tyrosine kinases (RTKs), which consist of FLT3, KIT (164920), FMS (164770), and PDGF receptor (173490), and share structural characteristics. Ligand binding to the extracellular domain of RTKs leads to receptor dimerization, stabilizing a conformation of the catalytic domain with the activation loop in an open conformation. Receptor dimerization and the subsequent phosphorylation of tyrosine residues accompanies RTK activation, followed by induction of multiple intracellular signaling pathways leading to cell proliferation and activation. Amplification, overexpression, or somatic mutation of RTK results in increased receptor signaling, causing tumorigenesis. An internal tandem duplication of the juxtamembrane domain-coding sequence of the FLT3 gene (136351.0001) is found in 20% of patients with acute myeloid leukemia and is strongly associated with leukocytosis and a poor prognosis. On the other hand, mutations of the KIT gene, which have been found in mast cell leukemia and acute myeloid leukemia, are clustered in 2 distinct regions, the juxtamembrane domain and D816, within the activation loop. This observation prompted Yamamoto et al. (2001) to search for mutations of D835 of FLT3; this codon corresponds to D816 of KIT (164920.0018), which is mutant in acute myeloid leukemia. Yamamoto et al. (2001) found missense mutations in 30 of 429 (7.0%) acute myeloid leukemia cases, 1 of 29 (3.4%) myelodysplastic syndrome cases, and 1 of 36 (2.8%) acute lymphocytic leukemia patients. Among the acute myeloid leukemia cases, asp835 to tyr (D835Y; 136351.0007) was found in 22, asp835 to val (D835V; 136351.0003) in 5, and asp835 to his (D835H; 136351.0004), asp835 to asn (D835N; 136351.0005), and asp835 to glu (136351.0006) in 1 case each. The D835 mutations occurred independently of the FLT3 internal tandem duplication. Analysis of 201 patients newly diagnosed with acute myeloid leukemia revealed that, in contrast to the FLT3 internal tandem deletion mutation, D835 mutations were not significantly related to the leukocytosis, but tended to worsen disease-free survival.
Activating mutations of the FLT3 receptor tyrosine kinase are common in AML but are rare in adult acute lymphoblastic leukemia (ALL; 613065). Armstrong et al. (2004) found that 6 of 25 (approximately 25%) hyperdiploid ALL samples had somatic mutations in the FLT3 gene (see 136351.0003; 136351.0007; 136351.0009). Three mutations were novel in-frame deletions within a 7-amino acid region of the receptor juxtamembrane domain. In 3 samples from patients whose disease would relapse, FLT3 mutations were identified. These data suggested that patients with hyperdiploid or relapsed ALL in childhood might be considered candidates for therapy with small-molecule inhibitors of FLT3.
Myeloid sarcoma is an extramedullary tumor that typically occurs in the setting of acute myeloid leukemia or myeloproliferative disorders. Ansari-Lari et al. (2004) analyzed 24 myeloid sarcoma specimens from 20 patients for FLT3 internal tandem duplications (ITDs; 136351.0001) and mutations in the asp835 codon. FLT3 ITD mutations were identified in 3 of 20 cases; no D835 mutations were identified. Two cases showed discordance in FLT3 ITD mutation status. In one case, the leukemia specimen was positive for an FLT3 ITD mutation and the myeloid sarcoma specimen was negative. In the second case, the myeloid sarcoma was positive for an FLT3 ITD mutation at diagnosis, but negative in subsequent relapse samples.
Reindl et al. (2006) characterized a new class of activating point mutations in the FLT3 gene as a cause of acute myeloid leukemia. The mutations clustered in a 16-amino acid stretch of the juxtamembrane domain of FLT3, including V592A, Y591C, and F594L. Expression of the mutations in mouse cells led to IL3-independent growth, hyperresponsiveness to FLT3 ligand, and resistance to apoptotic cell death. The mutant receptors were autophosphorylated and showed a higher constitutive dimerization rate compared to wildtype. Further investigation showed that the mutations resulted in activation of STAT5 (601511) and upregulation of Bclxl (see 600039). The FLT3 inhibitor PKC412 abrogated the factor-independent growth of these mutant cells. Compared with the internal tandem duplication mutations and mutations in the tyrosine kinase domain, the juxtamembrane domain mutations showed a weaker transforming potential. Examination of the crystal structure of FLT3 showed that these mutations reduced the stability of the autoinhibitory juxtamembrane domain.
Activating internal tandem duplication (ITD) mutations in FLT3 (FLT3-ITD) are detected in approximately 20% of acute myeloid leukemia (601626) patients and are associated with a poor prognosis. Abundant laboratory and clinical evidence, including the lack of convincing clinical activity of early FLT3 inhibitors, suggested that FLT3-ITD probably represents a passenger lesion. Smith et al. (2012) reported point mutations at 3 residues within the kinase domain of FLT3-ITD that confer substantial in vitro resistance to AC220 (quizartinib), an active investigational inhibitor of FLT3, KIT (164920), PDGFRA (173490), PDGFRB (173410), and RET (164761); evolution of AC220-resistant substitutions at 2 of these amino acids was observed in 8 of 8 FLT3-ITD-positive AML patients with acquired resistance to AC220. Smith et al. (2012) concluded that FLT3-ITD can represent a driver lesion and valid therapeutic target in human AML.
The Cancer Genome Atlas Research Network (2013) analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA methylation analysis. The Cancer Genome Atlas Research Network (2013) identified recurrent mutations in the FLT3 gene in 56/200 (28%) samples.
Brewin et al. (2013) noted that the study of the Cancer Genome Atlas Research Network (2013) did not reveal which mutations occurred in the founding clone, as would be expected for an initiator of disease, and which occurred in minor clones, which subsequently drive disease. Miller et al. (2013) responded that FLT3 was among several genes in their study whose mutations were often found in subclones, suggesting that they are often cooperating mutations. The authors also identified other genes that contained mutations they considered probable initiators.
Associations Pending Confirmation
In a genomewide association study of 30,234 cases of autoimmune thyroid disease (see 608173) and 725,172 controls from Iceland and the UK Biobank, Saevarsdottir et al. (2020) identified a low-frequency (1.36%) intronic variant in FLT3, rs76428106C, that had the largest effect on risk of autoimmune thyroid disease (odds ratio (OR) = 1.46, p = 2.37 x 10(-24)). This variant, located deep in intron 15 of FLT3, generates a cryptic splice site, the use of which results in intron retention and protein truncation at amino acid 650. The truncation fully removes one of the intracellular kinase domains and 80% of the other, which is predicted to result in a kinase-dead receptor. The mutation was therefore predicted to have a loss-of-function effect. Saevarsdottir et al. (2020) found that rs76428106C increases the total mRNA expression of FLT3 by 13.2%, whereas the number of normally spliced transcripts is 21.9% less in carriers than in wildtype individuals. Therefore, Saevarsdottir et al. (2020) estimated that in the blood of heterozygous carriers, the abnormally spliced FLT3 transcripts represent around 30% of the FLT3 transcripts. Each copy of rs76428106C doubled the plasma levels of the FTL3 ligand FLT3LG (600007). Saevarsdottir et al. (2020) concluded that a predicted loss-of-function germline mutation in FLT3 causes a reduction in full-length FLT3, with a compensatory increase in the levels of its ligand and an increased disease risk, similar to that of a gain-of-function mutation. The variant rs76428106C was also associated with systemic lupus erythematosus (152700) (OR = 1.90, p = 6.46 x 10(-4)), rheumatoid factor and/or anti-CCP-positive rheumatoid arthritis (see 180300) (OR = 1.41, p = 4.31 x 10(-4)), and celiac disease (see 212750) (OR = 1.62, p = 1.20 x 10(-4)).
Gale et al. (2008) found that 354 (26%) of 1,425 patients with AML had the FLT3 internal duplication. The median total mutant level for all patients was 35% of total FLT3, but there was wide variation with levels ranging from 1 to 96%. There was a significant correlation between worse overall survival, relapse risk, and increased white blood cell count with increased mutant level, but the size of the duplication and the number of mutations had no significant impact on outcome. Those patients with the FLT3 duplication had a worse risk of relapse than patients without the FLT3 duplication. Among a subset of 1,217 patients, 503 (41%) had a mutation in the NPM1 gene (164040), and 208 (17%) had mutations in both genes. The presence of an NPM1 mutation had a beneficial effect on the remission rate, most likely due to a lower rate of resistant disease, both in patients with and without FLT3 duplications. Gale et al. (2008) identified 3 prognostic groups among AML patients: good in those with only a NPM1 mutation; intermediate in those with either no FLT3 or NPM1 mutations or mutations in both genes; and poor in those with only FLT3 mutations.
Using mice deficient in Il7r (146661) and/or the common cytokine receptor gamma chain, Il2rg (308380), Vosshenrich et al. (2003) determined the cytokines responsible for fetal and perinatal lymphopoiesis in the absence of Il7 (146660). Fetal and perinatal B-cell lymphopoiesis occurred in the bone marrow of Il2rg -/- mice until 12 weeks of age, but it was absent in Il7r -/- mice by 4 weeks of age. Lymphopoiesis in Il7r -/- mice was restricted to fetal liver and was dependent on the presence of thymic stromal lymphopoietin (TSLP; 607003). The residual lymphopoiesis that occurred in Il7r -/- mice was dependent on Flk2. Vosshenrich et al. (2003) concluded that TSLP is the main factor driving IL7-independent fetal and perinatal lymphopoiesis, although FLK2 is involved.
The most common activating mutations in the FLT3 gene implicated in acute myeloid leukemia (601626) are internal tandem duplications (ITD) in exons 14 and 15 of the FLT3 gene, ranging in size from 3 to more than hundreds of nucleotides. ITDs most often occur in the cytoplasmic juxtamembrane domain (JMD) and are thought to disrupt autoinhibitory conformation of the FLT3 receptor, thus resulting in constitutive activation of downstream signaling. Some ITDs occur in the tyrosine kinase domain-1 (TKD1) (summary by Kayser et al., 2009).
Abu-Duhier et al. (2000) confirmed the findings of others that an ITD within the FLT3 gene occurs in a significant percentage of adult cases of acute myeloid leukemia and is associated with reduced survival when compared with the individuals who lack the FLT3 duplication.
Yamamoto et al. (2001) found an ITD of the JMD-coding sequence of the FLT3 gene in 46 of 201 patients newly diagnosed with acute myeloid leukemia (excluding the M3 type). Mutations in the duplicated sequence occurred independently of the various mutations in the asp835 codon of the FLT3 gene (see 136351.0003).
Thornton and Levis (2007) stated that ITD mutations of FLT3 are detectable in roughly 25% of patients with newly diagnosed acute myelogenous leukemia. They described an example of associated profound leukostasis throughout multiple organs, including the heart, lungs, adrenal glands, liver, and spleen.
Internal tandem duplications in the FLT3 gene disrupt the autoinhibitory JMD, resulting in constitutive activation of the catalytic domain of FLT3. Among 284 patients with acute leukemias carrying ITD of FLT3, Vempati et al. (2007) found that duplications had a mean length of 17 amino acids (range, 2 to 42). Duplications were localized in amino acids 591 to 599, and arg595 was the most frequently duplicated residue (77% of patients). In vitro mutagenesis studies indicated that arg595 has transforming potential and caused increased phosphorylation and activity of STAT5 (601511). Deletion of this residue resulted in decreased cell growth. Further studies indicated that the positive charge of arg595 has an essential role in transformation.
Among 241 AML patients who were FTL3-ITD-positive, Kayser et al. (2009) found that the majority (69.5%) had an ITD in the JMD between amino acids 572 and 609. The remaining 30.5% had ITDs in the 3-prime direction from the JMD, predominantly in the beta-1-sheet of the tyrosine kinase-1 domain (TKD1). ITD size ranged from 15 to 180 nucleotides. Among both groups, longer duplication size was significantly associated with C-terminal localization, whereas increased number of ITDs was associated with a more N-terminal localization. Duplication of at least 1 residue in the critical region between residues 591 and 599 (Vempati et al., 2007) was found in 96.1% of ITDs. The most commonly affected residue was Y597 (78.4%), followed by R595 (75.5%). Combined duplication of Y589 and Y591, which are important for STAT5 (601511) signaling, was found in 42.2% of cases. A number of samples had concurrent mutations in other leukemia genes, particularly NPM1 (164040). Statistical analysis of patient outcome showed that ITDs in the beta-1-sheet of TKD1 were significantly associated with an inferior rate of complete remission after treatment (odds ratio of 0.22, p = 0.01), as well as survival.
In bone marrow samples from 2 of 359 patients with newly diagnosed and untreated acute myeloid leukemia (601626), Spiekermann et al. (2002) found an identical 6-bp insertion in the activation loop of the FLT3 gene between codons 840 and 841. This resulted in the insertion of glycine and serine after residue 840. Screening for other activating mutations of the FLT3, KIT (164920), and NRAS (164790) genes showed no further genetic alterations in these 2 patients. In functional analyses, Spiekermann et al. (2002) showed that this mutant is hyperphosphorylated on tyrosine and confers interleukin-3 (147740)-independent growth to Ba/F3 cells, which could be inhibited by a specific FLT3 protein tyrosine kinase inhibitor.
In tumor cells from 5 patients with acute myeloid leukemia (601626), Yamamoto et al. (2001) found an A-to-T transversion in the FLT3 gene that resulted in an asp835-to-val (D835V) mutation.
In blast cells from a case of childhood hyperdiploid acute lymphoblastic leukemia (613065), Armstrong et al. (2004) identified a somatic D835V mutation. Complete clinical remission was achieved.
Abu-Duhier et al. (2001) found that 7 of 97 cases of adult de novo acute myeloid leukemia (601626) had mutations affecting the asp835 codon of the FLT3 gene, 1 of which was asp835 to his (D835H).
Yamamoto et al. (2001) found this mutation in tumor cells from a patient with acute myeloid leukemia.
Yamamoto et al. (2001) found an asp835-to-asn (D835N) mutation in the FLT3 gene in tumor cells from a patient with acute myeloid leukemia (601626).
Yamamoto et al. (2001) found an asp835-to-glu (D835E) mutation in the FLT3 gene in compound heterozygosity with the asp835-to-tyr (D835Y; 136351.0007) mutation in tumor cells from a patient with acute myeloid leukemia (601626).
In tumor cells derived from 22 patients with acute myeloid leukemia (601626), Yamamoto et al. (2001) found a G-to-T transition in the FLT3 gene that resulted in an asp835-to-tyr (D835Y) mutation. This mutation was found in compound heterozygosity with the asp835-to-glu (D835E; 136351.0006) mutation in 1 patient.
Abu-Duhier et al. (2001) found that 7 of 97 cases of adult de novo acute myeloid leukemia had mutations affecting the asp835 codon of the FLT3 gene, 5 of which were D835Y.
In a case of childhood hyperdiploid acute lymphoblastic leukemia (613065), Armstrong et al. (2004) identified a somatic D835Y mutation. Complete clinical remission was achieved.
In 1 of 97 cases of adult de novo acute myeloid leukemia (601626), Abu-Duhier et al. (2001) found deletion of codon asp835 (D835del).
In blast cells derived from 6 of 25 patients with childhood hyperdiploid acute lymphoblastic leukemia (613065), Armstrong et al. (2004) identified somatic mutations in the FLT3 gene; 1 of the patients had a 3-bp deletion at nucleotides 1777-1779, resulting in deletion of an aspartic acid at codon 593 (D593del). The deletion was found in leukemic blast cells at diagnosis and at relapse, but was not found in bone marrow cells taken during remission. Thus, the deletion was not an uncommon polymorphism but was acquired in the leukemic blast cells.
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