Affinage

ETV6

Transcription factor ETV6 · UniProt P41212

Length
452 aa
Mass
53.0 kDa
Annotated
2026-04-28
100 papers in source corpus 35 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ETV6 (TEL) is an ETS-family transcriptional repressor that governs hematopoietic stem cell engraftment, megakaryocyte maturation, and dendritic cell lineage commitment, and whose disruption by chromosomal translocation or germline mutation drives leukemia and solid tumor pathogenesis. ETV6 binds GGAA-containing DNA elements through an autoinhibited ETS domain regulated by marginally stable C-terminal helices (PMID:22584210), and represses target genes—including Bcl-XL, MAFB, and GGAA-microsatellite enhancers controlling EPOR—by recruiting mSin3A via its pointed/PNT domain and N-CoR/HDAC3 via a central repression domain (PMID:10490596, PMID:11439334, PMID:36350827). Its activity is modulated by p38-mediated phosphorylation at Ser22/Ser257, PIAS3-mediated sumoylation at K11 (which impairs DNA binding), and Fbl6-directed ubiquitin-proteasomal degradation of sumoylated monomers (PMID:12435397, PMID:18212042, PMID:18426905). Germline loss-of-function mutations in ETV6 cause dominant-negative cytoplasmic mislocalization and defective transcriptional repression, resulting in thrombocytopenia and predisposition to acute lymphoblastic leukemia, while the PNT domain's oligomerization capacity is co-opted by chromosomal translocations that constitutively activate partner kinases such as JAK2, NTRK3, and ABL1 (PMID:25581430, PMID:9360930, PMID:9462753).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1997 High

    Establishing TEL as a nuclear phosphoprotein ETS-family DNA-binding factor resolved the basic biochemical identity of the ETV6 gene product, showing it recognizes canonical ETS sites and exists as two phosphorylated isoforms.

    Evidence Western blot, immunofluorescence, and EMSA on murine TEL cDNA products

    PMID:9018121

    Open questions at the time
    • Phosphorylation sites and responsible kinases not identified
    • Endogenous target genes unknown
  2. 1998 High

    Discovery that the TEL pointed/HLH domain drives constitutive kinase activation when fused to JAK2 or NTRK3 established the general principle by which ETV6 translocations cause oncogenesis—oligomerization-dependent kinase autophosphorylation.

    Evidence Cloning of t(9;12) TEL-JAK2 and t(12;15) TEL-NTRK3 fusions, in vitro kinase assay, Ba/F3 cytokine-independence assay

    PMID:9360930 PMID:9462753

    Open questions at the time
    • Downstream signaling pathways not yet mapped for all fusions
    • Whether oligomerization suffices or additional PNT-domain functions contribute was unresolved
  3. 1998 High

    Knockout chimera studies demonstrated that ETV6 is specifically required for bone marrow hematopoiesis—the first transcription factor shown to be dispensable for yolk sac/fetal liver blood formation but essential for marrow engraftment.

    Evidence TEL-/- ES cell chimeras, lineage analysis of hematopoietic organs in mice

    PMID:9694803

    Open questions at the time
    • Direct transcriptional targets mediating engraftment not identified
    • Whether ETV6 acts cell-autonomously in HSCs vs. niche cells was unresolved
  4. 1999 High

    Identification of mSin3A, SMRT, and UBC9 as pointed-domain and central-region interactors revealed that ETV6 represses transcription through recruitment of corepressor/HDAC complexes and is post-translationally regulated by the SUMO conjugation machinery.

    Evidence Co-immunoprecipitation, GAL4 reporter assays, deletion mutagenesis, UBC9 interaction assay

    PMID:10377438 PMID:10490596 PMID:10544023

    Open questions at the time
    • Identity of HDAC isoform in the complex not yet determined
    • Sumoylation site not mapped
  5. 2000 High

    Mapping N-CoR recruitment to ETV6's central domain, demonstrating STAT5 as the critical downstream effector of TEL-JAK fusions, and showing TEL overexpression causes G1 arrest and suppresses Ras transformation collectively defined ETV6 as both a tumor suppressor and (when translocated) an oncogene activating JAK-STAT signaling.

    Evidence Co-IP/reporter assays for N-CoR, Ba/F3 assays with dominant-negative STAT5, soft agar and nude mouse assays for tumor suppression

    PMID:10706877 PMID:10845925 PMID:11001911 PMID:11077441

    Open questions at the time
    • Direct target genes mediating G1 arrest not identified
    • Whether N-CoR and mSin3A act in the same or distinct complexes on chromatin was unclear
  6. 2001 High

    Demonstration that HDAC3 directly binds ETV6's central region independently of N-CoR, and that HDAC inhibition reverses ETV6-dependent repression and cellular phenotypes, established the chromatin-modifying mechanism underlying ETV6 target gene silencing.

    Evidence Co-IP, ChIP for histone H3 acetylation at stromelysin-1 promoter, trichostatin A treatment

    PMID:11439334

    Open questions at the time
    • Genome-wide target identification not performed
    • Whether HDAC3 is required at all ETV6-bound loci was unknown
  7. 2002 High

    Identification of p38 MAPK as a direct ETV6 kinase phosphorylating Ser22 and Ser257 provided the first signal-responsive regulatory mechanism controlling ETV6 repressor activity.

    Evidence In vitro kinase assay, in vivo phosphorylation, site-directed mutagenesis, reporter assay

    PMID:12435397

    Open questions at the time
    • Physiological stimuli triggering p38-ETV6 axis not defined
    • Functional consequence of each individual phosphosite not fully dissected
  8. 2008 High

    Mapping sumoylation to K11 by mass spectrometry and showing that PIAS3-catalyzed sumoylation impairs ETV6 DNA binding, while Fbl6-mediated ubiquitination selectively degrades sumoylated monomers, revealed a SUMO–ubiquitin switch governing ETV6 protein stability and activity.

    Evidence Mass spectrometry, sumoylation and ubiquitination assays, proteasome inhibitor experiments, DNA-binding assays

    PMID:18212042 PMID:18426905

    Open questions at the time
    • Whether this switch operates in primary hematopoietic cells in vivo is untested
    • Structural basis of how K11 sumoylation blocks DNA binding not resolved
  9. 2012 High

    NMR analysis revealed that C-terminal helices H4/H5 autoinhibit the ETS domain by sterically blocking DNA contact and dampening millisecond dynamics required for DNA recognition, explaining how ETV6 DNA binding is kept in check in the absence of activating signals.

    Evidence NMR amide hydrogen exchange and 15N relaxation measurements on ETS domain ± CID

    PMID:22584210

    Open questions at the time
    • What relieves autoinhibition in vivo (partner protein, PTM, or oligomerization) is unknown
    • No full-length ETV6 structure available
  10. 2015 High

    Discovery that germline ETV6 mutations cause dominant-negative cytoplasmic mislocalization, impaired DNA binding, and defective megakaryocyte maturation linked ETV6 loss-of-function to inherited thrombocytopenia and leukemia predisposition in humans.

    Evidence Whole-exome sequencing of affected families, functional reporter and localization assays, megakaryocyte differentiation assays

    PMID:25581430 PMID:25807284 PMID:26102509

    Open questions at the time
    • Mechanism of cytoplasmic mislocalization by linker-domain mutations not structurally explained
    • Penetrance and modifier genes for leukemia progression unknown
  11. 2018 High

    Conditional knockout studies established ETV6 as a lineage-determining factor for dendritic cells: it represses MAFB to permit monocyte-to-DC differentiation and maintains cDC1 identity including CD8α expression and cross-priming capacity.

    Evidence Monocyte- and DC-specific Etv6 conditional KO mice, MAFB ChIP, ATAC-seq, cross-priming assays, EAE model

    PMID:30087163 PMID:36543959

    Open questions at the time
    • Whether ETV6 cooperates with ETV3 at all DC-specific loci is not resolved
    • Direct ETV6 chromatin targets in cDC1 not comprehensively mapped
  12. 2023 High

    Epigenomic studies revealed that ETV6 functions as a gatekeeper at GGAA tandem-repeat microsatellite enhancers, directly binding these elements to maintain repressive histone marks; loss of ETV6 permits replacement by ERG or EWS-FLI1, hyper-activating adjacent genes including EPOR and SOX11.

    Evidence ChIP-seq for ETV6/ERG at GGAA repeats, histone acetylation ChIP, CRISPR screen, dominant-interfering peptide, xenograft assays

    PMID:36350827 PMID:36658219

    Open questions at the time
    • Whether ETV6 competes with all ETS factors at GGAA repeats or selectively with ERG/FLI1 is unresolved
    • Structural basis of ETV6 preference for tandem GGAA repeats not determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full-length structure of ETV6, the mechanism by which autoinhibition is relieved in vivo, the comprehensive identification of direct ETV6 target genes in HSCs mediating bone marrow engraftment, and how ETV6 loss cooperates with secondary hits to drive leukemic transformation.
  • No full-length structural model
  • In vivo mechanism of autoinhibition relief unknown
  • Cooperating genetic events for leukemia transformation not systematically defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 11 GO:0003677 DNA binding 5
Localization
GO:0005634 nucleus 5
Pathway
R-HSA-74160 Gene expression (Transcription) 8 R-HSA-1643685 Disease 7 R-HSA-1266738 Developmental Biology 4 R-HSA-168256 Immune System 2 R-HSA-4839726 Chromatin organization 2
Partners
FBXL6HDAC3MAPK14NCOR1PIAS3SIN3ASTAT3UBE2I
Complex memberships
N-CoR/HDAC3 corepressor complexmSin3A corepressor complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 TEL (ETV6) protein products are nuclear phosphoproteins that display specific DNA-binding activity toward classical ETS binding sites; two isoforms of 50 kDa and 57 kDa are produced by translation initiation at either of the two first in-frame ATGs (codon 1 and 43), and both are modified by multiple phosphorylation events in vivo. Western blot, immunofluorescence, EMSA, murine TEL cDNA isolation Oncogene High 9018121
1997 The TEL-JAK2 fusion protein, generated by t(9;12)(p24;p13), includes the TEL oligomerization (pointed/HLH) domain fused to the JAK2 catalytic domain; TEL-induced oligomerization results in constitutive tyrosine kinase activity and confers cytokine-independent proliferation to Ba/F3 cells. Characterization of t(9;12) translocation product, in vitro kinase assay, Ba/F3 growth factor independence assay Science High 9360930
1998 The ETV6-NTRK3 fusion gene, arising from t(12;15)(p13;q25) in congenital fibrosarcoma, encodes a chimeric protein containing the ETV6 helix-loop-helix (HLH) dimerization domain fused to the NTRK3 protein tyrosine kinase domain, producing a constitutively active chimeric tyrosine kinase. Cloning of chromosomal breakpoints, RT-PCR, sequencing of fusion transcripts Nature genetics High 9462753
1998 TEL (ETV6) is required specifically for hematopoiesis in the bone marrow; TEL-/- hematopoietic cells can populate yolk sac and fetal liver but fail to establish bone marrow hematopoiesis, establishing TEL as the first transcription factor specifically required for bone marrow hematopoietic activity. Gene targeting in mice, chimera generation with TEL-/- ES cells, lineage analysis Genes & development High 9694803
1999 The TEL pointed (HLH) domain functions as a portable transcriptional repression motif; the TEL-AML1 fusion protein and wild-type TEL both bind the mSin3A corepressor via the pointed domain, and AML1B also contributes an mSin3-interaction domain to the fusion protein, making the complex bind mSin3A more stably than either alone. GAL4 reporter assays, deletion mutagenesis, co-immunoprecipitation Molecular and cellular biology High 10490596
1999 TEL (ETV6) functions as a transcriptional repressor by recruiting two distinct corepressor complexes: the central region of TEL recruits SMRT and mSin3A, while the HLH domain represses transcription through a corepressor-independent mechanism. GAL4 reporter assay, co-immunoprecipitation, deletion mutagenesis Biochemical and biophysical research communications High 10544023
1999 UBC9 (a SUMO E2-conjugating enzyme) physically interacts with TEL specifically through its HLH domain in vitro and in vivo, and co-expression of UBC9 restores promoter activity repressed by TEL without inducing TEL degradation, indicating UBC9 modulates TEL transcriptional repressor activity. In vivo interaction assay (two-hybrid equivalent), co-immunoprecipitation, GAL4 reporter assay, mutagenesis of UBC9 catalytic residues Proceedings of the National Academy of Sciences of the United States of America High 10377438
1999 ETV6 (TEL) represses the MCSFR proximal promoter in a DNA-binding-dependent manner, requiring the ETS DNA-binding domain; deletion of the HLH region reduces but does not abolish repression, and inhibition requires interaction with other promoter-bound proteins such as CBFA2B and C/EBPα. Reporter gene (luciferase) assays, deletion/mutational analysis of ETV6 and MCSFR promoter Proceedings of the National Academy of Sciences of the United States of America Medium 9050885
2000 TEL (ETV6) recruits the nuclear receptor corepressor N-CoR through its central region, and this interaction is required for full transcriptional repression; TEL-AML1 fusion also binds N-CoR via the TEL central region retained in the fusion. Co-immunoprecipitation, deletion mutagenesis, reporter assays Blood High 11001911
2000 Fusion proteins containing the TEL oligomerization (pointed) domain fused to the kinase domains of JAK1, JAK2, JAK3, or TYK2 all confer cytokine-independent growth to Ba/F3 cells; STAT5 is the principal activated STAT in TEL-JAK2 and TEL-JAK1 cells, and a dominant-negative STAT5A blocks cytokine independence; TEL-JAK3 and TEL-TYK2 additionally activate STAT1 and STAT3. Ba/F3 growth factor independence assay, EMSA, dominant-negative STAT5 expression, gene expression analysis Blood High 10706877
2000 TEL overexpression induces a G1 cell cycle arrest in multiple cell types and suppresses Ras-mediated transformation (colony formation in soft agar, tumor formation in nude mice); both the pointed domain and DNA-binding domain of TEL are required for these tumor suppressor phenotypes. Cell proliferation assays, soft agar colony assay, nude mouse tumor assay, TEL domain mutagenesis Oncogene High 11077441
2000 TEL-JAK2 transgenic mice develop fatal T-cell leukemia with selective expansion of CD8+ T cells; the TEL-JAK2 protein is tyrosine-phosphorylated in leukemic tissue and activates STAT1 and STAT5 in vivo. Transgenic mouse model, flow cytometry, Western blot/phospho-analysis, TCR clonality analysis Blood High 10845925
2001 TEL repression requires both the N-terminal pointed domain (which binds mSin3A) and a central repression domain (amino acids 268-303, which binds N-CoR); HDAC3, but not other HDACs, directly associates with the central region of TEL independently of N-CoR, and HDAC inhibition with trichostatin A impairs TEL-dependent repression and reverses TEL-induced cellular aggregation. Deletion mutagenesis, co-immunoprecipitation, ChIP (histone H3 acetylation at stromelysin-1 promoter), TSA treatment, reporter assay Oncogene High 11439334
2002 ETV6-NTRK3 chimeric tyrosine kinase transforms murine mammary epithelial cells and forms tumors in nude mice that express epithelial antigens, establishing ETV6-NTRK3 as a dominantly acting oncogene in breast epithelial transformation; this fusion is present in 92% of human secretory breast carcinomas. Retroviral gene transfer, nude mouse tumor assay, immunohistochemistry, RT-PCR of patient tumors Cancer cell High 12450792
2002 TEL-Abl (ETV6-ABL1) fusion requires the TEL pointed domain oligomerization and ABL tyrosine kinase activity to induce myeloproliferative disease in mice; the fusion transforms multipotent hematopoietic progenitors capable of multilineage repopulation. Retroviral bone marrow transduction-transplantation model, domain mutagenesis, multilineage repopulation assays Blood High 12036890
2002 p38 MAP kinase directly phosphorylates TEL in vitro and in vivo at Ser22 (constitutive) and Ser257 (inducible); TEL binds p38 physically, and p38-dependent phosphorylation reduces TEL trans-repressional activity at ETS-binding sites. In vivo phosphorylation assay, in vitro kinase assay, reporter assay, co-immunoprecipitation, site-directed mutagenesis Biochemical and biophysical research communications High 12435397
2003 TEL represses the Bcl-XL promoter in a DNA-binding-dependent manner, reducing Bcl-XL mRNA and protein levels, and promotes apoptosis in serum-starved cells; this identifies Bcl-XL as a direct transcriptional target of TEL. Reporter gene assay, RT-PCR/Western blot for endogenous Bcl-XL, apoptosis assay, domain mutagenesis The Journal of biological chemistry Medium 12960174
2004 TEL-Syk fusion protein (from t(9;12)) is localized in the cytoplasm and constitutively activates PI3K/Akt, Vav, PLCγ2, MAPK, and STAT5 (independently of JAK2); the oligomerization (PNT) domain of TEL is required for all these signaling activities; TEL-Syk confers IL-3-independent growth to Ba/F3 cells. Immunofluorescence localization, Western blot of signaling pathway activation, Ba/F3 transformation assay, deletion mutagenesis (ΔPNTdomain) Leukemia High 14749700
2004 TEL/ETV6 functions as a STAT3-induced repressor of STAT3 activity; STAT3 activates ETV6 transcription, and ETV6 in turn represses STAT3 transcriptional activity through physical recruitment of ETV6 to STAT3 without requiring ETV6 DNA binding, forming a negative feedback loop. Microarray (STAT3 target identification), siRNA knockdown of TEL, reporter assay, co-immunoprecipitation, ETV6 overexpression The Journal of biological chemistry Medium 15229229
2005 The pointed domain of TEL/AML1, which recruits transcriptional repressors and directs oligomerization with TEL/AML1 or wild-type TEL, is essential for impaired B-cell differentiation and increased self-renewal of progenitors in vivo; another oligomerization domain cannot substitute for it. Bone marrow transplantation model, in vitro replating assays, domain substitution mutagenesis Oncogene Medium 16044150
2008 The F-box protein Fbl6 binds TEL (ETV6) via its SAM (PNT) domain and stimulates ubiquitination of TEL leading to proteasomal degradation; sumoylation of Tel monomers (but not oligomers) sensitizes them for Fbl6-mediated proteasomal degradation, while Tel oligomers are stably sumoylated at K11 but more resistant to degradation. Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor experiments, sumoylation assay Molecular and cellular biology High 18426905
2008 TEL (ETV6) is sumoylated at lysine 11 (K11); PIAS3 binds to TEL in the nucleus and stimulates K11 sumoylation; sumoylation of K11 inhibits TEL repression of gene expression by impeding TEL association with DNA; a TelM43 isoform lacking K11 is strongly repressive; PIAS3 can also augment TEL repressive function in a sumoylation-independent manner. Site-directed mutagenesis of K11, mass spectrometry identification of sumoylation site, co-immunoprecipitation with PIAS3, DNA-binding assay, reporter assay Molecular and cellular biology High 18212042
2009 CBFβ heterodimerization with the Runt domain of AML1 in TEL-AML1 is essential for TEL-AML1's ability to promote self-renewal of B-cell precursors; Runt domain mutations that disrupt CBFβ binding without affecting DNA binding abrogate this function. Runt domain mutagenesis, B-cell precursor self-renewal assay in vitro, bone marrow reconstitution Blood Medium 19179469
2010 ETV6-NTRK3-driven transformation of mammary epithelial cells requires the IGF1R/INSR signaling axis; PI3K-Akt is activated in an IGF1- or insulin-dependent manner downstream of ETV6-NTRK3, and dual IGF1R/INSR inhibitors block EN transformation in vitro and tumor growth in vivo. 3D Matrigel culture, tumor formation assay, pharmacological inhibition (BMS-536924, BMS-754807), Western blot of PI3K-Akt signaling Cancer research High 21148487
2012 ETV6 DNA binding is autoinhibited by two C-terminal helices (H4 and H5) that sterically block the DNA-binding interface of the ETS domain; these helices are only marginally stable and the CID dampens millisecond-timescale motions of the ETS domain critical for specific DNA recognition. NMR spectroscopy (amide hydrogen exchange, 15N relaxation measurements), structural analysis of ETS domain + CID Journal of molecular biology High 22584210
2015 Germline missense mutations in the ETV6 ETS DNA-binding domain (p.Arg369Gln, p.Arg399Cys) and the internal linker domain (p.Pro214Leu) abrogate DNA binding, alter subcellular localization (cytoplasmic mislocalization of mutant and endogenous ETV6), decrease transcriptional repression in a dominant-negative fashion, and impair megakaryocyte maturation and hematopoiesis. Whole-exome sequencing, functional reporter assays, subcellular localization by microscopy, megakaryocyte differentiation assay Nature genetics High 25581430
2015 ETV6 mutations (p.Pro214Leu in central domain; p.Arg418Gly in DNA-binding domain) cause aberrant cytoplasmic localization of both mutant and endogenous ETV6, decreased transcriptional repression, and altered megakaryocyte maturation. Whole-exome sequencing, subcellular localization microscopy, transcriptional reporter assay, megakaryocyte maturation assay Nature genetics High 25807284
2015 Germline ETV6 mutations (p.L349P, p.N385fs) impair nuclear localization of ETV6 and significantly reduce its ability to regulate transcription of ETV6 target genes, establishing a dominant-negative mechanism for leukemia predisposition. Enforced expression of ETV6 mutants, subcellular localization assay, transcriptional target gene reporter assay PLoS genetics Medium 26102509
2016 ETV6-RUNX1 fusion drives widespread repression of RUNX1 motif-containing enhancers at target gene loci, including super-enhancers of the CD19+/CD20+ B-cell lineage; this repression depends on the wild-type DNA-binding Runt domain of RUNX1 and results in downregulation of genes involved in B-cell signaling and adhesion. Global run-on sequencing (GRO-seq), ChIP-seq, enhancer RNA profiling, Runt domain mutant analysis Genome research High 27620872
2018 ETV6 and ETV3 transcriptional repressors control human monocyte differentiation into dendritic cells by directly repressing MAFB expression (thus suppressing macrophage fate); in vivo, monocyte-specific Etv6 deletion causes spontaneous IFN-stimulated gene expression and impairs mo-DC differentiation during inflammation. Conditional Etv6 knockout in monocytes, gene expression analysis, MAFB ChIP, DC differentiation assay, EAE model Nature immunology High 36543959
2018 Etv6 deletion in the bone marrow abolishes CD8α expression on cDC1 conventional dendritic cells in vivo and impairs cDC1-specific gene expression and chromatin signatures while causing aberrant up-regulation of pDC-specific signatures; DC-specific Etv6 deletion impairs CD8+ T-cell cross-priming and tumor-specific T-cell responses. Bone marrow-specific Etv6 deletion, flow cytometry, gene expression profiling, chromatin accessibility (ATAC-seq-related), cross-priming functional assay The Journal of experimental medicine High 30087163
2019 In Xenopus, Etv6 positively regulates vegfa expression during blood stem cell development through two mechanisms: (1) directly repressing the transcriptional repressor foxo3 (preventing Foxo3 from binding and repressing the vegfa promoter — a double-negative gate); (2) directly activating klf4, which then recruits Etv6 to the vegfa promoter to activate its expression (feed-forward loop). Xenopus embryo loss-of-function (morpholino), ChIP, reporter assay, rescue experiments Nature communications Medium 30842454
2021 Germline ETV6 variants linked to ALL predisposition show impaired transcription repressor activity, loss of DNA binding, and altered nuclear localization; missense variants retain dimerization with wild-type ETV6 exerting dominant-negative effects; ATAC-seq profiling identified specific ETV6 genomic targets relevant to tumor suppressor activity. Functional reporter assay, DNA-binding assay, nuclear localization microscopy, dimerization assay, ATAC-seq, whole-transcriptome and whole-genome sequencing Blood High 32693409
2023 ETV6 acts as a transcriptional repressor that competes with EWS-FLI1 for binding to select DNA elements enriched for short GGAA repeat sequences; upon ETV6 inactivation, EWS-FLI1 hyper-activates these cis-elements promoting mesenchymal differentiation (via SOX11); a dominant-interfering ETV6 peptide phenocopies ETV6 loss and suppresses Ewing sarcoma growth in vivo. CRISPR domain-focused screen, ChIP-seq, ATAC-seq, biochemical competition assay, dominant-interfering peptide, in vivo xenograft Nature cell biology High 36658219
2023 ETV6 functions as an epigenetic gatekeeper by directly binding GGAA tandem repeat enhancers, repressing their histone acetylation, and downregulating adjacent genes including EPOR; in ETV6-deficient B-ALL, the ETS factor ERG occupies these GGAA microsatellite enhancers and drives aberrant gene activation. ChIP-seq for ETV6 binding at GGAA repeats, histone acetylation ChIP, ERG knockdown, ETV6 restoration experiments Blood cancer discovery High 36350827

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 689 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 628 9462753
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 279 25581430
2012 The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity. Nature 278 23103865
1996 TEL/AML-1 dimerizes and is associated with a favorable outcome in childhood acute lymphoblastic leukemia. Blood 263 8943861
2017 Multidrug-Resistant Candida haemulonii and C. auris, Tel Aviv, Israel. Emerging infectious diseases 254 28098529
2000 Molecular detection of the ETV6-NTRK3 gene fusion differentiates congenital fibrosarcoma from other childhood spindle cell tumors. The American journal of surgical pathology 253 10895816
2015 Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia. Nature genetics 221 25807284
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
2016 Transcriptome sequencing identifies ETV6-NTRK3 as a gene fusion involved in GIST. The Journal of pathology 156 26606880
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 124 10544023
2015 Germline ETV6 Mutations Confer Susceptibility to Acute Lymphoblastic Leukemia and Thrombocytopenia. PLoS genetics 118 26102509
2000 Transforming properties of chimeric TEL-JAK proteins in Ba/F3 cells. Blood 117 10706877
2000 TEL-JAK2 transgenic mice develop T-cell leukemia. Blood 103 10845925
2000 Recruitment of the nuclear receptor corepressor N-CoR by the TEL moiety of the childhood leukemia-associated TEL-AML1 oncoprotein. Blood 99 11001911
1997 The TEL gene products: nuclear phosphoproteins with DNA binding properties. Oncogene 99 9018121
2017 ETV6 in hematopoiesis and leukemia predisposition. Seminars in hematology 97 28637624
1999 The role of TEL fusion genes in pediatric leukemias. Leukemia 96 10049061
2009 Hsa-mir-125b-2 is highly expressed in childhood ETV6/RUNX1 (TEL/AML1) leukemias and confers survival advantage to growth inhibitory signals independent of p53. Leukemia 94 19890372
2001 TEL contacts multiple co-repressors and specifically associates with histone deacetylase-3. Oncogene 88 11439334
2018 Novel gene fusions in secretory carcinoma of the salivary glands: enlarging the ETV6 family. Human pathology 85 30130630
2011 Characterization of a newly identified ETV6-NTRK3 fusion transcript in acute myeloid leukemia. Diagnostic pathology 78 21401966
2016 Characterization of leukemias with ETV6-ABL1 fusion. Haematologica 77 27229714
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
2017 Infection Exposure Promotes ETV6-RUNX1 Precursor B-cell Leukemia via Impaired H3K4 Demethylases. Cancer research 73 28630052
1999 Structure and possible mechanisms of TEL-AML1 gene fusions in childhood acute lymphoblastic leukemia. Cancer research 69 10463610
2010 TEL-AML1 regulation of survivin and apoptosis via miRNA-494 and miRNA-320a. Blood 64 20807887
2019 ETV6-related thrombocytopenia and leukemia predisposition. Blood 62 31248877
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
2021 Molecular basis of ETV6-mediated predisposition to childhood acute lymphoblastic leukemia. Blood 57 32693409
2017 Pathogenesis of ETV6/RUNX1-positive childhood acute lymphoblastic leukemia and mechanisms underlying its relapse. Oncotarget 56 28418909
2006 Expression of ETV6-NTRK in classical, cellular and mixed subtypes of congenital mesoblastic nephroma. Histopathology 50 16681692
2015 Congenital mesoblastic nephroma: a study of 19 cases using immunohistochemistry and ETV6-NTRK3 fusion gene rearrangement. Pathology 49 27020209
2000 t(7;12)(q36;p13), a new recurrent translocation involving ETV6 in infant leukemia. Genes, chromosomes & cancer 49 11066076
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 46 29046324
2022 ETV3 and ETV6 enable monocyte differentiation into dendritic cells by repressing macrophage fate commitment. Nature immunology 45 36543959
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
2011 Silencing of ETV6/RUNX1 abrogates PI3K/AKT/mTOR signaling and impairs reconstitution of leukemia in xenografts. Leukemia 43 22094587
2009 The fusion proteins TEL-PDGFRbeta and FIP1L1-PDGFRalpha escape ubiquitination and degradation. Haematologica 42 19644140
2004 TEL-Syk fusion constitutively activates PI3-K/Akt, MAPK and JAK2-independent STAT5 signal pathways. Leukemia 42 14749700
2000 Tel induces a G1 arrest and suppresses Ras-induced transformation. Oncogene 42 11077441
2023 ETV6 dependency in Ewing sarcoma by antagonism of EWS-FLI1-mediated enhancer activation. Nature cell biology 40 36658219
2017 Molecular role of the PAX5-ETV6 oncoprotein in promoting B-cell acute lymphoblastic leukemia. The EMBO journal 40 28219927
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 39 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
1997 Deletions of CDKN1B and ETV6 in acute myeloid leukemia and myelodysplastic syndromes without cytogenetic evidence of 12p abnormalities. Genes, chromosomes & cancer 37 9171997
2012 Detection of ETV6 gene rearrangements in adult acute lymphoblastic leukemia. Annals of hematology 35 22373549
2011 The leukemia-specific fusion gene ETV6/RUNX1 perturbs distinct key biological functions primarily by gene repression. PloS one 35 22028862
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
2005 Conditional MN1-TEL knock-in mice develop acute myeloid leukemia in conjunction with overexpression of HOXA9. Blood 35 16105979
1998 Analysis of TEL proteins in human leukemias. Oncogene 34 9671410
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 33 30088951
2017 Antitumor Activity of Entrectinib, a Pan-TRK, ROS1, and ALK Inhibitor, in ETV6-NTRK3-Positive Acute Myeloid Leukemia. Molecular cancer therapeutics 32 29237803
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
2012 Autoinhibition of ETV6 (TEL) DNA binding: appended helices sterically block the ETS domain. Journal of molecular biology 30 22584210
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, 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
2008 Identification of a new site of sumoylation on Tel (ETV6) uncovers a PIAS-dependent mode of regulating Tel function. Molecular and cellular biology 28 18212042
2014 Haploinsufficiency of ETV6 and CDKN1B in patients with acute myeloid leukemia and complex karyotype. BMC genomics 27 25213837
2006 Expression of TEL-JAK2 in primary human hematopoietic cells drives erythropoietin-independent erythropoiesis and induces myelofibrosis in vivo. Proceedings of the National Academy of Sciences of the United States of America 27 17077140
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
2002 Functional regulation of TEL by p38-induced phosphorylation. Biochemical and biophysical research communications 25 12435397
2015 Somatic drivers of B-ALL in a model of ETV6-RUNX1; Pax5(+/-) leukemia. BMC cancer 24 26269126
2012 Gene duplication within the Green Lineage: the case of TEL genes. Journal of experimental botany 24 22865910
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
2001 Low incidence of TEL/AML1 fusion and TEL deletion in Korean childhood acute leukemia by extra-signal fluorescence in situ hybridization. Cancer genetics and cytogenetics 23 11343784
2018 Acute myeloid leukemia carrying ETV6 mutations: biologic and clinical features. Hematology (Amsterdam, Netherlands) 21 29894279
2016 A quantitative proteomics approach identifies ETV6 and IKZF1 as new regulators of an ERG-driven transcriptional network. Nucleic acids research 21 27604872
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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
2014 Identification and characterization of OSTL (RNF217) encoding a RING-IBR-RING protein adjacent to a translocation breakpoint involving ETV6 in childhood ALL. Scientific reports 19 25298122
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 18 32659251
2002 Transformation of Ba/F3 cells and Rat-1 cells by ETV6/ARG. Oncogene 18 12080468
2020 A novel ETV6-miR-429-CRKL regulatory circuitry contributes to aggressiveness of hepatocellular carcinoma. Journal of experimental & clinical cancer research : CR 17 32326970
2015 Determination of ETV6-RUNX1 genomic breakpoint by next-generation sequencing. Cancer medicine 17 26711002
2012 Variant of ETV6/ABL1 gene is associated with leukemia phenotype. Acta haematologica 17 23171811
1999 Tel, a frequent target of leukemic translocations, induces cellular aggregation and influences expression of extracellular matrix components. Neoplasia (New York, N.Y.) 17 10935500
2019 Etv6 activates vegfa expression through positive and negative transcriptional regulatory networks in Xenopus embryos. Nature communications 16 30842454
2017 A new ETV6-NTRK3 cell line model reveals MALAT1 as a novel therapeutic target - a short report. Cellular oncology (Dordrecht, Netherlands) 16 29119387
2006 Identification of transcripts modulated by ETV6 expression. British journal of haematology 16 17069581
2002 Mutational analysis of ETV6 in prostate carcinoma. The Prostate 16 12210491
2019 ZBTB46, SPDEF, and ETV6: Novel Potential Biomarkers and Therapeutic Targets in Castration-Resistant Prostate Cancer. International journal of molecular sciences 15 31181727