Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: FLI1
Cytogenetic location: 11q24.3 Genomic coordinates (GRCh38): 11:128,685,351-128,813,267 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q24.3 | Bleeding disorder, platelet-type, 21 | 617443 | Autosomal dominant; Autosomal recessive | 3 |
The FLI1 protooncogene encodes a member of the ETS family of winged helix-turn-helix transcription factors that bind a purine-rich consensus sequence GGA(A/T). The FLI1 gene plays an essential role in embryogenesis, vascular development, and megakaryopoiesis (summary by Hart et al., 2000).
Using PCR with partially degenerate primers corresponding to ETS (see ETS1; 164720) domains, Hromas et al. (1993) cloned human FLI1 from an erythroleukemia cDNA library. The deduced 451-amino acid protein contains a conserved ETS DNA-binding domain and shares 96% homology with mouse Fli1. Northern blot analysis showed high expression of a 2.7-kb transcript only in hematopoietic cell lines.
Fli1, previously called Sic1, is a small DNA region identified in the mouse genome as a viral integration site common to 2 retroviruses involved in virus-induced leukemias and lymphomas. The mouse Fli1 region is near the centromere of chromosome 9 (Bergeron et al., 1991), which shares homology of synteny with a portion of the long arm of human chromosome 11. Using an evolutionarily conserved mouse probe and Southern hybridization to rodent/human somatic cell hybrid DNAs, Baud et al. (1991) mapped the human FLI1 gene to chromosome 11q23-q24. It lies on a fragment flanked on the centromeric side by the translocation breakpoint in acute lymphoblastic leukemia-associated t(4;11)(q21;q23) and on the telomeric side by the Ewing sarcoma (ES; 612219)-associated t(11;22)(q24;q12) breakpoint.
By in situ hybridization, Hromas et al. (1993) mapped the FLI1 gene to chromosome 11q24, a region of aberrations in Ewing sarcoma and neuroepithelioma.
Selleri et al. (1994) cloned in 2 YAC contigs (separated by 200 to 400 kb) approximately 3.2 Mb (or 70%) of the DNA within human chromosomal band 11q24. One of the contigs encompassed Ewing sarcoma breakpoint region-2 (EWSR2). Selleri et al. (1994) linked ETS1 and FLI1, 2 members of the ETS family of transcription factors, within 400 kb of intervening DNA on the same contig. They further demonstrated that the 2 genes are most likely transcribed in the same orientation, in a tail-to-head configuration.
Donaldson et al. (2005) developed computational tools for the identification of gene regulatory sequences functionally related to the stem cell enhancer, SCL (TAL1; 187040). Two candidate enhancers discovered in this way were located in intron 1 of the FLI1 and HHEX (604420) genes, both transcription factors previously implicated in controlling blood and endothelial development. Transgenic and biochemical analyses demonstrated that the 2 enhancers were functionally related to the SCL stem cell enhancer.
Pimanda et al. (2007) identified Gata2 (137295), Tal1, and Fli1 and their enhancers as components of a gene regulatory network that operates during specification of mouse hematopoietic stem cells in the aorta-gonad-mesonephrose region and in fetal liver at midgestation.
Using binding studies and reporter gene assays, Oram et al. (2010) found that ERG (165080) and FLI1 bound and activated the intermediate promoter of the LMO2 gene (180385) in T-cell acute lymphoblastic leukemia (T-ALL) samples. LMO2 also bound enhancers in the FLI1 and ERG loci, and all 3 proteins bound an enhancer element in the first intron of the hematopoietically expressed HHEX gene and upregulated expression of an HHEX reporter gene. Oram et al. (2010) proposed that a self-sustaining triad of LMO2, ERG, and FLI1 are involved in T-ALL by stabilizing HHEX expression.
FLI1/EWS Fusion Protein
Because ETS transcription factors, such as FLI1, regulate expression of TGF-beta type II receptor (TGFBR2; 190182), a putative tumor suppressor gene, Hahm et al. (1999) hypothesized that TGFBR2 may be a target of the EWSR1 (133450)/FLI1 fusion protein. They showed that Ewing sarcoma cells with the EWSR1-FLI1 fusion had reduced TGF-beta sensitivity, and that fusion-positive ES cells and primary tumors both expressed low or undetectable levels of TGFBR2 mRNA and protein product. Cotransfection of FLI1 and the TGFBR2 promoter induced promoter activity, whereas EWSR1-FLI1 led to suppression of TGFBR2 promoter activity and FLI1-induced promoter activity. Introduction of EWSR1-FLI1 into cells lacking the EWSR1-FLI1 fusion suppressed TGFBR2 expression, whereas antisense to EWSR1-FLI1 in ES cells positive for this gene fusion restored TGFBR2 expression. Furthermore, introduction of normal TGFBR2 into ES cell lines restored sensitivity to TGF-beta and blocked tumorigenesis. Hahm et al. (1999) concluded that TGFBR2 is a direct target of EWSR1/FLI1.
By electrophoretic mobility shift assays, Nakatani et al. (2003) found that EWS-FLI1 interacted with the ETS consensus sequence within the promoter region of the p21(WAF1) gene (CDKN1A; 116899). Reporter gene assays indicated that the binding of EWS-FLI1 to at least 2 ETS-binding sites negatively regulated p21(WAF1) promoter activity. EWS-FLI1 also suppressed p21(WAF1) induction by interacting with p300 (602700) and inhibiting its histone acetyltransferase activity.
FLI1/EWS Fusion Gene
Hromas et al. (1993) found that the FLI1 transcript had an aberrant structure in a neuroepithelioma cell line with a t(11;22)(q24;q12) translocation, indicating that FLI1 may be rearranged in neuroepithelioma.
Delattre et al. (1992) demonstrated that the translocation t(11;22)(q24;q12) substitutes a putative RNA-binding domain of the Ewing sarcoma gene on chromosome 22 (EWS; 133450) for the DNA-binding domain of the FLI1 gene on chromosome 11. The breakpoints on chromosome 22 were clustered within a 7-kb region, whereas the breakpoints on chromosome 11 were scattered over a 40-kb region, termed EWSR2. May et al. (1993) clarified the situation further by confirming that the 11;22 translocation of Ewing sarcoma produces a chimeric transcription factor that requires the DNA-binding domain encoded by FLI1 for transformation.
Lin et al. (1999) stated that the translocation resulting in formation of the EWS/FLI1 fusion gene is present in up to 95% of cases of Ewing sarcoma. Alternative forms of the chimeric gene exist because of variations in the locations of the EWS and FLI1 genomic breakpoints. The most common form, designated type 1, consists of the first 7 exons of EWS joined to exons 6 to 9 of FLI1 and accounts for approximately 60% of cases. The type-2 EWS/FLI1 fusion includes FLI1 exon 5 also and is present in another 25%. Lin et al. (1999) observed that the type-1 fusion is associated with a significantly better prognosis than the other fusion types. They found that the type-1 EWS/FLI1 fusion encodes a less active chimeric transcription factor, thus providing a molecular explanation of clinical heterogeneity in Ewing sarcoma.
FLI1 Deletion in Paris-Trousseau Thrombocytopenia and Jacobsen Syndrome
Hart et al. (2000) found that all 14 patients with Jacobsen syndrome (JBS; 147791), in which thrombocytopenia is a feature, had hemizygous terminal deletions of 11q including the FLI1 gene. Based on mouse studies (see ANIMAL MODEL), the authors suggested that hemizygous loss of FLI1 was responsible for the dysmegakaryopoiesis in these patients.
Favier et al. (2003) reported 10 unrelated children with deletions of 11q23 and Paris-Trousseau thrombocytopenia (TCPT; 188025), 9 of whom were heterozygous for a deletion of the FLI1 gene. They noted clinical, hematologic, and cytogenetic similarities between this cohort of patients and patients with Jacobsen syndrome and stated that their findings demonstrated a clear overlap between the 2 syndromes.
Raslova et al. (2004) demonstrated that lentivirus-mediated overexpression of FLI1 in CD34 (142230)-positive cells of patients with Paris-Trousseau thrombocytopenia restored megakaryopoiesis in vitro, indicating that FLI1 hemizygous deletion contributes to the hematopoietic defects in TCPT. FISH analysis on pre-mRNA and single-cell RT-PCR revealed FLI1 expression to be mainly monoallelic in CD41-positive (see 607759)/CD42-negative progenitors, whereas it was predominantly biallelic in the other stages of megakaryopoiesis. In TCPT cells, the hemizygous deletion of FLI1 generated a subpopulation of CD41-positive/CD42-negative cells completely lacking FLI1 transcription. Raslova et al. (2004) proposed that the absence of FLI1 expression in those CD41-positive/CD42-negative cells might prevent their differentiation, resulting in the segregation of the TCPT megakaryocytes into 2 subpopulations: one normal and the other composed of small immature megakaryocytes undergoing massive lysis, presumably originating from FLI1-positive and FLI1-negative CD41-positive/CD42-negative cells, respectively.
In affected members of 3 unrelated families with platelet-type bleeding disorder-21 (BDPLT21; 617443), Stockley et al. (2013) identified heterozygous mutations in the FLI1 gene (193067.0001-193067.0003). The mutations, which were found by next-generation sequencing analysis of candidate genes in 13 families with an inherited platelet disorder, were confirmed by Sanger sequencing. There were 2 missense mutations and 1 frameshift mutation. In vitro functional expression assays showed that the missense FLI1 variants were unable to bind to a transcription site in the promoter for GP6 (605546), one of the genes that is regulated by FLI1. Coexpression of the variants with wildtype FLI1 resulted in a significant reduction in transcriptional activity to 60% of wildtype alone.
In 3 members of 2 unrelated families with BDPLT21, Saultier et al. (2017) identified heterozygous missense mutations in the FLI1 gene (193067.0004-193067.0005). In vitro functional expression studies using a luciferase reporter showed that both mutations resulted in reduced transcriptional activity compared to wildtype. The mutant proteins were unable to inhibit luciferase activity as well as the wildtype protein; however, cotransfection of mutant FLI1 and wildtype FLI1 led to normal transcriptional activity. Western blot analysis and immunofluorescence staining showed that both mutant proteins were located primarily in the cytoplasm rather than the nucleus, suggesting altered subcellular localization. Cultured patient-derived megakaryocytes were smaller and formed very few proplatelets compared to controls; patient megakaryocytes also had a lower percentage of mature markers compared to controls, indicating a defect in differentiation.
In 2 sibs, born of consanguineous parents, with autosomal recessive BDPLT21, Stevenson et al. (2015) identified a homozygous missense mutation in the FLI1 gene (R324W; 193067.0006). The mutation was found by Sanger sequencing and segregated with the disorder in the family. Western blot analysis and in vitro luciferase assays in HEK293 cells showed that the mutation caused a significant decrease in transcriptional activity compared to wildtype as well as decreased levels of platelet GP6, GP9 (173515), and GPIIb (ITGA2B, 607759)/GPIIIa (ITGB3, 173470), indicating a transcriptional defect affecting the promoter of known target genes. MYH10 was detected in the platelets of the probands. Stevenson et al. (2015) noted the unusual recessive inheritance pattern in this family, and stated that neither parent had observable platelet defects or abnormal expression of MYH10, suggesting that the R324W mutant retains residual activity and is not a null allele. Other FLI1 mutations that cause disease in the heterozygous state are likely more damaging to protein function.
Spyropoulos et al. (2000) described aberrant hematopoiesis and hemorrhaging in mouse embryos homozygous for a targeted disruption of the Fli1 gene. Mutant embryos were found to hemorrhage from the dorsal aorta to the lumen of the neural tube and ventricles of the brain on embryonic day 11 (E11) and to die by E12.5. Histologic examinations and in situ hybridization showed disorganization of columnar epithelium and the presence of hematomas within the neuroepithelium and disruption of the basement membrane lying between this and mesenchymal tissues, both of which expressed Fli1 at the time of hemorrhaging.
Hart et al. (2000) found that homozygous Fli1-null mice embryos died during early to mid-gestation between E9.5 and 11.5 with obvious intracranial hemorrhaging in the midbrain/forebrain boundary and in the hindbrain. During embryogenesis, Fli1 was expressed at day E8 in endothelial cells comprising the vascular plexus of the extraembryonic visceral yolk sac and individual cells within the blood islands. By embryonic day 9.5-10, high levels of Fli1 expression were evident throughout the developing vasculature and endocardium. The intersomitic blood vessels, aorta, and cerebral blood vessels also showed high levels of Fli1 expression, as did endothelial cells of the midbrain and forebrain meninges. In mutant mice, bleeding appeared to result from disruption of the vascular plexus, possibly due to attenuation of cell-to-cell adhesion between the endothelial cells that comprise the meninges. Studies of chimeric mice showed that Fli1-null cells were unable to contribute to the vascular endothelium of major cerebral blood vessels or to fetal liver beginning around day E12.5, suggesting a cell-autonomous effect. Fli1-null embryos were able to form the initial stages of primary angiogenesis, but later stages were interrupted. Finally, megakaryocytes from Fli1-null embryos showed abnormalities, including reduced numbers of alpha-granules, disorganization of membranes, and reduced size, characteristic of poor differentiation. This was associated with reduced expression of endothelial- and megakaryocyte-restricted genes, such as TEK (600221), which is the receptor for angiopoietin-1 (ANGPT1; 601667), and GP9 (173515).
In 3 members of a 2-generation family with platelet-type bleeding disorder-21 (BDPLT21; 617443), Stockley et al. (2013) identified a heterozygous c.1009C-T transition (c.1009C-T, NM_002017.3) in the FLI1 gene, resulting in an arg337-to-trp (R337W) substitution in the highly conserved DNA-binding domain. The mutation, which was found by next-generation sequencing analysis of candidate genes, was confirmed by Sanger sequencing.
In a father and son with platelet-type bleeding disorder-21 (BDPLT21; 617443), Stockley et al. (2013) identified a heterozygous c.1028A-G transition (c.1028A-G, NM_002017.3) in the FLI1 gene, resulting in a tyr343-to-cys (Y343C) substitution in the highly conserved DNA-binding domain. The mutation, which was found by next-generation sequencing analysis of candidate genes, was confirmed by Sanger sequencing.
In 2 members of a family with platelet-type bleeding disorder-21 (BDPLT21; 617443), Stockley et al. (2013) identified a heterozygous 4-bp deletion (c.992_995del, NM_002017.3) in the FLI1 gene, resulting in a frameshift and premature termination (Asn331ThrfsTer4) in the DNA-binding domain. The mutation, which was found by next-generation sequencing analysis of candidate genes, was confirmed by Sanger sequencing. The mutation was predicted to result in haploinsufficiency.
In a father and son with platelet-type bleeding disorder-21 (BDPLT21; 617443), Saultier et al. (2017) identified a heterozygous c.1010G-A transition (c.1010G-A, NM_002017.3) in the FLI1 gene, resulting in an arg337-to-gln (R337Q) substitution in the highly conserved DNA-binding domain. The mutation was also predicted to occur within the nuclear localization signal sequence, and Western blot analysis and immunofluorescence staining showed that the mutant protein was located primarily in the cytoplasm rather than the nucleus, consistent with altered subcellular localization. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The variant was filtered against the ExAC, 1000 Genomes Project, and Exome Sequencing Project databases.
In a 52-year-old woman with platelet-type bleeding disorder-21 (BDPLT21; 617443), Saultier et al. (2017) identified a heterozygous c.1033A-G transition (c.1033A-G, NM_002017.3) in the FLI1 gene, resulting in a lys345-to-glu (K345E) substitution in the highly conserved DNA-binding domain. The mutation was also predicted to occur within the nuclear localization signal sequence, and Western blot analysis and immunofluorescence staining showed that the mutant protein was located primarily in the cytoplasm rather than the nucleus, consistent with altered subcellular localization. The mutation was found by next-generation sequencing of a panel of genes and confirmed by Sanger sequencing. The variant was filtered against the ExAC, 1000 Genomes Project, and Exome Sequencing Project databases.
In 2 sibs, born of consanguineous parents, with autosomal recessive platelet-type bleeding disorder-21 (BDPLT21; 617443), Stevenson et al. (2015) identified a homozygous c.970C-T transition in exon 9 of the FLI1 gene, resulting in an arg324-to-trp (R324W) substitution at a conserved residue in the DNA-binding loop, but this residue was not predicted to interact directly with DNA. The mutation was found by Sanger sequencing and segregated with the disorder in the family. Western blot analysis and in vitro luciferase assays in HEK293 cells showed that the mutation caused a significant decrease in transcriptional activity compared to wildtype as well as decreased levels of platelet glycoproteins VI (GP6; 605546), GP9 (173515), and GPIIb (ITGA2B, 607759)/GPIIIa (ITGB3, 173470), indicating a transcriptional defect affecting the promoter of known target genes. Neither parent had observable platelet defects, suggesting that the R324W mutant retains residual activity and is not a null allele.
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