Affinage

FLI1

Friend leukemia integration 1 transcription factor · UniProt Q01543

Length
452 aa
Mass
51.0 kDa
Annotated
2026-06-09
100 papers in source corpus 46 papers cited in narrative 46 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 10/10 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FLI1 is an ETS-family sequence-specific transcription factor that orchestrates hematopoietic, megakaryocytic, vascular, and immune gene-regulatory programs through a C-terminal ETS DNA-binding domain that recognizes GGAA-core elements (PMID:7517940, PMID:10981960, PMID:17962413). Its DNA-binding domain can form a helix-swapped homodimer (disrupted by the F362A mutation), enabling regulation at promoters bearing multiple FLI1 sites (PMID:26618620). FLI1 acts in a context-dependent manner—as an activator or repressor—through both autonomous activation domains and combinatorial protein partnerships: it interacts with RUNX1 in a phosphorylation-controlled (Ser10) switch to synergistically drive megakaryocytic genes such as c-mpl (PMID:19470763), with EKLF and GATA-1 to balance erythroid versus megakaryocytic fate (PMID:12556498), and with Sp1 to repress collagen COL1A2 production in fibroblasts (PMID:11278621). It participates in a recursively wired triad with GATA2 and SCL/TAL1 during hematopoietic stem cell specification and autoregulates its own locus, including through a Fli-1–miR-145 repressive loop (PMID:17962413, PMID:11991951, PMID:22829238). FLI1 directly binds and transactivates survival and lineage genes including BCL-2 (PMID:11847117), and is required in vivo for vascular integrity via Tek/Tie-2, with its loss causing embryonic vascular failure and dysmegakaryopoiesis (PMID:10981960). It broadly governs inflammatory and immune gene expression—directly occupying CCL5, G-CSF, GM-CSF, caspase-1, IL33/IL6, and IDO1 regulatory regions—where its output is tuned by phosphorylation and acetylation (PMID:25098295, PMID:27431361, PMID:33268481, PMID:30739075, PMID:29415756, PMID:38816360). In CD8+ T cells FLI1 restrains effector differentiation by occupying ETS:RUNX cis-elements that otherwise license Runx3-driven effector programs (PMID:33636129). FLI1 protein stability is set by SPOP-mediated ubiquitination, enhanced by CK1 phosphorylation of a VTSSS degron and opposed by the deubiquitinase OTUD7A (PMID:34060252). The oncogenic EWS-FLI1 fusion repurposes these activities, creating de novo enhancers at non-conserved GGAA microsatellites while displacing wild-type ETS factors at conserved enhancers (PMID:25453903), with competition from ETV6 and ETS1 shaping its genomic occupancy (PMID:36658219). FLI1 missense variants cause autosomal macrothrombocytopenia with platelet granule and secretion defects (PMID:28255014).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1992 Medium

    Establishing that FLI1 encodes an ETS-family protein with a conserved DNA-binding domain framed it as a candidate sequence-specific transcription factor and placed it within a defined ETS subset.

    Evidence cDNA cloning and structural domain mapping of the 452-residue human protein

    PMID:1394211

    Open questions at the time
    • No direct demonstration of DNA-binding specificity or target genes at this stage
    • Functional role of the 5'-ETS homology region undefined
  2. 1994 High

    Defining the ETS domain as necessary and sufficient for binding a specific GGAA-core consensus established the molecular grammar of FLI1 target-site recognition.

    Evidence Binding-site selection and truncation analysis with in vitro DNA binding assays

    PMID:7517940

    Open questions at the time
    • In vitro consensus does not establish in vivo occupancy
    • Does not address cofactor-dependent target selection
  3. 1995 Medium

    Mapping two autonomous activation domains and showing the EWS fusion potentiates the C-terminal domain distinguished wild-type transcriptional output from the stronger oncogenic fusion.

    Evidence Deletion analysis and transcriptional activation assays in cell lines

    PMID:7503813

    Open questions at the time
    • Cofactors mediating activation not identified
    • Native target genes not yet defined
  4. 2000 High

    The Fli-1 knockout showed FLI1 is required in vivo for vascular integrity (via Tek/Tie-2) and normal megakaryopoiesis, anchoring its physiological role beyond in vitro transcription.

    Evidence Targeted null mouse with histology and gene expression analysis

    PMID:10981960

    Open questions at the time
    • Embryonic lethality limits analysis of later/tissue-specific roles
    • Direct versus indirect regulation of Tek not resolved at the chromatin level
  5. 2003 High

    Reciprocal interactions with EKLF and GATA-1 revealed FLI1 as a bifunctional regulator that balances erythroid versus megakaryocytic fate through both intrinsic repression and partner recruitment.

    Evidence Co-IP, Gal4 domain mapping, and promoter reporter assays across cell types

    PMID:12556498

    Open questions at the time
    • Quantitative contribution of direct repression versus tethering not separated in vivo
    • Switch controlling activator versus repressor mode not defined
  6. 2002 High

    Identifying BCL-2 as a directly bound, functionally required FLI1 target linked FLI1 transcriptional activity to survival of transformed erythroblasts.

    Evidence ChIP, in vitro binding, mutant rescue, and BCL-2 inhibitor studies

    PMID:11847117

    Open questions at the time
    • Generalizability of the survival program to normal cells unclear
    • Cofactors at the BCL-2 promoter not defined
  7. 2007 High

    Demonstrating a fully connected GATA2–FLI1–SCL enhancer triad established FLI1 as a node in a recursive regulatory network specifying hematopoietic stem cells.

    Evidence ChIP, enhancer reporter assays, and transgenic analysis

    PMID:17962413

    Open questions at the time
    • Dynamics of triad assembly over differentiation not resolved
    • Quantitative weight of each input on Fli1+12 enhancer undefined
  8. 2009 High

    Showing that Ser10 dephosphorylation gates FLI1–RUNX1 interaction during megakaryocyte differentiation revealed a phospho-switch coupling signaling to combinatorial transcription.

    Evidence Complex purification, reciprocal co-IP, gel filtration, and phosphomimetic mutagenesis in primary megakaryocytes

    PMID:19470763

    Open questions at the time
    • Kinase/phosphatase acting on Ser10 not identified
    • Whether the switch operates at other FLI1 targets unknown
  9. 2015 High

    Crystal structures of the apo and DNA-bound FLI1 DBD revealed a helix-swapped homodimer, providing a structural basis for cooperative regulation at multi-site promoters.

    Evidence X-ray crystallography with F362A dimer-disrupting mutagenesis

    PMID:26618620

    Open questions at the time
    • In vivo significance of DBD dimerization not directly tested at native loci
    • Which target promoters require dimerization unresolved
  10. 2016 Medium

    Mapping direct FLI1 occupancy of inflammatory cytokine/chemokine promoters (CCL5, G-CSF, GM-CSF) showed FLI1 is a dose-dependent transcriptional driver whose output is tuned by acetylation and phosphorylation.

    Evidence ChIP, reporter assays, and site-directed mutagenesis of DNA-binding and modification sites

    PMID:25098295 PMID:27431361 PMID:33268481

    Open questions at the time
    • Enzymes responsible for the modifications not all identified
    • Cell-type specificity of these promoter programs not fully mapped
  11. 2017 Medium

    Conditional knockouts and human variant/iPSC studies extended FLI1 function to thymic AIRE control, fibroblast cytokine restraint, megakaryocyte maturation, and human macrothrombocytopenia.

    Evidence Tissue-specific Cre knockouts, ChIP, patient/isogenic iPSC megakaryocytes, and variant transcriptional assays

    PMID:28232470 PMID:28255014 PMID:28432223 PMID:29415756

    Open questions at the time
    • Mechanistic link between haploinsufficiency dosage and distinct phenotypes incompletely resolved
    • Direct targets driving autoimmunity/fibrosis not fully enumerated
  12. 2020 High

    Genome-wide chromatin and in vivo CRISPR studies in CD8+ T cells defined FLI1 as a brake on effector differentiation by occupying ETS:RUNX cis-elements competing with Runx3.

    Evidence In vivo CRISPR screen, conditional deletion, ATAC-seq/ChIP-seq, and infection/tumor models

    PMID:33636129 PMID:36074578

    Open questions at the time
    • Mechanism by which FLI1 occupancy reduces accessibility not fully resolved
    • Lineage-specific cofactors distinguishing CD4 versus CD8 effects undefined
  13. 2021 High

    Identifying SPOP/CK1/OTUD7A control of the VTSSS degron established the post-translational machinery setting FLI1 (and EWS-FLI1) protein abundance.

    Evidence Ubiquitination assays, phospho-degron mapping, reciprocal co-IP, and xenograft validation

    PMID:34060252

    Open questions at the time
    • Signals controlling CK1 activity on the degron not defined
    • Whether degron control is differentiation-stage-regulated unknown
  14. 2023 Medium

    Linking FLI1 to IDO1/TIE1 transcriptional programs connected FLI1 to immune evasion and therapy resistance in carcinoma, broadening its role into the tumor immune microenvironment.

    Evidence ChIP, chromatin accessibility, RNA-seq, and T-cell co-culture functional assays

    PMID:36814284 PMID:38816360

    Open questions at the time
    • Causal hierarchy between FLI1, CBP/STAT1, and IDO1 not fully dissected
    • Generalizability beyond nasopharyngeal carcinoma untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How FLI1's mode-switching between activation and repression is selected at individual loci—integrating partner identity, post-translational modification, DBD dimerization, and chromatin state—remains incompletely defined.
  • No unified model linking phospho/acetyl state to activator-versus-repressor output genome-wide
  • Stoichiometry of cofactor competition (ETS1, ETV6, EKLF) at native loci unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0003677 DNA binding 4
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1266738 Developmental Biology 3 R-HSA-168256 Immune System 3
Partners
CBPEKLFERGGATA1GATA2RUNX1SCLSP1

Evidence

Reading pass · 46 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 Human FLI1 encodes a 452-residue protein with two ETS homology domains: a 3'-ETS domain responsible for sequence-specific DNA binding (shared by all ETS family members) and a 5'-ETS homology region conserved only in FLI1, c-ets-1, ets-2, GABP-alpha, and ERG, suggesting a shared biological function among this subset. cDNA cloning, nucleotide sequence analysis, structural domain mapping Cancer research Medium 1394211
1993 FLI-1 functions as a sequence-specific transcriptional activator with two autonomous transcriptional activation domains (one N-terminal, one C-terminal). In the EWS-FLI1 fusion, the EWS domain acts as a modulatory/regulatory domain that activates the C-terminal transcriptional activation domain of FLI1, making EWS-FLI1 a transcriptional activator stronger than wild-type FLI1. Deletion analysis, transcriptional activation assays in cell lines Cancer research Medium 7503813
1994 The ETS domain of FLI1 is necessary and sufficient for sequence-specific DNA binding, with a consensus binding sequence of ACCGGAAG/aT/c, showing greater specificity 5' of the GGAA core than other ETS proteins. EWS-FLI1 displays the same DNA binding specificity and affinity as wild-type FLI1. Epitope-tagging and SELEX-like binding site selection, truncation analysis, in vitro DNA binding assays The Journal of biological chemistry High 7517940
1996 Unlike wild-type FLI1, EWS-FLI1 can form a ternary complex on the c-fos serum response element (SRE) and binds DNA at this site without requiring SRF. Both FLI1 and EWS-FLI1 interact directly with SRF in vitro in the absence of DNA. Deletion of the N-terminal region of FLI1 (normally an inhibitory domain) converts it to behave like EWS-FLI1 with respect to SRE binding. EMSA, GST pull-down assay, deletion analysis Nucleic acids research Medium 8604338
1999 FLI-1 overexpression in primary erythroblasts inhibits Epo-induced terminal differentiation, inhibits apoptosis following Epo withdrawal, and induces proliferation. Enhanced survival correlates with FLI-1-driven upregulation of BCL-2 and prevention of cyclin D2/D3 downregulation during differentiation. Retroviral transduction of primary avian erythroblasts, differentiation/proliferation assays, gene expression analysis Oncogene Medium 10102630
2000 Fli-1 null mice die at embryonic day 11.5 with loss of vascular integrity causing cerebral meningeal bleeding and specific downregulation of Tek/Tie-2 (angiopoietin-1 receptor), demonstrating a required role for Fli-1 in vascular development. Fli-1 null embryos also exhibit dysmegakaryopoiesis resembling Jacobsen/Paris-Trousseau syndrome. Targeted null mutation (knockout mouse), histology, gene expression analysis Immunity High 10981960
2001 FLI-1 inhibits COL1A2 (collagen alpha2(I)) promoter activity and collagen production in dermal fibroblasts through both direct DNA binding at a critical ETS site and indirect mechanisms via protein-protein interaction with Sp1. Fli-1 and Ets-1 compete for the same COL1A2 promoter site with opposing effects (Fli-1 inhibits; Ets-1 stimulates). Stable transfection, in vitro DNA binding (EMSA), promoter deletion/mutation analysis, Gal4 reporter assays, dominant-negative and DNA-binding mutant constructs The Journal of biological chemistry High 11278621
2002 FLI-1 directly binds to specific ETS binding sites in the BCL-2 promoter in transformed erythroblasts and transactivates BCL-2 expression. The ability of FLI-1 mutants to transactivate BCL-2 correlates with their ability to inhibit apoptosis. BCL-2 is an in vivo target gene of FLI-1 required for survival of FLI-1-transformed erythroblasts. ChIP, in vitro binding assays, FLI-1 deletion/point mutants, promoter reporter assays, BCL-2 inhibitor studies The EMBO journal High 11847117
2002 Ets-1 directly activates transcription from the fli-1 gene promoter by binding to ETS binding sites including a third site unique to Ets-1 (not used by Spi-1). Endogenous Fli-1 also binds its own promoter and promotes auto-regulatory transcription, establishing a positive feedback loop of Fli-1 expression in endothelial cells. Promoter deletion/mutation analysis, transient transfection reporter assays, ChIP The Journal of biological chemistry Medium 11991951
2003 FLI-1 represses EKLF-dependent transcription (including the beta-globin promoter) by two mechanisms: (1) direct repression activity of the ETS DNA-binding domain (which behaves as an autonomous repression domain when fused to Gal4-DBD), and (2) indirect recruitment to erythroid promoters via protein-protein interaction with EKLF. FLI-1 also interacts with GATA-1, enhancing GATA-1 activity rather than repressing it. Reciprocally, EKLF represses FLI-1-dependent megakaryocytic GPIX promoter activity, suggesting cross-antagonism controls erythroid vs. megakaryocytic fate. Co-immunoprecipitation, Gal4 fusion reporter assays, promoter reporter assays, domain mapping Molecular and cellular biology High 12556498
2003 EWS-FLI1 self-associates and can interact with both germline EWS and wild-type FLI1. Self-association of EWS-FLI1 is mediated by its C-terminal FLI1 DNA-binding motif and is RNA-independent. The EWS N-terminal domain mediates homotypic and heterotypic interactions of EWS and EWS-FLI1. Despite oligomerization capacity, EWS-FLI1 binds a tandem ETS-binding site as a monomer. FRET, mammalian two-hybrid assay, GST pull-down, co-immunoprecipitation, RNase A treatment Oncogene High 14534527
2004 EWS-FLI1 and FLI-1 interact with CBP (CREB-binding protein) through their amino-terminal region and inhibit CBP-dependent transcriptional activity of RXR. This antiapoptotic activity is independent of the DNA-binding activity of EWS-FLI1/FLI-1. Dominant-negative CBP sensitizes Ewing sarcoma cells to apoptosis. Co-immunoprecipitation, transcriptional reporter assays, dominant-negative CBP expression, apoptosis assays Oncogene Medium 15273724
2005 Fli1, Elf1, and Ets1 directly bind to three conserved ETS sites in the LMO2 proximal promoter and activate its transcription in hematopoietic progenitor and endothelial cells. In vivo, the LMO2 proximal promoter is sufficient for endothelial but not hematopoietic expression in transgenic mice. ChIP, transient/stable transfection reporter assays, transgenic mouse analysis Blood Medium 15994290
2006 RNA helicase A (RHA) binds directly to EWS-FLI1 (specifically to RHA amino acids 630-1020 containing the region identified by phage display). Endogenous RHA forms a protein complex with EWS-FLI1 in ESFT cells; both co-occupy EWS-FLI1 target gene promoters by ChIP. RHA stimulates transcriptional activity of EWS-FLI1 regulated promoters including Id2 and enhances anchorage-independent growth of EWS-FLI1-expressing cells. Phage display, GST pull-down, ELISA, co-immunoprecipitation, ChIP, transcriptional reporter assays, anchorage-independent growth assay Cancer research High 16740692
2007 Gata2, Fli1, and Scl/Tal1 form a recursively wired gene-regulatory circuit during hematopoiesis. All three transcription factors bind to each other's enhancers (Gata2-3, Fli1+12, Scl+19) in embryonic hematopoietic tissues, forming a fully connected triad. The Fli1+12 enhancer relies on a combination of Ets, Gata, and E-Box motifs and targets hematopoietic stem cells. ChIP, enhancer reporter assays, transgenic analysis Proceedings of the National Academy of Sciences of the United States of America High 17962413
2009 FLI-1 interacts directly with RUNX-1 in a differentiation-dependent manner during megakaryocyte development, synergistically activating the c-mpl promoter. This interaction is absent in uninduced megakaryoblastic cells and correlates with dephosphorylation of FLI-1 at serine 10. Substitution of Ser10 with phosphomimetic aspartate impairs RUNX-1 binding and abrogates synergy; alanine substitution (blocking phosphorylation) augments primary megakaryocyte differentiation. Protein complex purification, co-immunoprecipitation, gel filtration chromatography, reporter assays, phosphorylation analysis, point mutation studies, primary fetal liver megakaryocyte differentiation assay Molecular and cellular biology High 19470763
2009 Fli-1 directly binds to promoters of ribosome biogenesis genes (containing conserved ETS binding sites) in Friend erythroleukemic cells and contributes to their transcriptional activation. Fli-1 and Spi-1 additively regulate this common set of targets. Fli-1 knockdown contributes to proliferation arrest, apoptosis induction, and differentiation of erythroleukemic cells. Inducible shRNA knockdown, ChIP, transcriptome profiling, clonal analysis Molecular and cellular biology Medium 19289502
2012 FLI-1 inhibitors decrease Fli-1 DNA binding to target genes (SHIP-1, GATA-1) and reveal a positive relationship between loss of Fli-1 DNA binding activity and increased Fli-1 phosphorylation. Fli-1 represses its own expression via a Fli-1-miR-145 autoregulatory loop (Fli-1 normally represses the miR-145 promoter; loss of Fli-1 allows miR-145 upregulation which further suppresses Fli-1). Drug screening, DNA binding assays, ChIP, miRNA expression analysis, promoter reporter assays Blood cancer journal Medium 22829238
2013 The C-terminal transcriptional activation domain (CTA) of Fli-1 negatively regulates mononuclear phagocyte (monocyte, macrophage, dendritic cell) development. Fli-1 protein directly binds the Flt3L gene promoter, suppressing Flt3L expression in multipotent progenitors. Truncated Fli-1 CTA-deletion knock-in mice, bone marrow reconstitution, flow cytometry, ChIP Immunology Medium 23320737
2014 Fli-1 directly binds ETS binding sites in the distal region of the CCL5/RANTES promoter and drives dose-dependent transcriptional activation. Mutation of the Fli-1 DNA binding domain significantly reduces this activation. Ets1 competes with Fli-1 for binding, acting as a dominant-negative for Fli-1-driven CCL5 transcription. ChIP, transient transfection reporter assays, promoter deletion/mutation analysis, siRNA knockdown Journal of immunology Medium 25098295
2014 EWS-FLI1 reprograms gene regulatory circuits by two mechanisms: (1) at GGAA repeat elements lacking evolutionary conservation, EWS-FLI1 multimers induce chromatin opening and create de novo enhancers that physically interact with target promoters; (2) at conserved enhancers containing canonical ETS motifs, EWS-FLI1 displaces wild-type ETS transcription factors to inactivate enhancers. ChIP-seq, ATAC-seq, 3C/chromatin interaction assays, gene expression analysis Cancer cell High 25453903
2015 EWS-FLI1 regulates alternative splicing by interacting with spliceosomal complex partners including DDX5, hnRNP K, and PRPF6. In CLIP-seq, EWS-FLI1 RNA-binding motifs occur most frequently adjacent to intron-exon boundaries. EWS-FLI1 alters splicing of oncogenesis-related genes including CLK1, CASP3, PPFIBP1, and TERT. CLIP-seq, exon array, RNA-seq, co-immunoprecipitation, small molecule inhibitor (YK-4-279) validation Proceedings of the National Academy of Sciences of the United States of America High 25737553
2015 Crystal structures of the FLI1 DNA-binding domain (ETS/DBD) alone and in complex with cognate GGAA-containing DNA reveal a previously unrecognized homodimer, with a helix-swapped dimerization interface dominated by hydrophobic interactions including Phe362. Mutation of Phe362 to alanine disrupts dimerization without perturbing structure or DNA binding function, supporting a role for DBD dimerization in transcriptional regulation at promoters with multiple FLI1 binding sites. X-ray crystallography, solution dimerization assays, site-directed mutagenesis (F362A) Biochemistry High 26618620
2016 Fli-1 directly binds the G-CSF promoter and drives dose-dependent transcriptional activation. Mutation of the Fli-1 DNA binding domain results in 94% loss of transcriptional activation. Mutation of a known acetylation site within Fli-1 leads to increased G-CSF promoter activation; p300/CBP and PCAF acetyltransferases decrease Fli-1-specific activation of the G-CSF promoter, indicating acetylation negatively regulates Fli-1 activity at this promoter. ChIP, transient transfection reporter assays, site-directed mutagenesis, siRNA knockdown European journal of immunology Medium 27431361
2017 Fli1 directly regulates AIRE expression in thymic epithelial cells; keratinocyte/epithelial-specific Fli1 knockout mice develop thymic defects with AIRE downregulation, systemic autoimmunity, and organ fibrosis. Fli1 occupancy of the AIRE promoter was demonstrated by ChIP. Conditional Keratin14-Cre Fli1 knockout mice, ChIP, gene expression analysis, histology The Journal of experimental medicine Medium 28232470
2017 FLI-1 deficiency in human dermal microvascular endothelial cells promotes migration, proliferation, and cell survival while impairing tube formation on Matrigel, demonstrating that FLI-1 normally limits angiogenic sprouting behavior. siRNA knockdown, scratch assay, transwell migration, BrdU proliferation assay, flow cytometry apoptosis assay, Matrigel tube formation assay Experimental dermatology Medium 28370536
2017 FLI1 haploinsufficiency impairs megakaryocyte yield, proplatelet formation, and platelet half-life/function. FLI1 overexpression in iPSC-derived megakaryocytes increases iMeg yield and improves in vivo platelet yield, half-life, and functionality. FLI1 appears to negatively regulate ETS1 expression during megakaryopoiesis. iPSC-derived megakaryocytes (Paris-Trousseau patient and FLI1+/- targeted iPSCs), in vivo platelet infusion and survival studies Blood Medium 28432223
2017 Combined knockdown of ERG and FLI1 in endothelial cells induces endothelial-to-mesenchymal transition (EndMT) accompanied by dynamic epigenomic changes. ERG and FLI1 act as critical transcriptional activators for EC-specific genes; their loss reduces microRNA-126 expression, which partially contributes to EndMT induction. siRNA double knockdown, RNA-seq, ChIP-seq, genome-wide chromatin analysis PLoS genetics Medium 30500808
2017 FLI1 deficiency in Foxd1-derived pericytes prevents CLP-induced pericyte loss, vascular leak, and improves survival in sepsis. FLI-1 transcriptionally regulates inflammatory cytokines and chemokines in pericytes, and CLP-induced pericyte pyroptosis is mitigated by pericyte-specific Fli-1 knockout. Foxd1-Cre conditional Fli-1 knockout mice, CLP sepsis model, siRNA knockdown in cultured pericytes, gene expression analysis The Journal of infectious diseases Medium 30053030
2018 Fli-1 directly occupies the IL33 and IL6 promoters in dermal fibroblasts (demonstrated by ChIP). Fli-1 haploinsufficiency leads to overproduction of IL-33 and IL-6 in fibroblasts, and IL-33 from Fli-1-deficient fibroblasts drives Th2-like Treg transdifferentiation in skin. ChIP, co-culture experiments with neutralizing antibodies, flow cytometry, qRT-PCR in Fli-1+/- mice Arthritis research & therapy Medium 29415756
2018 EWS-FLI1 increases transcription at target loci, causing accumulation of R-loops that block BRCA1 repair. BRCA1 is enriched in interaction with the elongating transcription machinery in Ewing sarcoma cells, impairing homologous recombination. Wild-type EWSR1 normally suppresses R-loops and promotes homologous recombination. R-loop detection, co-immunoprecipitation, DNA damage response assays, replication stress markers, PARP inhibitor sensitivity assays Nature High 29513652
2019 USP19 deubiquitinase stabilizes EWS-FLI1 by binding to the N-terminal EWS region and deubiquitinating it. Depletion of USP19 reduces EWS-FLI1 protein levels and Ewing sarcoma cell growth in vitro and in vivo. Notably, USP19 does not stabilize wild-type FLI1 protein, despite binding to the EWS domain present in both EWS-FLI1 and EWSR1. siRNA screen, co-immunoprecipitation, Western blot of protein levels after modulation, shRNA stable depletion, xenograft mouse model Scientific reports Medium 30700749
2019 Diterpenoid compounds inhibit Fli-1 transcriptional activity by binding to nucleotide residues in a pocket near the major groove of the Fli-1 DNA-binding domain (computational docking). Functional inhibition of Fli-1 triggers a Fli-1-miR145 autoregulatory loop: loss of Fli-1 activity upregulates miR-145 (whose promoter is normally repressed by Fli-1), which further suppresses Fli-1 translation. High-content transcriptional reporter screen, apoptosis/differentiation assays, computational docking, miR-145 expression analysis, leukemia mouse model Cell death & disease Medium 30741932
2019 Fli-1 directly binds caspase-1 promoter regions (demonstrated by ChIP and luciferase reporter assay) and drives caspase-1 and IL-18 expression in lung pericytes. Overexpressed Fli-1 increases caspase-1 and IL-18; Fli-1 siRNA blocks outer membrane vesicle-induced caspase-1, caspase-11, and IL-18 expression. ChIP, luciferase reporter assay, siRNA knockdown, bacterial OMV model of pyroptosis Molecular immunology Medium 30739075
2020 Fli-1 in CD8+ T cells binds to cis-regulatory elements of effector-associated genes to restrain effector T cell (TEFF) lineage differentiation. Loss of Fli-1 increases chromatin accessibility at ETS:RUNX motifs, enabling more efficient Runx3-driven TEFF biology. Genetic deletion of Fli-1 enhances TEFF responses without compromising memory or exhaustion precursor populations. In vivo CRISPR screen, conditional genetic deletion, ATAC-seq, ChIP-seq, viral infection and tumor protection models Cell High 33636129
2020 FLI1 controls expression of CCND1 (cyclin D1) and E2F2, regulating G1/S cell cycle progression. FLI1 depletion causes G1/S arrest and reduced cell proliferation in pancreatic cancer cells. FLI1 preferentially binds the mutant hTERT core promoter and regulates hTERT expression. siRNA knockdown, cell cycle analysis, protein microarray of transcription factor DNA-binding domains, gene expression analysis International journal of cancer Medium 31846072
2020 Fli-1 directly binds the GM-CSF promoter and drives dose-dependent transcriptional activation. Mutation of the Fli-1 DNA binding domain results in significant loss of activation. Mutation of a phosphorylation site within Fli-1 leads to increased GM-CSF promoter activation, indicating that phosphorylation negatively regulates Fli-1 activity at this promoter. Fli-1 acts additively with Sp1 in regulating GM-CSF expression. ChIP, transient transfection reporter assays, site-directed mutagenesis (DNA-binding domain and phosphorylation site), siRNA knockdown Journal of immunology Medium 33268481
2020 Crystal structures of ERG/FLI1 DNA-binding domain in complex with Runx2, core-binding factor beta (Cbfβ), and mithramycin (MTM) on a DNA enhancer site reveal that MTM allosterically inhibits ERG and FLI1 transactions by disrupting the FLI1-DBD/Runx2/DNA complex rather than directly blocking DNA binding. X-ray crystallography (series of crystal structures), DNA binding assays with MTM and analogues Structure High 33275876
2021 SPOP (E3 ubiquitin ligase) and OTUD7A (deubiquitinase) are the bona fide regulators of EWS-FLI1 protein stability. Casein kinase 1-mediated phosphorylation of the VTSSS degron in the FLI1 domain of EWS-FLI1 enhances SPOP-mediated degradation. OTUD7A counteracts SPOP by deubiquitinating and stabilizing EWS-FLI1. Co-immunoprecipitation, ubiquitination assays, phosphorylation mapping, siRNA/shRNA depletion, xenograft mouse model, AI-based virtual drug screen Advanced science High 34060252
2021 EWS-FLI1 incorporates into a protein granule/assembly in cells through its low-complexity (LC) domain. Cross-linking studies show the LC domain is required for the observed protein assemblies. EWS-FLI1 can bind RNA polymerase II and self-assemble through its LC domain, potentially enabling interaction with its wide network of protein partners. siRNA knockdown, RNA-seq, cross-linking-based protein assembly detection, co-immunoprecipitation RNA Medium 34035145
2021 YAP interacts with TEAD1, and this complex inhibits FLI1 expression during endothelial differentiation from pluripotent stem cells. Luciferase assay confirms TEAD1-mediated inhibition of the FLI1 promoter. FLI1 overexpression rescues the inhibition of endothelial differentiation caused by YAP overexpression. Luciferase reporter assay, siRNA/overexpression, microarray analysis, rescue experiments Journal of molecular and cellular cardiology Medium 34666000
2022 Fli-1 promotes the transcription of Th1/Th17 pathways and TCR-inducible transcription factors in CD4+ T cells, while suppressing activation- and function-related gene pathways in CD8+ T cells, as revealed by single-cell RNA-seq analysis of heterozygous and homozygous Fli1-deficient T cells. Genetic Fli-1 deletion (hetero- and homozygous), single-cell RNA-seq, GVHD allogeneic models, xenograft model The Journal of clinical investigation Medium 36074578
2023 ETV6 competes with EWS-FLI1 for binding to DNA elements enriched for short GGAA repeat sequences. Inactivation of ETV6 allows EWS-FLI1 to overtake and hyper-activate these cis-elements, promoting mesenchymal differentiation with SOX11 as a key downstream target. A dominant-interfering peptide that squelches ETV6 phenocopies these effects and suppresses Ewing sarcoma growth in vivo. Domain-focused CRISPR screen, biochemical DNA binding assays, ChIP-seq/epigenomics, dominant-interfering peptide, in vivo xenograft Nature cell biology High 36658219
2023 FLI1 orchestrates IDO1 transcriptional activation in response to IFN-γ by regulating expression of CBP and STAT1, facilitating chromatin accessibility at the IDO1 locus. This leads to kynurenine production, CD8+ T cell exhaustion, and Treg differentiation, enabling immune evasion in nasopharyngeal carcinoma. siRNA knockdown, ChIP assays, chromatin accessibility assays, gene expression analysis, T cell co-culture functional assays Nature communications Medium 38816360
2023 FLI1 directly upregulates TIE1 transcription by binding to the TIE1 promoter (demonstrated by ChIP and dual luciferase reporter assay), thereby activating the PI3K/AKT signaling pathway to promote radiotherapy resistance in nasopharyngeal carcinoma. ChIP, dual luciferase reporter assay, RNA-seq, loss/gain-of-function in vitro and in vivo Journal of translational medicine Medium 36814284
2017 FLI1 variants (c.1010G>A and c.1033A>G) cause macrothrombocytopenia with dense granule deficiency. Carrier platelets show defects in aggregation, ATP secretion, and mepacrine uptake/release. In vitro megakaryocyte studies reveal maturation defect and reduced proplatelet formation. The FLI1 variants show significantly reduced nuclear accumulation and transcriptional activity. High-throughput gene sequencing, electron microscopy, flow cytometry, megakaryocyte differentiation from CD34+ cells, transcriptional activity assays Haematologica Medium 28255014

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Immunohistochemical expression of endothelial markers CD31, CD34, von Willebrand factor, and Fli-1 in normal human tissues. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 668 16234507
2014 EWS-FLI1 utilizes divergent chromatin remodeling mechanisms to directly activate or repress enhancer elements in Ewing sarcoma. Cancer cell 363 25453903
2000 Fli-1 is required for murine vascular and megakaryocytic development and is hemizygously deleted in patients with thrombocytopenia. Immunity 297 10981960
2018 EWS-FLI1 increases transcription to cause R-loops and block BRCA1 repair in Ewing sarcoma. Nature 261 29513652
2001 Expression of Fli-1, a nuclear transcription factor, distinguishes vascular neoplasms from potential mimics. The American journal of surgical pathology 185 11474291
2007 Gata2, Fli1, and Scl form a recursively wired gene-regulatory circuit during early hematopoietic development. Proceedings of the National Academy of Sciences of the United States of America 184 17962413
2021 In vivo CD8+ T cell CRISPR screening reveals control by Fli1 in infection and cancer. Cell 171 33636129
1993 EWS/Fli-1 chimeric protein is a transcriptional activator. Cancer research 159 7503813
2001 Fli-1 inhibits collagen type I production in dermal fibroblasts via an Sp1-dependent pathway. The Journal of biological chemistry 144 11278621
2010 Oncogenic partnerships: EWS-FLI1 protein interactions initiate key pathways of Ewing's sarcoma. Clinical cancer research : an official journal of the American Association for Cancer Research 123 20547696
2015 Oncogenic fusion protein EWS-FLI1 is a network hub that regulates alternative splicing. Proceedings of the National Academy of Sciences of the United States of America 121 25737553
2001 Loss of p16 pathways stabilizes EWS/FLI1 expression and complements EWS/FLI1 mediated transformation. Oncogene 115 11709708
2003 Functional cross-antagonism between transcription factors FLI-1 and EKLF. Molecular and cellular biology 114 12556498
2014 The ets transcription factor Fli-1 in development, cancer and disease. Oncogene 113 24909161
2006 Oncoprotein EWS-FLI1 activity is enhanced by RNA helicase A. Cancer research 113 16740692
1994 The FLI-1 and chimeric EWS-FLI-1 oncoproteins display similar DNA binding specificities. The Journal of biological chemistry 111 7517940
2000 The role of Fli-1 in normal cell function and malignant transformation. Oncogene 105 11175364
1999 FLI-1 inhibits differentiation and induces proliferation of primary erythroblasts. Oncogene 90 10102630
2007 EWS/FLI-1 induces rapid onset of myeloid/erythroid leukemia in mice. Molecular and cellular biology 79 17875932
2005 Ewing's sarcoma oncoprotein EWS-FLI1: the perfect target without a therapeutic agent. Future oncology (London, England) 72 16556028
2009 Differentiation-dependent interactions between RUNX-1 and FLI-1 during megakaryocyte development. Molecular and cellular biology 70 19470763
1997 Inhibition of EWS-FLI-1 fusion protein with antisense oligodeoxynucleotides. Journal of neuro-oncology 70 9049825
2017 Epithelial Fli1 deficiency drives systemic autoimmunity and fibrosis: Possible roles in scleroderma. The Journal of experimental medicine 69 28232470
2008 The transcription factor Fli-1 modulates marginal zone and follicular B cell development in mice. Journal of immunology (Baltimore, Md. : 1950) 63 18641300
1992 Structure and expression of human Fli-1 gene. Cancer research 63 1394211
2018 Downregulation of ERG and FLI1 expression in endothelial cells triggers endothelial-to-mesenchymal transition. PLoS genetics 62 30500808
2021 SPOP and OTUD7A Control EWS-FLI1 Protein Stability to Govern Ewing Sarcoma Growth. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 60 34060252
2019 EWS-FLI1 modulated alternative splicing of ARID1A reveals novel oncogenic function through the BAF complex. Nucleic acids research 51 31392992
2005 Fli1, Elf1, and Ets1 regulate the proximal promoter of the LMO2 gene in endothelial cells. Blood 51 15994290
2004 Recombinant EWS-FLI1 oncoprotein activates transcription. Biochemistry 51 15491164
2015 EWS/FLI1 Target Genes and Therapeutic Opportunities in Ewing Sarcoma. Frontiers in oncology 49 26258070
2017 EWS-FLI1 perturbs MRTFB/YAP-1/TEAD target gene regulation inhibiting cytoskeletal autoregulatory feedback in Ewing sarcoma. Oncogene 48 28671673
2006 Combined transcriptional and translational targeting of EWS/FLI-1 in Ewing's sarcoma. Clinical cancer research : an official journal of the American Association for Cancer Research 48 17121899
2019 Trabectedin Inhibits EWS-FLI1 and Evicts SWI/SNF from Chromatin in a Schedule-dependent Manner. Clinical cancer research : an official journal of the American Association for Cancer Research 46 30723142
1995 EWS-FLI-1 and EWS-ERG chimeric mRNAs in Ewing's sarcoma and primitive neuroectodermal tumor. International journal of cancer 46 7591257
2012 Drug-mediated inhibition of Fli-1 for the treatment of leukemia. Blood cancer journal 43 22829238
2003 Homotypic and heterotypic interactions of EWS, FLI1 and their oncogenic fusion protein. Oncogene 43 14534527
1996 SRE elements are binding sites for the fusion protein EWS-FLI-1. Nucleic acids research 42 8604338
2023 ETV6 dependency in Ewing sarcoma by antagonism of EWS-FLI1-mediated enhancer activation. Nature cell biology 41 36658219
2001 Alternative EWS-FLI1 fusion gene and MIC2 expression in peripheral and central primitive neuroectodermal tumors. Neuropathology : official journal of the Japanese Society of Neuropathology 40 11304041
2017 Synergistic Role of Endothelial ERG and FLI1 in Mediating Pulmonary Vascular Homeostasis. American journal of respiratory cell and molecular biology 38 28248553
2004 Dysregulation of granulocyte, erythrocyte, and NK cell lineages in Fli-1 gene-targeted mice. Blood 38 15367440
2024 FLI1 promotes IFN-γ-induced kynurenine production to impair anti-tumor immunity. Nature communications 37 38816360
2022 Current insights into the role of Fli-1 in hematopoiesis and malignant transformation. Cellular and molecular life sciences : CMLS 37 35412146
2014 The Fli-1 transcription factor regulates the expression of CCL5/RANTES. Journal of immunology (Baltimore, Md. : 1950) 37 25098295
2019 Identification of diterpenoid compounds that interfere with Fli-1 DNA binding to suppress leukemogenesis. Cell death & disease 36 30741932
2002 EWS-FLI1 and Ewing's sarcoma: recent molecular data and new insights. Cancer biology & therapy 36 12432241
2020 circCAMSAP1 promotes osteosarcoma progression and metastasis by sponging miR-145-5p and regulating FLI1 expression. Molecular therapy. Nucleic acids 35 33664993
2017 Macrothrombocytopenia and dense granule deficiency associated with FLI1 variants: ultrastructural and pathogenic features. Haematologica 35 28255014
2020 EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma. Nucleic acids research 34 33080033
2017 FLI1 level during megakaryopoiesis affects thrombopoiesis and platelet biology. Blood 33 28432223
2008 Fli-1 expression in malignant melanoma. Histology and histopathology 33 18785112
2019 USP19 deubiquitinates EWS-FLI1 to regulate Ewing sarcoma growth. Scientific reports 32 30700749
2011 FLI-1 distinguishes Ewing sarcoma from small cell osteosarcoma and mesenchymal chondrosarcoma. Applied immunohistochemistry & molecular morphology : AIMM 32 21084965
2007 EWS/FLI-1 oncoprotein subtypes impose different requirements for transformation and metastatic activity in a murine model. Journal of molecular medicine (Berlin, Germany) 32 17453169
2004 Role of protein-protein interactions in the antiapoptotic function of EWS-Fli-1. Oncogene 32 15273724
2002 Direct regulation of BCL-2 by FLI-1 is involved in the survival of FLI-1-transformed erythroblasts. The EMBO journal 32 11847117
2013 The transcription factor Fli-1 regulates monocyte, macrophage and dendritic cell development in mice. Immunology 31 23320737
2016 Englerin A Inhibits EWS-FLI1 DNA Binding in Ewing Sarcoma Cells. The Journal of biological chemistry 30 26961871
2018 Fli-1 Governs Pericyte Dysfunction in a Murine Model of Sepsis. The Journal of infectious diseases 29 30053030
2017 The impact of transcription factor Fli1 deficiency on the regulation of angiogenesis. Experimental dermatology 29 28370536
2022 EWS::FLI1 and HOXD13 Control Tumor Cell Plasticity in Ewing Sarcoma. Clinical cancer research : an official journal of the American Association for Cancer Research 28 35653119
2015 Epigenetic suppression of Fli1, a potential predisposing factor in the pathogenesis of systemic sclerosis. The international journal of biochemistry & cell biology 28 26055516
2021 Fusion protein EWS-FLI1 is incorporated into a protein granule in cells. RNA (New York, N.Y.) 27 34035145
2008 EWS/FLI1 suppresses retinoblastoma protein function and senescence in Ewing's sarcoma cells. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 27 18271016
2002 Ets-1 regulates fli-1 expression in endothelial cells. Identification of ETS binding sites in the fli-1 gene promoter. The Journal of biological chemistry 26 11991951
2022 Suppression of Fli-1 protects against pericyte loss and cognitive deficits in Alzheimer's disease. Molecular therapy : the journal of the American Society of Gene Therapy 25 35038582
2018 Fli1-haploinsufficient dermal fibroblasts promote skin-localized transdifferentiation of Th2-like regulatory T cells. Arthritis research & therapy 25 29415756
2010 EWS/Fli-1 chimeric fusion gene upregulates vascular endothelial growth factor-A. International journal of cancer 24 19642105
2022 The druggable transcription factor Fli-1 regulates T cell immunity and tolerance in graft-versus-host disease. The Journal of clinical investigation 23 36074578
2022 Therapeutic targeting the oncogenic driver EWSR1::FLI1 in Ewing sarcoma through inhibition of the FACT complex. Oncogene 23 36357572
2013 Fli-1 overexpression in hematopoietic progenitors deregulates T cell development and induces pre-T cell lymphoblastic leukaemia/lymphoma. PloS one 23 23667468
2009 Spi-1 and Fli-1 directly activate common target genes involved in ribosome biogenesis in Friend erythroleukemic cells. Molecular and cellular biology 23 19289502
2023 Regulation of EWSR1-FLI1 Function by Post-Transcriptional and Post-Translational Modifications. Cancers 22 36672331
2020 Fli1 Downregulation in Scleroderma Myeloid Cells Has Profibrotic and Proinflammatory Effects. Frontiers in immunology 22 32508810
2020 Emerging role of Fli1 in autoimmune diseases. International immunopharmacology 22 33234418
2019 EWSR1-FLI1 Activation of the Cancer/Testis Antigen FATE1 Promotes Ewing Sarcoma Survival. Molecular and cellular biology 22 31036566
2016 Acetylation impacts Fli-1-driven regulation of granulocyte colony stimulating factor. European journal of immunology 22 27431361
2008 A role for Fli-1 in B cell proliferation: implications for SLE pathogenesis. Clinical immunology (Orlando, Fla.) 22 18692443
2023 EWS/FLI1 Characterization, Activation, Repression, Target Genes and Therapeutic Opportunities in Ewing Sarcoma. International journal of molecular sciences 21 37894854
2014 EWS-FLI-1 regulates the neuronal repressor gene REST, which controls Ewing sarcoma growth and vascular morphology. Cancer 21 24415532
2021 YAP inhibition promotes endothelial cell differentiation from pluripotent stem cell through EC master transcription factor FLI1. Journal of molecular and cellular cardiology 20 34666000
2020 The transcription factor FLI1 promotes cancer progression by affecting cell cycle regulation. International journal of cancer 20 31846072
2015 PI3K/AKT signaling modulates transcriptional expression of EWS/FLI1 through specificity protein 1. Oncotarget 20 26336820
2012 Acetylation Increases EWS-FLI1 DNA Binding and Transcriptional Activity. Frontiers in oncology 20 22973553
2023 FLI1 regulates radiotherapy resistance in nasopharyngeal carcinoma through TIE1-mediated PI3K/AKT signaling pathway. Journal of translational medicine 18 36814284
2020 High Specificity of BCL11B and GLG1 for EWSR1-FLI1 and EWSR1-ERG Positive Ewing Sarcoma. Cancers 18 32164354
2015 Structural Basis for Dimerization and DNA Binding of Transcription Factor FLI1. Biochemistry 18 26618620
2021 Fli1+ cells transcriptional analysis reveals an Lmo2-Prdm16 axis in angiogenesis. Proceedings of the National Academy of Sciences of the United States of America 17 34330825
2012 Spi-1, Fli-1 and Fli-3 (miR-17-92) oncogenes contribute to a single oncogenic network controlling cell proliferation in friend erythroleukemia. PloS one 17 23056458
2023 Targeted Therapy for EWS-FLI1 in Ewing Sarcoma. Cancers 16 37627063
2021 Challenges in modeling EWS-FLI1-driven transgenic mouse model for Ewing sarcoma. American journal of translational research 16 34956445
2019 Fli-1 transcription factor regulates the expression of caspase-1 in lung pericytes. Molecular immunology 16 30739075
2015 ERG and FLI1 are useful immunohistochemical markers in phosphaturic mesenchymal tumors. Medical molecular morphology 16 26122367
2020 Expression of GM-CSF Is Regulated by Fli-1 Transcription Factor, a Potential Drug Target. Journal of immunology (Baltimore, Md. : 1950) 15 33268481
2016 Increased survival and cell cycle progression pathways are required for EWS/FLI1-induced malignant transformation. Cell death & disease 15 27735950
2023 FLI1 and FRA1 transcription factors drive the transcriptional regulatory networks characterizing muscle invasive bladder cancer. Communications biology 14 36805539
2023 USP1 Expression Driven by EWS::FLI1 Transcription Factor Stabilizes Survivin and Mitigates Replication Stress in Ewing Sarcoma. Molecular cancer research : MCR 14 37478161
2020 MicroRNA-33b regulates hepatocellular carcinoma cell proliferation, apoptosis, and mobility via targeting Fli-1-mediated Notch1 pathway. Journal of cellular physiology 14 32239672
2020 Allosteric interference in oncogenic FLI1 and ERG transactions by mithramycins. Structure (London, England : 1993) 14 33275876

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