Affinage

ETV6

Transcription factor ETV6 · UniProt P41212

Length
452 aa
Mass
53.0 kDa
Annotated
2026-06-09
100 papers in source corpus 37 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ETV6 (TEL) is a nuclear ETS-family transcriptional repressor that controls bone marrow hematopoiesis and myeloid/dendritic cell fate, and acts as a tumor suppressor frequently subverted by oncogenic chromosomal translocations (PMID:9018121, PMID:9694803, PMID:10514502). It binds classical GGAA-containing ETS sites as a sequence-specific repressor whose activity depends on self-association through its PNT (pointed/SAM/HLH) oligomerization domain; loss or monomerization of this domain abolishes repression, while heterologous oligomerization domains restore it (PMID:10514502). DNA binding is autoinhibited by a C-terminal inhibitory domain (CID) whose two marginally stable helices (H4/H5), resolved by NMR, sterically block the ETS interface and reduce DNA affinity, while PNT-mediated cooperative, polymer-like binding to tandem ETS sites compensates for this autoinhibition (PMID:20400516, PMID:22584210). ETV6 represses transcription by recruiting corepressor machinery — mSin3A via the PNT domain, N-CoR/SMRT via the central region, and HDAC3 directly via a central repression domain (aa 268-303) — driving histone deacetylation at target loci (PMID:10490596, PMID:10544023, PMID:11439334); direct targets include Bcl-XL, CLIC5, MAFB, and GGAA-microsatellite enhancers (PMID:12960174, PMID:27540136, PMID:36543959, PMID:36350827). It additionally represses STAT3 through direct protein-protein contact independent of DNA binding, forming a negative feedback loop (PMID:15229229). Repressor activity is tuned by p38-MAPK phosphorylation at Ser22/Ser257, by SUMOylation through UBC9 (directing it to nuclear TEL bodies), and by Fbl6-mediated ubiquitination and proteasomal degradation of SUMOylated monomers (PMID:12435397, PMID:10377438, PMID:11078523, PMID:18426905). ETV6 is selectively required for adult HSC survival and bone marrow colonization, megakaryocyte maturation, and the monocyte-to-dendritic cell and cDC1 differentiation programs, where it directly represses MAFB and interferon-stimulated genes (PMID:15371326, PMID:9694803, PMID:36543959, PMID:30087163). Germline missense variants that abrogate DNA binding, cause nuclear/cytoplasmic mislocalization, or impair repression while retaining dimerization act dominant-negatively to cause inherited thrombocytopenia and leukemia/ALL predisposition (PMID:25581430, PMID:26102509, PMID:32693409). In cancer, ETV6's PNT domain fuses to and constitutively activates partner kinases (JAK family, NTRK3) by ligand-independent oligomerization, driving STAT5, Ras-MEK-ERK, PI3K-Akt, and IGF1R/IRS1 signaling (PMID:9360930, PMID:10845925, PMID:10702799, PMID:10706877, PMID:11751416, PMID:21804605), whereas ETS-domain-retaining fusions such as ETV6-RUNX1 co-opt mSin3A/HDAC complexes to repress RUNX1-motif enhancers and B-cell super-enhancers, and ETV6 loss permits EWS-FLI1 or ERG to hyperactivate GGAA-repeat elements (PMID:10490596, PMID:10544023, PMID:27620872, PMID:36658219, PMID:36350827).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1997 Medium

    Establishing that ETV6 is a nuclear, sequence-specific DNA-binding phosphoprotein defined its identity as a candidate ETS transcription factor rather than a cytoplasmic effector.

    Evidence Western blot, immunofluorescence, and DNA-binding assays of two translation-initiation isoforms

    PMID:9018121

    Open questions at the time
    • Did not define target genes or whether ETV6 activates or represses
    • Functional consequence of the two isoforms unresolved
  2. 1997 High

    Discovery that the t(9;12) fusion joins the ETV6 oligomerization domain to JAK2 to produce constitutive kinase activity revealed how ETV6 self-association can be hijacked to drive ligand-independent proliferation.

    Evidence Biochemical kinase assays and cytokine-independent Ba/F3 proliferation, with later transgenic confirmation

    PMID:10845925 PMID:9360930

    Open questions at the time
    • Downstream effectors not yet defined at this stage
    • Did not address ETV6's normal repressor function
  3. 1998 High

    Identification of ETV6-NTRK3 in fibrosarcoma and mesoblastic nephroma, and demonstration that ETV6 is required specifically for bone marrow hematopoiesis, established ETV6 both as a recurrent fusion partner and an essential hematopoietic regulator.

    Evidence Breakpoint cloning/RT-PCR/FISH in tumors; ES cell chimera gene targeting with multi-tissue hematopoietic analysis

    PMID:9462753 PMID:9694803 PMID:9823307

    Open questions at the time
    • Mechanism by which ETV6 supports bone marrow but not yolk sac/fetal liver hematopoiesis unresolved
    • Target genes in HSCs not identified
  4. 1999 High

    Domain dissection showed ETV6 is a transcriptional repressor whose activity requires oligomerization and which recruits corepressors, defining the core repression mechanism.

    Evidence Reporter/GAL4 fusion assays with deletion mutagenesis; reciprocal Co-IP mapping mSin3A to the PNT domain and SMRT/mSin3A to the central region

    PMID:10490596 PMID:10514502 PMID:10544023 PMID:9050885

    Open questions at the time
    • Corepressor-independent HLH repression mechanism not mechanistically explained
    • Endogenous target promoters largely unknown
  5. 1999 Medium

    Identification of UBC9 binding to the PNT domain linked ETV6 repressor activity to post-translational modification machinery without invoking degradation.

    Evidence Two-hybrid/co-expression, in vitro binding, GAL4 reporter assays with UBC9 mutagenesis

    PMID:10377438

    Open questions at the time
    • At this point SUMO conjugation itself was not yet demonstrated
    • Single lab
  6. 2000 High

    Demonstrating SUMO-1 modification of ETV6 and its localization to cell-cycle TEL bodies, and that ETV6-NTRK3 transforms via HLH-mediated dimerization with specific kinase signaling, connected modification, localization, and oncogenic dimerization.

    Evidence In vivo SUMOylation, confocal imaging; transformation assays with deletion/point mutagenesis and PLCγ effector mapping; TEL-JAK STAT5 dominant-negative epistasis

    PMID:10702799 PMID:10706877 PMID:11078523

    Open questions at the time
    • Functional role of TEL body localization for repression unresolved
    • SUMOylation consequence for stability not yet defined
  7. 2001 High

    Mapping direct HDAC3 recruitment to the central domain and demonstrating chromatin hypoacetylation at target sites established the enzymatic basis of ETV6-mediated repression.

    Evidence Co-IP, ChIP, TSA inhibitor treatment, and reporter assays on the stromelysin-1 promoter

    PMID:11439334

    Open questions at the time
    • Relative contributions of HDAC3 vs mSin3A/N-CoR to individual targets unresolved
  8. 2002 Medium

    Identification of p38-MAPK phosphorylation at Ser22/Ser257 that reduces repression placed ETV6 activity under signaling control.

    Evidence In vitro/in vivo phosphorylation, Co-IP with p38, phospho-site mutagenesis, reporter assays

    PMID:12435397

    Open questions at the time
    • Physiological stimulus driving p38-ETV6 phosphorylation unclear
    • Mechanism by which phosphorylation reduces repression not defined
  9. 2003 Medium

    Demonstrating direct DNA-binding-dependent repression of Bcl-XL and apoptosis induction provided a concrete pro-apoptotic target consistent with tumor-suppressor function.

    Evidence Apoptosis assays, reporter assays, RT-PCR/Western with DNA-binding domain deletion in NIH3T3

    PMID:12960174

    Open questions at the time
    • Relevance to hematopoietic cells not tested
    • Single lab/single cell type
  10. 2004 Medium

    Discovery that ETV6 represses STAT3 by direct protein-protein recruitment independent of DNA binding, and that ETV6-AML1 acts dominant-negatively over wild-type ETV6, expanded ETV6's repressive repertoire and clarified fusion pathogenicity.

    Evidence siRNA/overexpression, Co-IP, reporter assays, microarray; Co-IP and transformation assays for ETV6-AML1/ETV6 dimerization

    PMID:15229229 PMID:15325275

    Open questions at the time
    • DNA-binding-independent recruitment surface on ETV6 not mapped
    • In vivo relevance of STAT3 feedback unresolved
  11. 2004 High

    Conditional knockout established that ETV6 is selectively required for adult HSC survival and megakaryocyte maturation, refining its essential role beyond embryonic colonization.

    Evidence Conditional gene knockout in mouse with flow cytometry and bone marrow lineage analysis

    PMID:15371326

    Open questions at the time
    • Direct ETV6 target genes mediating HSC survival not identified
  12. 2008 Medium

    Identifying Fbl6 as an F-box protein that ubiquitinates SUMOylated ETV6 monomers for proteasomal degradation defined how ETV6 abundance is controlled and linked SUMOylation to turnover.

    Evidence Co-IP, ubiquitination assays, proteasome inhibition, SAM-domain mutagenesis; conserved with Drosophila Yan

    PMID:18426905

    Open questions at the time
    • Signals controlling Fbl6 engagement unknown
    • Single lab
  13. 2010 High

    Biophysical characterization showed ETV6 DNA binding is autoinhibited by a C-terminal inhibitory domain and rescued by PNT-mediated cooperative polymer binding, explaining how oligomerization governs occupancy.

    Evidence Quantitative equilibrium DNA-binding assays, deletion analysis, CID mutagenesis (E431A/E434A), trypsin sensitivity

    PMID:20400516

    Open questions at the time
    • Genome-wide consequences of cooperative binding not yet shown
    • Regulation of autoinhibition in cells unresolved
  14. 2010 Medium

    Demonstrating ETV6-RUNX1 directly represses miR-494/miR-320a to sustain survivin tied fusion repression to an anti-apoptotic survival program.

    Evidence siRNA, miRNA microarray, ChIP, luciferase reporter, Western

    PMID:20807887

    Open questions at the time
    • Contribution relative to other ETV6-RUNX1 targets unclear
    • Single lab
  15. 2011 High

    Showing ETV6-NTRK3 transformation requires an EN/IRS1/IGF1R tripartite complex and that ERK and PI3K-Akt pathways act synergistically defined the membrane-proximal signaling circuitry of this fusion.

    Evidence Co-IP, IF co-localization, IGF1R Y950 mutagenesis, pharmacological inhibition, soft agar/tumor assays; pathway inhibitor studies with Western readouts

    PMID:11751416 PMID:21804605

    Open questions at the time
    • How a nuclear-derived fusion accesses plasma-membrane IGF1R not fully resolved
  16. 2012 High

    NMR determination of the CID structure resolved the autoinhibition mechanism at atomic resolution, showing marginally stable helices that sterically block the ETS interface.

    Evidence NMR structure determination, amide hydrogen exchange, 15N relaxation

    PMID:22584210

    Open questions at the time
    • How CID disengages upon cooperative binding not directly visualized
  17. 2015 High

    Identification of germline ETS- and linker-domain missense mutations that abrogate DNA binding, mislocalize the protein, and impair repression in a dominant-negative manner established ETV6 as a Mendelian thrombocytopenia/leukemia-predisposition gene.

    Evidence Germline sequencing with DNA-binding, repression, localization, and hematopoiesis assays; independent replication

    PMID:25581430 PMID:26102509

    Open questions at the time
    • Mechanism linking ETV6 loss to thrombocytopenia versus leukemia not separated
    • Affected target genes in patient cells not defined
  18. 2016 High

    Identification of CLIC5 as a direct ETV6 target connecting its loss to oxidative-stress apoptosis resistance, plus genome-wide ETV6-RUNX1 repression of RUNX1-motif enhancers and B-cell super-enhancers, mapped the chromatin-level consequences of ETV6 dysfunction.

    Evidence ChIP/transcriptome/apoptosis assays for CLIC5; GRO-seq, ChIP-seq, and Runt-domain mutagenesis for ETV6-RUNX1

    PMID:27540136 PMID:27620872

    Open questions at the time
    • Direct demonstration that ETV6-RUNX1 repression initiates leukemogenesis in vivo not provided here
  19. 2018 High

    Conditional knockout showed ETV6 is required for cDC1 functional differentiation and CD8+ T cell cross-priming, extending its role into dendritic cell biology and antitumor immunity.

    Evidence Conditional KO, flow cytometry, ATAC-seq, in vivo cross-priming and tumor models

    PMID:30087163

    Open questions at the time
    • Direct cDC1 target genes only partially defined
  20. 2022 High

    Demonstrating that ETV6 (with ETV3) drives monocyte-to-DC fate by directly repressing MAFB and interferon-stimulated genes, and that ETV6-NCOA2 recruits p300 to derepress ETV6 targets, clarified lineage-specifying repression and a gain-of-function fusion mechanism.

    Evidence Conditional KO, ChIP at the MAFB locus, EAE model; Co-IP and bone marrow/xenograft models for ETV6-NCOA2

    PMID:34624096 PMID:36543959

    Open questions at the time
    • ETV6-NCOA2 mechanism rests on single-lab Co-IP for complex composition
    • Interplay between ISG repression and DC differentiation not fully resolved
  21. 2023 High

    Showing ETV6 competes with EWS-FLI1 and ERG at GGAA microsatellite/repeat enhancers established a unifying mechanism in which ETV6 loss licenses oncogenic ETS factors to hyperactivate repeat cis-elements.

    Evidence CRISPR domain screen, biochemical competition, ChIP-seq/CUT&RUN, dominant-interfering peptide and in vivo models (Ewing sarcoma); ChIP-seq, ATAC-seq, rescue and ERG knockdown in B-ALL

    PMID:36350827 PMID:36658219

    Open questions at the time
    • Determinants of which GGAA elements ETV6 versus EWS-FLI1/ERG occupy not fully defined
  22. 2021 High

    Comprehensive functional profiling of 34 germline variants with ATAC-seq target identification consolidated the dominant-negative tumor-suppressor model and localized ETV6's genomic activity.

    Evidence Repression, DNA-binding, dimerization Co-IP, localization assays and ATAC-seq with genome/transcriptome sequencing

    PMID:32693409

    Open questions at the time
    • Genotype-phenotype correlation for leukemia risk not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ETV6 autoinhibition release, post-translational modification, and corepressor selection are integrated to choose specific target enhancers across HSC, megakaryocyte, and dendritic cell programs remains unresolved.
  • No unified model linking phosphorylation/SUMOylation/turnover to context-specific target selection
  • Structural basis of corepressor partner choice unknown
  • How germline ETV6 loss biases toward thrombocytopenia versus ALL undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 5 GO:0140110 transcription regulator activity 5 GO:0060089 molecular transducer activity 1
Localization
GO:0005634 nucleus 2 GO:0005654 nucleoplasm 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-162582 Signal Transduction 3 R-HSA-4839726 Chromatin organization 3
Partners
FBXL6HDAC3MAPK14 (P38)MSIN3ANCOR1/SMRTRUNX1STAT3UBC9
Complex memberships
N-CoR/SMRT-HDAC3 corepressor complexTEL bodies (SUMO-1 nuclear bodies)mSin3A corepressor complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 TEL (ETV6) proteins are nuclear phosphoproteins that bind specifically to classical ETS binding sites on DNA. Two isoforms (50 kDa and 57 kDa) are produced by translation initiation at two different in-frame ATGs, and both are subject to multiple phosphorylation events in vivo. Western blot, immunofluorescence, DNA binding assays, cDNA characterization Oncogene Medium 9018121
1997 The t(9;12)(p24;p13) translocation fuses the TEL oligomerization (PNT/pointed) domain to the catalytic domain of JAK2. TEL-induced oligomerization of the fusion protein results in constitutive tyrosine kinase activity and confers cytokine-independent proliferation to IL-3-dependent Ba/F3 cells. Biochemical kinase assays, Ba/F3 cell proliferation assay, characterization of fusion protein Science High 10845925 9360930
1998 ETV6-NTRK3 fusion encodes the HLH dimerization domain of ETV6 fused to the PTK domain of NTRK3, and this chimeric kinase is expressed in congenital fibrosarcoma and cellular congenital mesoblastic nephroma, establishing a histogenetic link between these tumors. RT-PCR, breakpoint cloning, FISH Nature genetics / Cancer research High 9462753 9823307
1999 TEL is a sequence-specific transcriptional repressor of ETS-binding site-driven promoters. Repression requires self-association via the oligomerization (PNT) domain — deletion of this domain or replacement with a monomeric ETS1 domain impairs repression, whereas substitution with unrelated oligomerization domains restores it. Two autonomous repression domains distinct from the oligomerization domain were identified. Reporter gene/transfection assays, deletion mutagenesis, GAL4 fusion assays Journal of Biological Chemistry High 10514502
1999 TEL-AML1 (ETV6-RUNX1) fusion protein binds the mSin3A corepressor via both the TEL pointed domain and the AML-1B portion. TEL/AML-1B associates with mSin3A more stably than either wild-type protein alone, and both the TEL and AML-1B mSin3-binding domains contribute to transcriptional repression by the fusion protein. Co-immunoprecipitation, GAL4 fusion reporter assays, deletion mutagenesis Molecular and Cellular Biology High 10490596 10544023
1999 The central region of TEL recruits a repression complex containing SMRT and mSin3A, while the HLH domain mediates transcriptional repression through a corepressor-independent mechanism. Co-immunoprecipitation, transcriptional reporter assays, domain mapping Biochemical and Biophysical Research Communications Medium 10544023
1999 UBC9, a ubiquitin-conjugating enzyme, physically interacts with TEL specifically through the HLH (pointed) domain. Coexpression of UBC9 restores promoter activity repressed by TEL, indicating that UBC9 modulates TEL transcriptional repression. This interaction does not lead to TEL degradation. In vivo interaction assay (two-hybrid/co-expression), in vitro binding, GAL4 reporter assays, targeted mutagenesis of UBC9 PNAS Medium 10377438
1999 ETV6 (TEL) and the ETV6/CBFA2 (TEL-AML1) fusion protein inhibit activation of the MCSFR proximal promoter by CBFA2B and C/EBPα; this inhibition requires both the ETS DNA-binding domain and the HLH domain of ETV6, and depends on binding of both CBFA2B and C/EBPα to their respective sites. Reporter gene/luciferase assays, deletion and mutational analysis of promoter and protein constructs PNAS Medium 9050885
2000 TEL/ETV6 is SUMOylated via its interaction with UBC9; the SUMO-1-modified TEL localizes to cell-cycle-specific nuclear bodies (TEL bodies). The leukemia-associated TEL/AML1 fusion protein is also SUMOylated and localizes to TEL bodies in a pattern distinct from AML1, suggesting that SUMO-1 modification causes aberrant localization of the fusion protein. In vivo SUMOylation assay, co-immunoprecipitation, immunofluorescence/confocal microscopy PNAS Medium 11078523
2000 ETV6-NTRK3 fusion protein homodimerizes and heterodimerizes with wild-type ETV6 via its HLH domain, has constitutive PTK activity and autophosphorylation, and transforms NIH3T3 cells. Deletion of the ETV6 HLH domain abolishes dimerization and transformation; mutation of the ATP-binding site abolishes kinase activity and transformation; mutation of NTRK3 activation-loop tyrosines reduces transformation. Only PLCγ (not other NTRK3 effectors) associated with ETV6-NTRK3. Co-immunoprecipitation, in vitro kinase assay, NIH3T3 transformation/soft agar/SCID mouse assay, deletion and point mutagenesis Oncogene High 10702799
2000 TEL-JAK fusion proteins containing the TEL oligomerization domain fused to the kinase domains of JAK1, JAK2, JAK3, or TYK2 all confer cytokine-independent growth to Ba/F3 cells. STAT5 is the primary activated STAT in TEL-JAK1 and TEL-JAK2 cells; expression of dominant-negative STAT5A abrogates TEL-JAK2-mediated growth factor independence, establishing STAT5 as a required effector. Ba/F3 transformation assay, EMSA, dominant-negative expression, target gene expression analysis Blood High 10706877
2001 TEL associates with HDAC3 (histone deacetylase-3) directly via its central repression domain (aa 268-303), independently of N-CoR binding. TEL also binds mSin3A via its pointed domain and N-CoR via the central domain. HDAC inhibition by trichostatin A impairs TEL-dependent repression of the stromelysin-1 promoter and reverses TEL-induced cellular aggregation; histone H3 is under-acetylated near TEL-binding sites in the stromelysin-1 promoter when TEL is expressed. Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), TSA inhibitor treatment, transcriptional reporter assays, deletion mapping Oncogene High 11439334
2001 ETV6-NTRK3 transformation of NIH3T3 fibroblasts requires both the Ras-Raf1-Mek1-Erk1/2 pathway and the PI3K-Akt pathway, acting synergistically; inhibition of either pathway alone almost completely abolishes soft agar colony formation. ETV6-NTRK3 expression leads to constitutive activation of Mek1 and Akt and elevated cyclin D1. Pharmacological pathway inhibition, soft agar colony formation assay, Western blot for pathway activation Cancer Research Medium 11751416
2002 TEL is phosphorylated in vivo by p38 MAP kinase (but not JNK1) at Ser22 (constitutive) and Ser257 (inducible). TEL binds p38 and is directly phosphorylated by p38 in vitro. p38-dependent phosphorylation reduces TEL's transcriptional repression activity. In vivo and in vitro phosphorylation assays, co-immunoprecipitation with p38, site-directed mutagenesis of phosphorylation sites, transcriptional reporter assays Biochemical and Biophysical Research Communications Medium 12435397
2003 TEL expression induces apoptosis in serum-starved NIH3T3 cells and directly represses the Bcl-XL promoter in a DNA-binding-dependent manner, reducing endogenous Bcl-XL mRNA and protein. Deletion of the TEL DNA-binding domain abolishes apoptosis induction. Apoptosis assays, reporter gene assays, Western blot, RT-PCR, deletion mutagenesis Journal of Biological Chemistry Medium 12960174
2004 TEL/ETV6 functions as a repressor of STAT3 transcriptional activity; Stat3-induced TEL expression creates a negative feedback loop. TEL repression of Stat3 does not require TEL DNA binding and proceeds via direct protein-protein recruitment of TEL to STAT3. siRNA knockdown, overexpression, co-immunoprecipitation, transcriptional reporter assays, microarray Journal of Biological Chemistry Medium 15229229
2004 TEL/AML1 associates with wild-type TEL via the HLH domain, inhibiting wild-type TEL-induced transcriptional repression and growth suppression in a dominant-negative manner. TEL/AML1 also inhibits wild-type AML1-mediated transforming activity. Co-immunoprecipitation, transcriptional reporter assays, NIH3T3 transformation assay Biochemical and Biophysical Research Communications Medium 15325275
2004 Tel/Etv6 is selectively required for hematopoietic stem cell (HSC) survival in adult bone marrow. Conditional inactivation of Tel/Etv6 causes loss of adult HSCs while committed progenitors and mature blood cells are transiently maintained; megakaryocyte maturation is also impaired. Conditional gene knockout (mouse), flow cytometry, bone marrow analysis Genes & Development High 15371326
2008 Downregulation/degradation of TEL (ETV6) is facilitated by Fbl6, an F-box protein that binds to TEL via its SAM (PNT) domain, promotes TEL ubiquitination, and leads to proteasomal degradation. This mechanism is evolutionarily conserved with Drosophila Yan/Fbl6. Sumoylation of TEL monomers (but not oligomers) sensitizes TEL for Fbl6-mediated proteasomal degradation. Co-immunoprecipitation, ubiquitination assays, proteasome inhibitor treatment, SAM domain mutagenesis Molecular and Cellular Biology Medium 18426905
2009 CBFβ interaction with the Runt domain of AML1 in TEL-AML1 is essential for the fusion protein's ability to promote self-renewal of B cell precursors in vitro; Runt domain mutations that disrupt CBFβ heterodimerization (without affecting DNA binding) abolish this activity. Site-directed mutagenesis, in vitro B-cell progenitor self-renewal assay, bone marrow transplantation Blood Medium 19179469
2010 TEL/ETV6 DNA binding is subject to autoinhibition by a C-terminal inhibitory domain (CID) that reduces DNA affinity ~10-fold. The PNT domain enables cooperative, polymer-mediated binding to tandem ETS sites, compensating for the autoinhibition. Mutation of conserved glutamic acids (E431A/E434A) in the CID activates DNA binding. Quantitative DNA binding assays (equilibrium binding), deletion analysis, site-directed mutagenesis, trypsin sensitivity assay Journal of Biological Chemistry High 20400516
2010 TEL-AML1 represses miRNA-494 and miRNA-320a; these miRNAs target survivin. TEL-AML1 silencing upregulates miRNA-494 and miRNA-320a, reducing survivin expression and inducing apoptosis. Chromatin immunoprecipitation confirmed miRNA-494 as a direct transcriptional target of the TEL-AML1 fusion protein. RNAi (siRNA), miRNA microarray, ChIP, luciferase reporter assay, Western blot Blood Medium 20807887
2011 ETV6-NTRK3 (EN) transformation requires a tripartite complex of EN, IRS1, and IGF1R. EN colocalizes with IGF1R at the plasma membrane; both IGF1R kinase activity and the Y950 IRS1-docking site of IGF1R are required for EN oncogenesis. Blocking IGF1R/INSR kinase activity disrupts the EN/IRS1/IGF1R complex and EN membrane localization. Co-immunoprecipitation, immunofluorescence co-localization, mutagenesis (IGF1R Y950), pharmacological inhibition (BMS-536924), soft agar/tumor assays Oncogene High 21804605
2012 NMR spectroscopy established that the C-terminal inhibitory domain (CID) of ETV6 contains two helices (H4 and H5) that sterically block the DNA-binding interface of the ETS domain. The CID helices are only marginally stable, facilitating a conformational change required for DNA binding. The CID also dampens millisecond timescale motions of the ETS domain. NMR spectroscopy (structure determination), amide hydrogen exchange, 15N relaxation measurements Journal of Molecular Biology High 22584210
2015 Germline missense mutations in ETV6 (p.Arg369Gln, p.Arg399Cys in the ETS domain; p.Pro214Leu in the internal linker domain) abrogate DNA binding, alter subcellular localization (cytoplasmic mislocalization), decrease transcriptional repression in a dominant-negative fashion, and impair hematopoiesis. Functional transcriptional repression assays, DNA binding assays, subcellular localization (immunofluorescence), hematopoiesis assays, germline sequencing Nature Genetics High 25581430 26102509
2015 Germline ETV6 mutations (p.L349P in the ETS domain; p.N385fs) cause impaired nuclear localization of the ETV6 protein; these mutants show significantly reduced ability to regulate transcription of ETV6 target genes. Immunofluorescence (subcellular localization), transcriptional target gene analysis, protein expression analysis PLoS Genetics Medium 26102509
2016 ETV6-RUNX1 fusion represses RUNX1-motif-containing enhancers genome-wide and suppresses multiple super-enhancers of the CD19+/CD20+ B-cell lineage, leading to downregulation of B-cell signaling and adhesion genes. This repression depends on the wild-type DNA-binding Runt domain of RUNX1 in the fusion. GRO-seq (global run-on sequencing), ChIP-seq, mutagenesis (Runt domain DNA-binding mutant), gene expression analysis Genome Research High 27620872
2021 Germline ETV6 variants causing ALL predisposition impair transcription repressor activity, abolish DNA binding, or alter nuclear localization. Missense variants retain dimerization with wild-type ETV6, producing dominant-negative effects. ATAC-seq identified specific genomic loci where ETV6's tumor suppressor activity is exerted. Transcriptional repression assays, DNA binding assays, co-immunoprecipitation (dimerization), subcellular localization, ATAC-seq, whole-genome/transcriptome sequencing Blood High 32693409
2022 ETV6 and ETV3 enable monocyte differentiation into dendritic cells (mo-DCs) by directly repressing MAFB expression, thereby suppressing macrophage fate commitment. ETV6 also inhibits IFN-stimulated genes in monocytes. Mice deficient for Etv6 in monocytes have spontaneous IFN-stimulated gene expression and impaired mo-DC differentiation during inflammation. Conditional knockout mouse, flow cytometry, ChIP (direct binding to MAFB locus), gene expression analysis, EAE disease model Nature Immunology High 36543959
2023 ETV6 competes with EWS-FLI1 for binding to GGAA repeat-containing DNA elements. Loss of ETV6 allows EWS-FLI1 to hyper-activate these cis-elements, promoting mesenchymal differentiation with SOX11 as a key downstream target. A dominant-interfering ETV6 peptide phenocopies ETV6 inactivation and suppresses Ewing sarcoma growth in vivo. CRISPR domain-focused screen, biochemical binding assays, ChIP-seq/epigenomics, dominant-interfering peptide, in vivo tumor model Nature Cell Biology High 36658219
2023 In ETV6-deficient B-ALL cells, ETV6 directly binds to GGAA microsatellite enhancers and represses their histone acetylation and the expression of adjacent genes including EPOR; the ETS transcription factor ERG occupies these enhancers when ETV6 is absent and is required for sustained activation of repeat enhancer-activated genes. ChIP-seq, ATAC-seq, CUT&RUN, functional rescue (ETV6 restoration), shRNA knockdown of ERG, gene expression analysis Blood Cancer Discovery High 36350827
2022 ETV6-NCOA2 fusion forms a transcriptional complex with ETV6 and the histone acetyltransferase p300, leading to derepression of ETV6 target genes. This mechanism drives aberrant transcriptional dysregulation that activates a lymphoid program while failing to repress myeloid gene expression (e.g., CSF1, MEF2C), causing T/myeloid mixed-phenotype leukemia. Co-immunoprecipitation, gene expression analysis, bone marrow transduction/transplantation mouse model, human cord blood xenograft model Blood Medium 34624096
2016 ETV6 directly represses the CLIC5 gene by binding its promoter/regulatory region; loss of ETV6 leads to CLIC5 overexpression, which in turn increases resistance to hydrogen peroxide-induced apoptosis through lysosomal-mediated cell death pathways involving the transferrin receptor. ChIP, transcriptome analysis, overexpression cell lines, apoptosis assays, co-localization imaging Haematologica Medium 27540136
2018 Transcription factor Etv6 is required for the functional differentiation of cross-presenting cDC1 dendritic cells. Deletion of Etv6 in bone marrow abolishes CD8α expression on cDC1 in vivo, impairs cDC1-specific and cDC1 chromatin signatures, causes aberrant upregulation of pDC-specific signatures, impairs CD8+ T cell cross-priming, and reduces tumor antigen-specific CD8+ T cell generation. Conditional knockout mouse, flow cytometry, gene expression profiling, ATAC-seq, in vivo T cell cross-priming assay, tumor model Journal of Experimental Medicine High 30087163
1998 TEL (ETV6) is required for the establishment of hematopoiesis of all lineages specifically in the bone marrow. TEL-/- ES cell chimeras show normal hematopoiesis in yolk sac and fetal liver, but fail to establish hematopoiesis in bone marrow in the first postnatal week, demonstrating TEL as the first transcription factor required specifically for bone marrow hematopoiesis. Gene targeting, ES cell chimera generation, hematopoietic analysis of multiple tissues Genes & Development High 9694803

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer cell 693 12450792
1997 A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia. Science (New York, N.Y.) 661 9360930
1998 A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nature genetics 629 9462753
1998 ETV6-NTRK3 gene fusions and trisomy 11 establish a histogenetic link between mesoblastic nephroma and congenital fibrosarcoma. Cancer research 297 9823307
2008 Initiating and cancer-propagating cells in TEL-AML1-associated childhood leukemia. Science (New York, N.Y.) 295 18202291
2015 Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy. Nature genetics 284 25581430
2012 The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity. Nature 284 23103865
1996 TEL/AML-1 dimerizes and is associated with a favorable outcome in childhood acute lymphoblastic leukemia. Blood 263 8943861
2004 Tel/Etv6 is an essential and selective regulator of adult hematopoietic stem cell survival. Genes & development 224 15371326
1998 The TEL/ETV6 gene is required specifically for hematopoiesis in the bone marrow. Genes & development 220 9694803
2011 ETV6 mutations in early immature human T cell leukemias. The Journal of experimental medicine 170 22162831
2012 ETV6 fusion genes in hematological malignancies: a review. Leukemia research 158 22578774
2016 Transcriptome sequencing identifies ETV6-NTRK3 as a gene fusion involved in GIST. The Journal of pathology 157 26606880
2005 ETV6: a versatile player in leukemogenesis. Seminars in cancer biology 157 15826831
1999 TEL is a sequence-specific transcriptional repressor. The Journal of biological chemistry 147 10514502
1999 Both TEL and AML-1 contribute repression domains to the t(12;21) fusion protein. Molecular and cellular biology 132 10490596
1999 The leukemia-associated gene TEL encodes a transcription repressor which associates with SMRT and mSin3A. Biochemical and biophysical research communications 125 10544023
2015 Germline ETV6 Mutations Confer Susceptibility to Acute Lymphoblastic Leukemia and Thrombocytopenia. PLoS genetics 122 26102509
2000 Transforming properties of chimeric TEL-JAK proteins in Ba/F3 cells. Blood 117 10706877
2005 ETV6-NTRK3: a chimeric protein tyrosine kinase with transformation activity in multiple cell lineages. Seminars in cancer biology 116 15826836
2000 The ETV6-NTRK3 gene fusion encodes a chimeric protein tyrosine kinase that transforms NIH3T3 cells. Oncogene 110 10702799
2001 The chimeric protein tyrosine kinase ETV6-NTRK3 requires both Ras-Erk1/2 and PI3-kinase-Akt signaling for fibroblast transformation. Cancer research 103 11751416
2000 TEL-JAK2 transgenic mice develop T-cell leukemia. Blood 103 10845925
2000 Posttranslational modification of TEL and TEL/AML1 by SUMO-1 and cell-cycle-dependent assembly into nuclear bodies. Proceedings of the National Academy of Sciences of the United States of America 99 11078523
1997 The TEL gene products: nuclear phosphoproteins with DNA binding properties. Oncogene 99 9018121
2017 ETV6 in hematopoiesis and leukemia predisposition. Seminars in hematology 98 28637624
1999 The role of TEL fusion genes in pediatric leukemias. Leukemia 97 10049061
2001 TEL contacts multiple co-repressors and specifically associates with histone deacetylase-3. Oncogene 89 11439334
2018 Novel gene fusions in secretory carcinoma of the salivary glands: enlarging the ETV6 family. Human pathology 85 30130630
2016 Characterization of leukemias with ETV6-ABL1 fusion. Haematologica 77 27229714
2017 Infection Exposure Promotes ETV6-RUNX1 Precursor B-cell Leukemia via Impaired H3K4 Demethylases. Cancer research 76 28630052
1999 Modulation of TEL transcription activity by interaction with the ubiquitin-conjugating enzyme UBC9. Proceedings of the National Academy of Sciences of the United States of America 75 10377438
2005 Defining the oncogenic function of the TEL/AML1 (ETV6/RUNX1) fusion protein in a mouse model. Oncogene 74 16044150
1999 Structure and possible mechanisms of TEL-AML1 gene fusions in childhood acute lymphoblastic leukemia. Cancer research 69 10463610
2001 Breakage and fusion of the TEL (ETV6) gene in immature B lymphocytes induced by apoptogenic signals. Blood 67 11157492
2019 ETV6-related thrombocytopenia and leukemia predisposition. Blood 64 31248877
2010 TEL-AML1 regulation of survivin and apoptosis via miRNA-494 and miRNA-320a. Blood 64 20807887
2021 Molecular basis of ETV6-mediated predisposition to childhood acute lymphoblastic leukemia. Blood 62 32693409
1997 Functional characterization of ETV6 and ETV6/CBFA2 in the regulation of the MCSFR proximal promoter. Proceedings of the National Academy of Sciences of the United States of America 61 9050885
1996 TEL-AML1 translocations with TEL and CDKN2 inactivation in acute lymphoblastic leukemia cell lines. Blood 58 8704231
2017 Pathogenesis of ETV6/RUNX1-positive childhood acute lymphoblastic leukemia and mechanisms underlying its relapse. Oncotarget 57 28418909
2010 DNA binding by the ETS protein TEL (ETV6) is regulated by autoinhibition and self-association. The Journal of biological chemistry 57 20400516
2004 Stable expression of small interfering RNA sensitizes TEL-PDGFbetaR to inhibition with imatinib or rapamycin. The Journal of clinical investigation 54 15199413
2000 TEL/PDGFbetaR fusion protein activates STAT1 and STAT5: a common mechanism for transformation by tyrosine kinase fusion proteins. Experimental hematology 53 10812249
1997 12p abnormalities and the TEL gene (ETV6) in childhood acute lymphoblastic leukemia. Blood 51 9373267
2015 Congenital mesoblastic nephroma: a study of 19 cases using immunohistochemistry and ETV6-NTRK3 fusion gene rearrangement. Pathology 50 27020209
2006 Expression of ETV6-NTRK in classical, cellular and mixed subtypes of congenital mesoblastic nephroma. Histopathology 50 16681692
2000 t(7;12)(q36;p13), a new recurrent translocation involving ETV6 in infant leukemia. Genes, chromosomes & cancer 49 11066076
2022 ETV3 and ETV6 enable monocyte differentiation into dendritic cells by repressing macrophage fate commitment. Nature immunology 48 36543959
2014 Clonal origins of ETV6-RUNX1⁺ acute lymphoblastic leukemia: studies in monozygotic twins. Leukemia 48 25388957
2010 ETV6-NTRK3-mediated breast epithelial cell transformation is blocked by targeting the IGF1R signaling pathway. Cancer research 48 21148487
2017 ETV6-NTRK3 and STRN-ALK kinase fusions are recurrent events in papillary thyroid cancer of adult population. European journal of endocrinology 47 29046324
2009 CBFbeta is critical for AML1-ETO and TEL-AML1 activity. Blood 45 19179469
2000 Tel-2 is a novel transcriptional repressor related to the Ets factor Tel/ETV-6. The Journal of biological chemistry 45 11108721
2009 The fusion proteins TEL-PDGFRbeta and FIP1L1-PDGFRalpha escape ubiquitination and degradation. Haematologica 43 19644140
2004 TEL-Syk fusion constitutively activates PI3-K/Akt, MAPK and JAK2-independent STAT5 signal pathways. Leukemia 42 14749700
2023 ETV6 dependency in Ewing sarcoma by antagonism of EWS-FLI1-mediated enhancer activation. Nature cell biology 41 36658219
2013 ETV6/RUNX1 induces reactive oxygen species and drives the accumulation of DNA damage in B cells. Neoplasia (New York, N.Y.) 40 24339741
2002 The Tel-Abl (ETV6-Abl) tyrosine kinase, product of complex (9;12) translocations in human leukemia, induces distinct myeloproliferative disease in mice. Blood 40 12036890
1999 ETV6-AML1 translocation breakpoints cluster near a purine/pyrimidine repeat region in the ETV6 gene. Blood 39 9864173
2018 Transcription factor Etv6 regulates functional differentiation of cross-presenting classical dendritic cells. The Journal of experimental medicine 38 30087163
2018 FOXO1 and ETV6 genes may represent novel regulators of splicing factor expression in cellular senescence. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 37 30088951
1999 The Tel-PDGFRbeta fusion gene produces a chronic myeloproliferative syndrome in transgenic mice. Leukemia 37 10557054
2012 Detection of ETV6 gene rearrangements in adult acute lymphoblastic leukemia. Annals of hematology 36 22373549
2008 Downregulation of vertebrate Tel (ETV6) and Drosophila Yan is facilitated by an evolutionarily conserved mechanism of F-box-mediated ubiquitination. Molecular and cellular biology 35 18426905
1996 ETV6 gene rearrangements in hematopoietic malignant disorders. Leukemia & lymphoma 35 9031109
2006 Pre-TCR expression cooperates with TEL-JAK2 to transform immature thymocytes and induce T-cell leukemia. Blood 34 17192390
1998 Analysis of TEL proteins in human leukemias. Oncogene 34 9671410
2013 Blocking ETV6/RUNX1-induced MDM2 overexpression by Nutlin-3 reactivates p53 signaling in childhood leukemia. Leukemia 32 24240203
2012 Autoinhibition of ETV6 (TEL) DNA binding: appended helices sterically block the ETS domain. Journal of molecular biology 31 22584210
2004 TEL/AML1 shows dominant-negative effects over TEL as well as AML1. Biochemical and biophysical research communications 31 15325275
2001 The TEL-Jak2 oncoprotein induces Socs1 expression and altered cytokine response in Ba/F3 cells. Oncogene 31 11314018
2016 Genome-wide repression of eRNA and target gene loci by the ETV6-RUNX1 fusion in acute leukemia. Genome research 30 27620872
2008 Role of the erythropoietin receptor in ETV6/RUNX1-positive acute lymphoblastic leukemia. Clinical cancer research : an official journal of the American Association for Cancer Research 30 19010836
2003 TEL-AML1 fusion precedes differentiation to pre-B cells in childhood acute lymphoblastic leukemia. Leukemia research 29 12526921
2003 TEL, a putative tumor suppressor, induces apoptosis and represses transcription of Bcl-XL. The Journal of biological chemistry 29 12960174
2017 An activating mutation of GNB1 is associated with resistance to tyrosine kinase inhibitors in ETV6-ABL1-positive leukemia. Oncogene 28 28650474
2014 Haploinsufficiency of ETV6 and CDKN1B in patients with acute myeloid leukemia and complex karyotype. BMC genomics 28 25213837
2006 RNAi-mediated silencing of TEL/AML1 reveals a heat-shock protein- and survivin-dependent mechanism for survival. Blood 27 17095626
2021 The Second Oncogenic Hit Determines the Cell Fate of ETV6-RUNX1 Positive Leukemia. Frontiers in cell and developmental biology 26 34336858
2004 TEL/ETV6 is a signal transducer and activator of transcription 3 (Stat3)-induced repressor of Stat3 activity. The Journal of biological chemistry 26 15229229
2004 High incidence and unique features of antigen receptor gene rearrangements in TEL-AML1-positive leukemias. Leukemia 25 14574333
2002 Functional regulation of TEL by p38-induced phosphorylation. Biochemical and biophysical research communications 25 12435397
2012 Gene duplication within the Green Lineage: the case of TEL genes. Journal of experimental botany 24 22865910
2022 ETV6-NCOA2 fusion induces T/myeloid mixed-phenotype leukemia through transformation of nonthymic hematopoietic progenitor cells. Blood 23 34624096
2019 Germline deletion of ETV6 in familial acute lymphoblastic leukemia. Blood advances 23 30940639
2016 CLIC5: a novel ETV6 target gene in childhood acute lymphoblastic leukemia. Haematologica 23 27540136
2018 Acute myeloid leukemia carrying ETV6 mutations: biologic and clinical features. Hematology (Amsterdam, Netherlands) 21 29894279
2017 Mechanism of ETV6-RUNX1 Leukemia. Advances in experimental medicine and biology 21 28299659
2020 ETV6 gene aberrations in non-haematological malignancies: A review highlighting ETV6 associated fusion genes in solid tumors. Biochimica et biophysica acta. Reviews on cancer 20 32659251
2011 A tripartite complex composed of ETV6-NTRK3, IRS1 and IGF1R is required for ETV6-NTRK3-mediated membrane localization and transformation. Oncogene 20 21804605
2023 ETV6 Deficiency Unlocks ERG-Dependent Microsatellite Enhancers to Drive Aberrant Gene Activation in B-Lymphoblastic Leukemia. Blood cancer discovery 19 36350827
2019 The study of METTL3 and METTL14 expressions in childhood ETV6/RUNX1-positive acute lymphoblastic leukemia. Molecular genetics & genomic medicine 19 31429529
2017 Detection of a new heterozygous germline ETV6 mutation in a case with hyperdiploid acute lymphoblastic leukemia. European journal of haematology 19 29034503
1999 The oncogenic TEL/PDGFR beta fusion protein induces cell death through JNK/SAPK pathway. Oncogene 19 10445851
2024 ETV6::ACSL6 translocation-driven super-enhancer activation leads to eosinophilia in acute lymphoblastic leukemia through IL-3 overexpression. Haematologica 17 38356460
2020 A novel ETV6-miR-429-CRKL regulatory circuitry contributes to aggressiveness of hepatocellular carcinoma. Journal of experimental & clinical cancer research : CR 17 32326970
2018 Tel-eVax: a genetic vaccine targeting telomerase for treatment of canine lymphoma. Journal of translational medicine 17 30537967
2015 Determination of ETV6-RUNX1 genomic breakpoint by next-generation sequencing. Cancer medicine 17 26711002
2006 Identification of transcripts modulated by ETV6 expression. British journal of haematology 17 17069581

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