FLI1

Summary

FLI1 (Fli-1 proto-oncogene, ETS transcription factor, HGNC:3749) is a protein-coding gene on chromosome 11q24.3, encoding Friend leukemia integration 1 transcription factor (Q01543). Sequence-specific transcriptional activator.

This gene encodes a transcription factor containing an ETS DNA-binding domain. The gene can undergo a t(11;22)(q24;q12) translocation with the Ewing sarcoma gene on chromosome 22, which results in a fusion gene that is present in the majority of Ewing sarcoma cases. An acute lymphoblastic leukemia-associated t(4;11)(q21;q23) translocation involving this gene has also been identified. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 2313 — RefSeq curated summary.

At a glance

• Gene–disease (curated): bleeding disorder, platelet-type, 21 (Strong, GenCC)
• Clinical variants (ClinVar): 303 total — 5 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 122
• Druggable target: yes
• MANE Select transcript: NM_002017

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3749
Approved symbol	FLI1
Name	Fli-1 proto-oncogene, ETS transcription factor
Location	11q24.3
Locus type	gene with protein product
Status	Approved
Aliases	SIC-1, EWSR2, FLI-1
Ensembl gene	ENSG00000151702
Ensembl biotype	protein_coding
OMIM	193067
Entrez	2313

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 11 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron

ENST00000429175, ENST00000527767, ENST00000527786, ENST00000528790, ENST00000534087, ENST00000608055, ENST00000608303, ENST00000696982, ENST00000897155, ENST00000897156, ENST00000897157, ENST00000897158, ENST00000897159, ENST00000935956, ENST00000965140

RefSeq mRNA: 4 — MANE Select: NM_002017 NM_001167681, NM_001271010, NM_001271012, NM_002017

CCDS: CCDS44768, CCDS53725

Canonical transcript exons

ENST00000527786 — 9 exons

Exon	Start	End
ENSE00002175028	128810459	128813267
ENSE00002188617	128694072	128694276
ENSE00003969178	128768118	128768272
ENSE00003969180	128772782	128772985
ENSE00003969181	128809157	128809204
ENSE00003969182	128805366	128805431
ENSE00003969183	128758115	128758326
ENSE00003969185	128781958	128782023
ENSE00003969186	128807180	128807239

Expression profiles

Bgee: expression breadth ubiquitous, 247 present calls, max score 96.61.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.5648 / max 490.8687, expressed in 1321 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
117560	26.8067	1304
206496	0.3994	196
117559	0.1918	85
117558	0.1670	99

Top tissues by expression

292 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	96.61	gold quality
leukocyte	CL:0000738	96.56	gold quality
mononuclear cell	CL:0000842	96.48	gold quality
granulocyte	CL:0000094	95.98	gold quality
blood	UBERON:0000178	95.74	gold quality
spleen	UBERON:0002106	95.50	gold quality
bone marrow cell	CL:0002092	95.29	gold quality
trabecular bone tissue	UBERON:0002483	94.88	gold quality
bone marrow	UBERON:0002371	93.45	gold quality
bone element	UBERON:0001474	93.18	gold quality
vermiform appendix	UBERON:0001154	93.08	gold quality
lymph node	UBERON:0000029	92.75	gold quality
right lung	UBERON:0002167	90.80	gold quality
upper lobe of left lung	UBERON:0008952	90.36	gold quality
upper lobe of lung	UBERON:0008948	90.03	gold quality
visceral pleura	UBERON:0002401	90.00	gold quality
caecum	UBERON:0001153	89.67	gold quality
subcutaneous adipose tissue	UBERON:0002190	89.65	gold quality
omental fat pad	UBERON:0010414	88.82	gold quality
peritoneum	UBERON:0002358	88.74	gold quality
adipose tissue	UBERON:0001013	88.57	gold quality
adipose tissue of abdominal region	UBERON:0007808	88.54	gold quality
connective tissue	UBERON:0002384	88.44	gold quality
lung	UBERON:0002048	88.14	gold quality
pleura	UBERON:0000977	87.89	gold quality
parietal pleura	UBERON:0002400	87.12	gold quality
gall bladder	UBERON:0002110	86.81	gold quality
lower lobe of lung	UBERON:0008949	86.38	gold quality
calcaneal tendon	UBERON:0003701	86.20	gold quality
smooth muscle tissue	UBERON:0001135	86.16	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	27.65
E-CURD-119	yes	24.10
E-MTAB-9388	yes	11.56
E-ANND-3	yes	10.96
E-MTAB-6386	no	1552.23

Regulation

Is transcription factor: yes

JASPAR motifs

Motif	Name	Family
MA0475.1	FLI1	Ets-related
MA0475.2	FLI1	Ets-related
MA0475.3	FLI1	Ets-related
MA1949.1	FLI1::DRGX	Paired-related HD factors::Ets-related
MA1949.2	FLI1::DRGX	Paired-related HD factors::Ets-related
MA1950.1	FLI1::FOXI1	Ets-related::FOX
MA1950.2	FLI1::FOXI1	Ets-related::FOX
MA1956.1	FOXO1::FLI1	FOX::Ets-related
MA1956.2	FOXO1::FLI1	FOX::Ets-related
MA1967.1	TFAP4::FLI1	bHLH-ZIP::Ets-related
MA1967.2	TFAP4::FLI1	bHLH-ZIP::Ets-related

JASPAR matrix evidence (PMIDs): PMID:7517940, PMID:24218641, PMID:31913281

miRNA regulators (miRDB)

142 targeting FLI1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-340-5P	100.00	72.50	4437
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-5193	100.00	67.26	1744
HSA-LET-7A-3P	100.00	74.03	3932
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-5696	99.98	72.36	4487
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-548AJ-3P	99.96	73.38	5345

Literature-anchored findings (GeneRIF, showing 40)

• role in regulating megakaryocyte-specific glycoprotein VI promoter (PMID:12359731)
• Fli-1 and GATA-1 work together to activate the expression of genes associated with the terminal differentiation of megakaryocytes (PMID:12724402)
• overexpression of this protein affects cell growth and differentiation of K562 cells (PMID:12739001)
• This study supports the role of Fli1 as a suppressor of collagen transcription in human skin in vivo. (PMID:12875977)
• FLI1 interacts with EWS and their oncogenic fusion protein. (PMID:14534527)
• oncogenic rearrangement of EWS to produce EWS/Fli-1 may enhance the antiapoptotic effect of Brn-3a and inhibit its ability to promote neuronal differentiation. (PMID:15021903)
• Overoverexpression of FLI1 in patient CD34(+) cells restores the megakaryopoiesis in vitro, indicating that FLI1 hemizygous deletion contributes to Paris-Troudeau syndrome hematopoietic defects. (PMID:15232614)
• Ability of Ewing Sarcoma-Fli-1/Fli-1 to target transcriptional cofactor(s) and modulate apoptotic pathways may be responsible for its antiapoptotic and tumorigenic activities. (PMID:15273724)
• These findings identify the repression of insulin-like growth factor binding protein 3 gene by EWS/FLI-1 as a key event in the development of Ewing’s sarcoma. (PMID:15282325)
• Two functional NLSs were shown to exist in Fli-1; each NLS is sufficient to target Fli-1 to the nucleus for activation of megakaryocyte-specific promoters. (PMID:15798196)
• Protein phosphatase 2A controls FLI-1 phosphorylation. Newly synthesized FLI-1 decreased during human T cell activation. Although the FLI-1 & ERG genes are highly homologous, their distinct properties may contribute to different roles in gene regulation. (PMID:15809330)
• EWS-Fli1 may play a role in the regulation of PDGF-induced tumor proliferation-signaling enzymes via PLD2 expression in Ewing sarcoma cells (PMID:15919668)
• the repressive properties of PIASxalpha/ARIP3 require its physical interaction with FLI-1, identifying PIASxalpha as a novel corepressor of FLI-1 (PMID:16148010)
• The signal transduction leading to the systemic sclerosis (SSc) fibrotic phenotype appears to converge on DNA methylation and histone deacetylation at the FLI1 gene. (PMID:16802366)
• Fli1 and Ets1 have roles in the pathological extracellular matrix regulation during fibrosis and cancer (PMID:16829517)
• Fli-1 is rather constitutively expressed by bone marrow cells in Ph(-) CMPD independent of the underlying JAK2 status (PMID:16930139)
• EWS/Fli-1 and Fli-1 increase PLD2 gene expression by binding to an erythroblast transformation-specific domain of PLD2 promoter (PMID:16964281)
• The gene that was most reproducibly up-regulated by EWS/FLI was NR0B1. (PMID:17114343)
• variation in overall gene expression patterns downstream of EWS-FLIl was observed, but also differential regulation of directly EWS-FLI1-bound genes (PMID:17163154)
• results suggest that Fli-1 contributes to the malignancy of human breast cancer by inhibiting apoptosis through upregulated expression of the bcl-2 gene. (PMID:17727680)
• PCAF-dependent acetylation of lysine 380 abrogates repressor function of Fli1 with respect to collagen expression; TGFb-dependent acetylation of Fli1 may represent the principal mechanism for TGFb-induced dissociation of Fli1 from the collagen promoter (PMID:17884818)
• EWS/FLI mediates transcriptional repression via NKX2.2 during oncogenic transformation in Ewing’s sarcoma (PMID:18414662)
• IGF1 is a common target gene of Ewing’s sarcoma fusion proteins EWS-FLI-1, EWS-ERG and FUS-ERG in mesenchymal progenitor cells (PMID:18648544)
• Expression of Fli-1 in malignant melanoma appears to be associated with biologically more aggressive tumors. (PMID:18785112)
• The phosphorylation-acetylation cascade triggered by PKC delta represents the primary mechanism whereby TGF-beta regulates the transcriptional activity of Fli1 in the context of the collagen promoter. (PMID:19158279)
• report FLI-1 expression in an expanded series of 75 cases of T-cell lymphoma and found high expression in anaplastic large cell lymphoma and angioimmunoblastic T-cell lymphoma (PMID:19349856)
• Interaction between EWSR1/FLI1 and EWSR1 in Ewing sarcoma may induce mitotic defects leading to genomic instability and subsequent malignant transformation. (PMID:19417137)
• The mouse (Fli1) and human Fli1 genes are similarly regulated by Ets factors in T cells. (PMID:19829305)
• GLI1 is a central mediator of EWS/FLI1 signaling in Ewing tumors (PMID:19859563)
• EWS/FLI1 inhibits both DKK-1 expression as well as beta-catenin/TCF-dependent transcription, which could contribute to progression of tumours of the Ewing family. (PMID:20019092)
• Findings suggest that EWS/FLI1 induces apoptosis, at least partially, through the activation of CASP3. (PMID:20103643)
• persistently reduced levels of Fli1 in endothelial cells may play a critical role in the development of SSc vasculopathy (PMID:20228226)
• Intensive treatment protocols for localized Ewing family sarcoma have erased the clinical differences observed in patients with EWS-FLI1/ERG fusions. (PMID:20308669)
• Propsectively evaluated the impact of EWS-FLI1/ERG fusions on disease progression in Ewing’s sarcoma/peripheral primitive neuroectodermal tumor. (PMID:20308673)
• EWS-FLI-1 and miRNA-145 function in a mutually repressive feedback loop and identify their common target gene, SOX2, in addition to miRNA145 itself, as key players in Ewing sarcoma family tumors cell differentiation and tumorigenicity (PMID:20382729)
• These results demonstrate that EWS-FLI blocks the ability of Runx2 to induce osteoblast specification of a mesenchymal progenitor cell. (PMID:20665663)
• a self-sustaining triad of LMO2/ERG/FLI1 stabilizes the expression of important mediators of the leukaemic phenotype such as (PMID:20676125)
• The rapid downregulation of FLI-1 expression after LPS stimulation attenuates the induction of various MMPs and IL-10 under inflammatory conditions. (PMID:20879862)
• these results suggest that suppression of FOXO1 function by EWS-Fli1 fusion protein may contribute to cellular transformation in Ewing’s family tumors. (PMID:20933505)
• study demonstrates that a GA(n) microsatellite in the human Fli1 promoter is highly polymorphic (PMID:21087477)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	fli1	ENSDARG00000054632
mus_musculus	Fli1	ENSMUSG00000016087
rattus_norvegicus	Fli1	ENSRNOG00000008904

Paralogs (28): ETV1 (ENSG00000006468), ETV7 (ENSG00000010030), SPI1 (ENSG00000066336), ELF4 (ENSG00000102034), ETV2 (ENSG00000105672), ERF (ENSG00000105722), ELF2 (ENSG00000109381), ELK3 (ENSG00000111145), ETV3 (ENSG00000117036), ELF1 (ENSG00000120690), SPDEF (ENSG00000124664), ELK1 (ENSG00000126767), ETS1 (ENSG00000134954), EHF (ENSG00000135373), ELF5 (ENSG00000135374), ETV6 (ENSG00000139083), GABPA (ENSG00000154727), ERG (ENSG00000157554), ETS2 (ENSG00000157557), ELK4 (ENSG00000158711), ELF3 (ENSG00000163435), FEV (ENSG00000163497), SPIC (ENSG00000166211), ETV4 (ENSG00000175832), ETV5 (ENSG00000244405), ETV3L (ENSG00000253831), ERFL (ENSG00000268041), SPIB (ENSG00000269404)

Protein

Protein identifiers

Friend leukemia integration 1 transcription factor — Q01543 (reviewed: Q01543)

Alternative names: Proto-oncogene Fli-1, Transcription factor ERGB

All UniProt accessions (5): Q01543, A0A0A0MSR4, A0A8V8TM04, V9GY62, V9GZ02

UniProt curated annotations — full annotation on UniProt →

Function. Sequence-specific transcriptional activator. Recognizes the DNA sequence 5’-C[CA]GGAAGT-3'.

Subunit / interactions. Can form homodimers or heterodimers with ETV6/TEL1.

Subcellular location. Nucleus.

Disease relevance. Ewing sarcoma (ES) [MIM:612219] A highly malignant, metastatic, primitive small round cell tumor of bone and soft tissue that affects children and adolescents. It belongs to the Ewing sarcoma family of tumors, a group of morphologically heterogeneous neoplasms that share the same cytogenetic features. They are considered neural tumors derived from cells of the neural crest. Ewing sarcoma represents the less differentiated form of the tumors. The gene represented in this entry is involved in disease pathogenesis. A chromosomal aberration involving FLI1 is found in patients with Erwing sarcoma. Translocation t(11;22)(q24;q12) with EWSR1. Bleeding disorder, platelet-type, 21 (BDPLT21) [MIM:617443] A disorder characterized by increased bleeding tendency due to platelet dysfunction. Clinical features include epistaxis, hematomas, bleeding after tooth extraction, and menorrhagia. BDPLT21 patients may have mild to moderate thrombocytopenia. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Located on a fragment of chromosome 11 flanked on the centromeric side by the acute lymphoblastic leukemia-associated t(4;11)(q21;q23) translocation breakpoint and on the telomeric side by the Ewing- and neuroepithelioma-associated t(11;22) (q24;q12) breakpoint.

Similarity. Belongs to the ETS family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q01543-1	1	yes
Q01543-2	2
Q01543-3	3
Q01543-4	4

RefSeq proteins (4): NP_001161153, NP_001257939, NP_001257941, NP_002008* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000418	Ets_dom	Domain
IPR003118	Pointed_dom	Domain
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR035573	SAM_PNT-FLI-1	Domain
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR046328	ETS_fam	Family

Pfam: PF00178, PF02198

UniProt features (45 total): helix 12, sequence conflict 7, strand 7, sequence variant 5, splice variant 3, turn 3, region of interest 2, compositionally biased region 2, chain 1, domain 1, DNA-binding region 1, modified residue 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
9CP6	X-RAY DIFFRACTION	1.66
9MX9	X-RAY DIFFRACTION	2.55
9MXA	X-RAY DIFFRACTION	2.59
5E8G	X-RAY DIFFRACTION	2.7
5JVT	X-RAY DIFFRACTION	3.1
9MX8	X-RAY DIFFRACTION	3.15
9MWY	X-RAY DIFFRACTION	3.28
5E8I	X-RAY DIFFRACTION	3.45
6VG2	X-RAY DIFFRACTION	3.9
6VGD	X-RAY DIFFRACTION	4.2
6VG8	X-RAY DIFFRACTION	4.31
1FLI	SOLUTION NMR
1X66	SOLUTION NMR
2YTU	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q01543-F1	64.32	0.32

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 39

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9616222	Transcriptional regulation of granulopoiesis

MSigDB gene sets: 636 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, FXR_IR1_Q6, MYAATNNNNNNNGGC_UNKNOWN, WALLACE_PROSTATE_CANCER_RACE_UP, BENPORATH_ES_WITH_H3K27ME3, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_MYELOID_CELL_DEVELOPMENT, RORA1_01, LFA1_Q6, HOFMANN_CELL_LYMPHOMA_UP, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, RACCACAR_AML_Q6, HNF1_Q6, AP2_Q3, GGGTGGRR_PAX4_03

GO Biological Process (9): regulation of transcription by RNA polymerase II (GO:0006357), hemostasis (GO:0007599), blood circulation (GO:0008015), animal organ morphogenesis (GO:0009887), cell differentiation (GO:0030154), megakaryocyte development (GO:0035855), positive regulation of DNA-templated transcription (GO:0045893), regulation of DNA-templated transcription (GO:0006355), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (10): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), chromatin binding (GO:0003682), DNA-binding transcription factor activity (GO:0003700), sequence-specific double-stranded DNA binding (GO:1990837), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), nuclear body (GO:0016604)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular anatomical structure	3
transcription by RNA polymerase II	2
DNA-templated transcription	2
regulation of transcription by RNA polymerase II	2
binding	2
regulation of body fluid levels	1
circulatory system process	1
anatomical structure morphogenesis	1
animal organ development	1
cellular developmental process	1
megakaryocyte differentiation	1
myeloid cell development	1
positive regulation of RNA biosynthetic process	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
transcription regulatory region nucleic acid binding	1
sequence-specific double-stranded DNA binding	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
nucleic acid binding	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
DNA binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
nucleoplasm	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1050 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FLI1	FBXW7	Q969H0	995
FLI1	TPP1	O14773	936
FLI1	EWSR1	Q01844	879
FLI1	PPT1	P50897	834
FLI1	CDC34	P49427	711
FLI1	CCNL2	Q96S94	710
FLI1	ANAPC11	Q9NYG5	709
FLI1	GATA2	P23769	650
FLI1	CDKN3	Q16667	638
FLI1	SKP1	P34991	606
FLI1	CDK1	P06493	603
FLI1	SWI5	Q1ZZU3	596
FLI1	PSMD14	O00487	590
FLI1	CDC14A	Q9UNH5	580
FLI1	RBX1	P62877	558

IntAct

27 interactions, top by confidence:

A	B	Type	Score
SOX30	FLI1	psi-mi:“MI:0915”(physical association)	0.560
FLI1	SIAH1	psi-mi:“MI:0915”(physical association)	0.560
CTBP2	FLI1	psi-mi:“MI:0915”(physical association)	0.560
FLI1	SOX30	psi-mi:“MI:0915”(physical association)	0.560
FLI1	SMAD3	psi-mi:“MI:0915”(physical association)	0.510
SMAD3	FLI1	psi-mi:“MI:0915”(physical association)	0.510
Grip1	FLI1	psi-mi:“MI:0407”(direct interaction)	0.440
SP100	ETS1	psi-mi:“MI:0915”(physical association)	0.400
FLI1	SMAD9	psi-mi:“MI:0915”(physical association)	0.370
ERG	BCL9	psi-mi:“MI:2364”(proximity)	0.270
ETV4	BCL9	psi-mi:“MI:2364”(proximity)	0.270
IRF8	BCL9	psi-mi:“MI:2364”(proximity)	0.270
PAX7	BCL9	psi-mi:“MI:2364”(proximity)	0.270
PAX9	BCL9	psi-mi:“MI:2364”(proximity)	0.270
SOX15	SMCHD1	psi-mi:“MI:2364”(proximity)	0.270
SOX2	SMCHD1	psi-mi:“MI:2364”(proximity)	0.270
SP7	IGF2BP3	psi-mi:“MI:2364”(proximity)	0.270
TLK2	PES1	psi-mi:“MI:2364”(proximity)	0.270
TLK2	SBNO1	psi-mi:“MI:2364”(proximity)	0.270
ilvD	FLI1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (78): FLI1 (Two-hybrid), SIAH1 (Two-hybrid), SOX30 (Two-hybrid), KAT2B (Affinity Capture-Western), FLI1 (Biochemical Activity), KAT2B (Affinity Capture-Western), PRKCD (Affinity Capture-Western), GATA1 (Two-hybrid), FLI1 (Reconstituted Complex), SMARCA4 (Affinity Capture-MS), SMARCA2 (Affinity Capture-MS), ARID1A (Affinity Capture-MS), ARID1B (Affinity Capture-MS), ARID2 (Affinity Capture-MS), SMARCC2 (Affinity Capture-MS)

ESM2 similar proteins: A3FEM2, A8WFJ9, F1R8Z9, G5EC89, G5EFY5, L8E946, O60381, P10157, P11308, P19102, P22816, P26323, P41157, P41935, P51023, P53544, P81270, Q01414, Q01543, Q18579, Q1LVQ7, Q21263, Q22355, Q25132, Q28D67, Q28HT3, Q29RS8, Q5NDM2, Q63ZH2, Q6P2Z3, Q6P8A3, Q7ZYQ0, Q8AXW8, Q8GWP0, Q8ITI5, Q8JIT5, Q90837, Q90VZ9, Q90WN4, Q91712

Diamond homologs: A0A1W2PQ73, A0JN51, A1A4L6, A1YF15, A1YG61, A1YG91, A2D4Z7, A2T737, A2T762, A3FEM2, A4GTP4, A8WFJ9, O00321, O01519, O70132, O70273, O95238, P01105, P10157, P11308, P11536, P13474, P14921, P15036, P15037, P15062, P18755, P18756, P19102, P19419, P20105, P26323, P27577, P28322, P28324, P29773, P29774, P29775, P29776, P32519

SIGNOR signaling

22 interactions.

A	Effect	B	Mechanism
CBP/p300	down-regulates	FLI1	acetylation
PRKCD	down-regulates	FLI1	phosphorylation
EP300	up-regulates	FLI1	binding
FLI1	“down-regulates quantity by repression”	COL1A2	“transcriptional regulation”
HDAC1	up-regulates	FLI1	deacetylation
ETV2	“up-regulates quantity by expression”	FLI1	“transcriptional regulation”
FLI1	“up-regulates quantity by expression”	ERG	“transcriptional regulation”
FLI1	“up-regulates quantity by expression”	GP6	“transcriptional regulation”
FLI1	“up-regulates quantity by expression”	GP9	“transcriptional regulation”
FLI1	“up-regulates quantity by expression”	MPL	“transcriptional regulation”
FLI1	“down-regulates quantity by repression”	HOXA10	“transcriptional regulation”
FLI1	up-regulates	IL10	“transcriptional regulation”
GATA1	“up-regulates quantity by expression”	FLI1	“transcriptional regulation”
SPI1	“up-regulates quantity by expression”	FLI1	“transcriptional regulation”
FLI1	up-regulates	Megakaryocyte_differentiation
KDM6A	“down-regulates quantity by repression”	FLI1	“transcriptional regulation”
FLI1	“down-regulates quantity by repression”	ANKRD26	“transcriptional regulation”
FLI1	“down-regulates activity”	KLF1	binding
FLI1	“up-regulates activity”	GATA1	binding
KLF1	“down-regulates activity”	FLI1	binding
FLI1	“up-regulates activity”	Monocyte_differentiation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 23 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
anatomical structure morphogenesis	5	33.2×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

303 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	5
Uncertain significance	116
Likely benign	105
Benign	42

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
1333008	Single allele	Pathogenic
1703851	NM_002017.5(FLI1):c.844C>T (p.Gln282Ter)	Pathogenic
217031	NM_002017.5(FLI1):c.970C>T (p.Arg324Trp)	Pathogenic
424636	NM_002017.5(FLI1):c.1033A>G (p.Lys345Glu)	Pathogenic
4541671	NM_002017.5(FLI1):c.338dup (p.Pro114fs)	Pathogenic
1684367	NM_002017.5(FLI1):c.946G>T (p.Glu316Ter)	Likely pathogenic
1684421	NM_002017.5(FLI1):c.1019G>C (p.Arg340Pro)	Likely pathogenic
424632	NM_002017.5(FLI1):c.1009C>T (p.Arg337Trp)	Likely pathogenic
4541672	NM_002017.5(FLI1):c.969_973del (p.Arg324fs)	Likely pathogenic
627497	Single allele	Likely pathogenic

SpliceAI

2648 predictions. Top by Δscore:

Variant	Effect	Δscore
11:128716529:G:GT	donor_gain	1.0000
11:128758104:T:TA	acceptor_gain	1.0000
11:128758105:G:A	acceptor_gain	1.0000
11:128758111:GCA:G	acceptor_loss	1.0000
11:128758112:CAGGA:C	acceptor_loss	1.0000
11:128758113:A:AC	acceptor_loss	1.0000
11:128758113:AGGAG:A	acceptor_gain	1.0000
11:128758114:G:GG	acceptor_loss	1.0000
11:128758114:G:GT	acceptor_gain	1.0000
11:128758114:GGAGG:G	acceptor_gain	1.0000
11:128758326:GGTAA:G	donor_loss	1.0000
11:128758327:G:GG	donor_gain	1.0000
11:128758327:GT:G	donor_loss	1.0000
11:128758328:T:G	donor_loss	1.0000
11:128768111:A:AG	acceptor_gain	1.0000
11:128768113:TTTA:T	acceptor_loss	1.0000
11:128768115:TA:T	acceptor_loss	1.0000
11:128768116:A:AG	acceptor_gain	1.0000
11:128768116:A:C	acceptor_loss	1.0000
11:128768116:AG:A	acceptor_gain	1.0000
11:128768116:AGG:A	acceptor_gain	1.0000
11:128768117:G:GC	acceptor_loss	1.0000
11:128768117:G:GG	acceptor_gain	1.0000
11:128768117:GG:G	acceptor_gain	1.0000
11:128768117:GGG:G	acceptor_gain	1.0000
11:128768117:GGGA:G	acceptor_gain	1.0000
11:128768254:A:T	donor_gain	1.0000
11:128768272:GGTAA:G	donor_loss	1.0000
11:128768273:G:GA	donor_loss	1.0000
11:128768274:T:A	donor_loss	1.0000

AlphaMissense

3005 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:128768258:T:A	V124D	1.000
11:128768264:T:A	V126D	1.000
11:128772785:C:A	P130H	1.000
11:128772793:T:A	W133R	1.000
11:128772793:T:C	W133R	1.000
11:128772794:G:C	W133S	1.000
11:128772795:G:C	W133C	1.000
11:128772795:G:T	W133C	1.000
11:128772817:T:A	W141R	1.000
11:128772817:T:C	W141R	1.000
11:128772818:G:C	W141S	1.000
11:128772819:G:C	W141C	1.000
11:128772819:G:T	W141C	1.000
11:128772821:T:C	L142P	1.000
11:128772826:T:A	W144R	1.000
11:128772826:T:C	W144R	1.000
11:128772828:G:C	W144C	1.000
11:128772828:G:T	W144C	1.000
11:128772829:G:C	A145P	1.000
11:128772830:C:A	A145D	1.000
11:128772886:G:C	G164R	1.000
11:128772886:G:T	G164C	1.000
11:128772887:G:A	G164D	1.000
11:128772887:G:T	G164V	1.000
11:128772896:T:C	L167P	1.000
11:128772956:T:C	L187P	1.000
11:128772964:C:G	H190D	1.000
11:128772968:T:C	L191P	1.000
11:128772977:T:C	L194P	1.000
11:128809183:A:C	S270R	1.000

dbSNP variants (sampled 300 via entrez): RS1000038036 (11:128773103 G>A), RS1000050060 (11:128693519 C>A,G,T), RS1000059353 (11:128812630 G>A,T), RS1000103137 (11:128770255 T>G), RS1000105875 (11:128732875 G>A,C), RS1000160585 (11:128683620 T>A), RS1000162045 (11:128728291 C>T), RS1000173517 (11:128760596 T>C), RS1000192236 (11:128767298 C>T), RS1000192689 (11:128734365 C>T), RS1000227086 (11:128804351 G>A), RS1000240127 (11:128775262 A>G), RS1000277206 (11:128728065 G>A,T), RS1000316765 (11:128688250 C>T), RS1000321988 (11:128747228 A>G)

Disease associations

OMIM: gene MIM:193067 | disease phenotypes: MIM:617443, MIM:147791

GenCC curated gene-disease

Disease	Classification	Inheritance
bleeding disorder, platelet-type, 21	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
bleeding disorder, platelet-type, 21	Moderate	AD

Mondo (3): bleeding disorder, platelet-type, 21 (MONDO:0054577), thrombocytopenia (MONDO:0002049), Jacobsen syndrome (MONDO:0007838)

Orphanet (1): Jacobsen syndrome (Orphanet:2308)

HPO phenotypes

122 total (30 of 122 shown, HPO-id order):

HPO	Term
HP:0000003	Multicystic kidney dysplasia
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000126	Hydronephrosis
HP:0000132	Menorrhagia
HP:0000174	Abnormal palate morphology
HP:0000243	Trigonocephaly
HP:0000256	Macrocephaly
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000324	Facial asymmetry
HP:0000343	Long philtrum
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000465	Webbed neck
HP:0000470	Short neck
HP:0000473	Torticollis
HP:0000482	Microcornea
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000520	Proptosis
HP:0000612	Iris coloboma
HP:0000625	Eyelid coloboma

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D013921	Thrombocytopenia	C15.378.140.855; C15.378.243.937

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3885568 (CHIMERIC PROTEIN), CHEMBL5465299 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

6 potent at pChembl≥5 of 6 total, top 6 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.82	IC50	150	nM	CHEMBL3360409
6.75	IC50	180	nM	CHEMBL3360408
6.48	IC50	330	nM	CHEMBL3360406
6.46	IC50	350	nM	CHEMBL2011500
6.11	IC50	770	nM	CHEMBL3360384
5.32	Kd	4800	nM	CHEMBL3360410

PubChem BioAssay actives

6 with measured affinity, of 21 total; 6 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4,7-dichloro-3-[2-[4-(dimethylamino)phenyl]-2-oxoethyl]-3-hydroxy-1H-indol-2-one	1171938: Inhibition of transcriptional activity of full-length EWS-FLI1 (unknown origin) expressed in COS7 cells by NR0B1-luciferase reporter gene assay	ic50	0.1500	uM
4,7-dichloro-3-hydroxy-3-[2-[4-(methylamino)phenyl]-2-oxoethyl]-1H-indol-2-one	1171938: Inhibition of transcriptional activity of full-length EWS-FLI1 (unknown origin) expressed in COS7 cells by NR0B1-luciferase reporter gene assay	ic50	0.1800	uM
4,7-dichloro-3-hydroxy-3-[2-(4-methylsulfanylphenyl)-2-oxoethyl]-1H-indol-2-one	1171938: Inhibition of transcriptional activity of full-length EWS-FLI1 (unknown origin) expressed in COS7 cells by NR0B1-luciferase reporter gene assay	ic50	0.3300	uM
4,7-dichloro-3-hydroxy-3-[2-(4-methoxyphenyl)-2-oxoethyl]-1H-indol-2-one	1171938: Inhibition of transcriptional activity of full-length EWS-FLI1 (unknown origin) expressed in COS7 cells by NR0B1-luciferase reporter gene assay	ic50	0.3500	uM
3-hydroxy-4,7-dimethoxy-3-[2-(4-methoxyphenyl)-2-oxoethyl]-1H-indol-2-one	1171938: Inhibition of transcriptional activity of full-length EWS-FLI1 (unknown origin) expressed in COS7 cells by NR0B1-luciferase reporter gene assay	ic50	0.7700	uM
N-[4-[2-(4,7-dichloro-3-hydroxy-2-oxo-1H-indol-3-yl)acetyl]phenyl]-N-methyl-6-[5-[(4R)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]hexanamide	1171939: Binding affinity to purified recombinant EWS-FLI1 (unknown origin) after 1 hr by colorimetric phosphatase assay	kd	4.8000	uM

CTD chemical–gene interactions

45 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, decreases expression, increases abundance, increases expression	5
Valproic Acid	decreases expression, increases expression	4
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	3
bisphenol A	decreases methylation, increases expression, affects cotreatment, affects methylation	2
Air Pollutants	increases expression, affects expression, increases abundance	2
Doxorubicin	decreases expression, affects response to substance	2
Phenylmercuric Acetate	increases expression, affects cotreatment	2
Tretinoin	increases expression	2
GSK-J4	increases expression	1
trichostatin A	increases expression	1
arsenite	increases methylation	1
anagrelide	decreases reaction, increases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	decreases expression	1
aflatoxin B2	increases methylation	1
cupric chloride	increases expression	1
nickel sulfate	increases expression	1
mercuric bromide	affects cotreatment, increases expression	1
chromium hexavalent ion	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
romidepsin	decreases activity, decreases expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	increases methylation	1
(+)-JQ1 compound	decreases expression	1
theaflavin-3,3’-digallate	affects expression	1
Fulvestrant	affects cotreatment, affects methylation	1
Arsenic	increases expression, increases abundance	1
Atrazine	increases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3383759	Binding	Inhibition of transcriptional activity of full-length EWS-FLI1 (unknown origin) expressed in COS7 cells by NR0B1-luciferase reporter gene assay	Synthesis and structure-activity relationship studies of small molecule disruptors of EWS-FLI1 interactions in Ewing’s sarcoma. — J Med Chem

Cellosaurus cell lines

104 cell lines: 100 cancer cell line, 4 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_0080	A-673	Cancer cell line	Female
CVCL_0530	SK-N-MC	Cancer cell line	Female
CVCL_0627	SK-ES-1	Cancer cell line	Male
CVCL_0631	SK-NEP-1	Cancer cell line	Female
CVCL_1198	ES1	Cancer cell line	Female
CVCL_1200	ES4	Cancer cell line	Male
CVCL_1202	ES6	Cancer cell line	Male
CVCL_1203	ES7	Cancer cell line	Male
CVCL_1204	ES8	Cancer cell line	Male
CVCL_1208	EW-1	Cancer cell line	Male

Clinical trials (associated diseases)

241 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00039858	PHASE4	COMPLETED	Evaluation of Argatroban Injection in Pediatric Patients Requiring Anticoagulant Alternatives to Heparin
NCT00239733	PHASE4	TERMINATED	Anti-D for Treating Thrombocytopenia in Adults Infected With Hepatitis C Virus With or Without HIV Co-Infection
NCT00907478	PHASE4	COMPLETED	Study on Bone Marrow Morphology in Adults Receiving Romiplostim for Treatment of Thrombocytopenia Associated With Immune Thrombocytopenia Purpura (ITP)
NCT01727401	PHASE4	TERMINATED	Thromboprophylaxis of Venous Thromboembolism in Acutely-ill Medical Inpatients With Thrombocytopenia
NCT02032134	PHASE4	TERMINATED	Protocol for the Infusion of Buffy Coat-derived Cryopreserved Platelets in Patients With Severe Thrombocytopenia
NCT02267993	PHASE4	COMPLETED	Efficacy and Safety of rhTPO for the Treatment of Thrombocytopenia After Chemotherapy in AML Patients
NCT03633019	PHASE4	UNKNOWN	High-dose Use of rhTPO in CIT Patients
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04906083	PHASE4	UNKNOWN	Avatrombopag in Patients With End-stage Liver Disease and Thrombocytopenia
NCT05217719	PHASE4	UNKNOWN	Effects of Recombinant Human Thrombopoietin on Platelet Levels in ICU Patients
NCT05255003	PHASE4	RECRUITING	STrategies for Anticoagulation in Patients With thRombocytopenia and Cancer-associated Thrombosis
NCT05382013	PHASE4	UNKNOWN	Efficacy and Safety of Avatrombopag for Treating TCP in HBV-ACLF Patients Receiving ALSS Treatment
NCT05944458	PHASE4	COMPLETED	Efficacy of Intravenous N-Acetylcysteine in Preventing Linezolid-Induced Thrombocytopenia in Critically Ill Patients
NCT06562738	PHASE4	RECRUITING	Clinical Study on Efficacy and Safety of Hetrombopag in the Preoperative Patients of Thrombocytopenia
NCT00037791	PHASE3	COMPLETED	Safety and Efficacy of (PN-152,243)/PN-196,444 in the Prevention of Thrombocytopenia
NCT00039910	PHASE3	COMPLETED	Safety and Efficacy of (PN-152,243)/PN-196,444 in the Prevention of Thrombocytopenia
NCT00073580	PHASE3	COMPLETED	Angiomax in Patients With HIT/HITTS Type II Undergoing Off-Pump Coronary Artery Bypass Grafting (CABG) (CHOOSE)
NCT00102323	PHASE3	COMPLETED	AMG 531 Treatment of Thrombocytopenic Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP) Refractory to Splenectomy
NCT00102336	PHASE3	COMPLETED	AMG 531 Treatment of Thrombocytopenic Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP) Prior to Splenectomy
NCT00116688	PHASE3	COMPLETED	Open Label Extension Study of Romiplostim (AMG 531) in Thrombocytopenic Patients With Immune (Idiopathic) Thrombocytopenic Purpura (ITP)
NCT00128713	PHASE3	COMPLETED	Optimal Platelet Dose Strategy for Management of Thrombocytopenia
NCT00151866	PHASE3	COMPLETED	Efficacy of Transfusions With Platelets Stored in Platelet Additive Solution II Versus Plasma
NCT00261924	PHASE3	COMPLETED	Efficacy and Safety Study of Platelets Treated for Pathogen Inactivation and Stored for Up to Seven Days
NCT00415532	PHASE3	COMPLETED	Romiplostim (AMG 531) Versus Medical Standard of Care for Immune (Idiopathic) Thrombocytopenic Purpura
NCT00420914	PHASE3	TERMINATED	Strategies for Transfusion of Platelets (SToP)
NCT00501345	PHASE3	TERMINATED	Aspirin in Patients With Myocardial Infarction and Thrombocytopenia
NCT00508820	PHASE3	COMPLETED	An Open Label Study of Romiplostim in Adult Thrombocytopenic Subjects With ITP
NCT00678587	PHASE3	TERMINATED	Eltrombopag To Reduce The Need For Platelet Transfusion In Subjects With Chronic Liver Disease And Thrombocytopenia Undergoing Elective Invasive Procedures
NCT01438840	PHASE3	COMPLETED	Efficacy and Safety of Oral E5501 Plus Standard of Care for the Treatment of Thrombocytopenia in Adults With Chronic Immune Thrombocytopenia (Amendment 02)
NCT01444417	PHASE3	COMPLETED	Safety and Efficacy Study of Romiplostim to Treat Immune Thrombocytopenia (ITP) in Pediatric Patients
NCT01805648	PHASE3	UNKNOWN	Efficacy and Safety Study of Maintenance Treatment With rhTPO in Thrombocytopenic Subjects With ITP
NCT02244658	PHASE3	UNKNOWN	Recombinant Human Thrombopoietin (rhTPO) in Management of Chemotherapy-induced Thrombocytopenia in Acute Myelocytic Leukemia
NCT02389621	PHASE3	COMPLETED	Safety and Efficacy Study of Lusutrombopag for Thrombocytopenia in Patients With Chronic Liver Disease Undergoing Elective Invasive Procedures
NCT02444728	PHASE3	TERMINATED	Cyclophosphamide and Hydroxychloroquine for Thrombocytopenia in SLE
NCT02487563	PHASE3	COMPLETED	Prospective Study of Patients With Thrombocytopenia Following HSCT
NCT02578901	PHASE3	COMPLETED	American Trial Using Tranexamic Acid in Thrombocytopenia
NCT03326843	PHASE3	TERMINATED	Avatrombopag for the Treatment of Thrombocytopenia in Adults Scheduled for a Surgical Procedure
NCT03515096	PHASE3	COMPLETED	Eltrombopag vs. rhTPO to Increase Platelet Level After HSCT
NCT05563064	PHASE3	UNKNOWN	Effect of Herbal Formulation on Thrombocytes Count
NCT07442513	PHASE3	RECRUITING	Comparison of Etamsylate Versus Placebo to Prevent Bleeding in HSCT