{"gene":"ETV7","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2000,"finding":"ETV7 (TEL2) localizes to the nucleus, binds the same consensus ETS DNA-binding sequence (GGAA core motif) as TEL1/ETV6, and associates with itself and with TEL1 through the PNT (pointed) domain of TEL1 in doubly transfected HeLa cells.","method":"DNA binding assays, co-immunoprecipitation in transfected HeLa cells, antibody-based nuclear localization","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2-3 — reciprocal interactions shown by Co-IP and DNA binding assay, single lab","pmids":["10828014"],"is_preprint":false},{"year":2000,"finding":"ETV7 (Tel-2) functions as a transcriptional repressor; only the isoform containing both the Pointed domain and the DNA-binding domain acts as a strong repressor. It represses the retinoic acid receptor alpha and BMP-6 gene promoters, suggesting a role as an inhibitor of differentiation.","method":"Reporter gene assays with isoform-specific constructs, domain deletion mutants","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — functional dissection with multiple isoforms and domain mutants, single lab","pmids":["11108721"],"is_preprint":false},{"year":2004,"finding":"ETV7 inhibits monocytic differentiation of U937 cells induced by vitamin D3; domain mutants lacking the PNT or functional ETS domain act as dominant negatives, inducing differentiation and blocking ETV7-mediated transcriptional repression. ETV7 also blocks the inhibitory effect of TEL1 on Ras-induced cellular transformation.","method":"Overexpression of wild-type and domain-deletion mutants, in vitro and in vivo growth assays, transcriptional reporter assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — domain mutant functional dissection with multiple readouts, single lab","pmids":["15342392"],"is_preprint":false},{"year":2005,"finding":"ETV7 augments proliferation and survival of mouse B cells and accelerates lymphoma development in Eμ-Myc transgenic mice, cooperating with Myc in B lymphomagenesis, with inactivation of the p53 pathway as a hallmark of TEL2/Eμ-Myc lymphomas.","method":"Transgenic mouse model (Eμ-Myc cross), bone marrow transplantation, in vivo tumor studies","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic epistasis with defined phenotypic readout in mouse model","pmids":["15743832"],"is_preprint":false},{"year":2005,"finding":"Forced expression of ETV7 alone in mouse bone marrow causes myeloproliferative disease and blocks vitamin D3-induced differentiation of U937 and HL60 myeloid cells, identifying ETV7 as a bona fide oncogene that promotes proliferation while TEL1 inhibits it.","method":"Bone marrow transplantation, retroviral overexpression, chemical carcinogen (ENU) acceleration, differentiation assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — in vivo loss/gain-of-function with defined cellular phenotypes, replicated across cell lines and mouse model","pmids":["16234363"],"is_preprint":false},{"year":2012,"finding":"The SAM domain of human ETV7 (TEL2) can inhibit the transcriptional activities of ETS1/ETS2 and TEL1 (ETV6), providing a mechanism by which ETV7 modulates output from these oncogenes via SAM domain-mediated interactions.","method":"Transcriptional reporter assays, SAM domain constructs, cross-species comparison with Drosophila Mae","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional reporter assays with domain-specific constructs, single lab","pmids":["22615925"],"is_preprint":false},{"year":2013,"finding":"ETV7 regulates red blood cell development in zebrafish by controlling transcription of the lanosterol synthase (lss) gene in the cholesterol synthesis pathway; etv7 morpholino knockdown causes loss of hemoglobin-containing red blood cells, rescued by exogenous cholesterol.","method":"Morpholino knockdown in zebrafish, cholesterol rescue experiment, gene expression analysis","journal":"Disease models & mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with rescue experiment in zebrafish model, single lab","pmids":["24357328"],"is_preprint":false},{"year":2015,"finding":"ETV7 (TEL2) inhibits cell migration and invasion in vitro and metastasis in vivo in nasopharyngeal carcinoma by directly suppressing the SERPINE1 promoter, as demonstrated by chromatin immunoprecipitation and luciferase assays showing direct ETV7 binding.","method":"ChIP assay, luciferase reporter assay, migration/invasion assays, in vivo metastasis model","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 1-2 — direct promoter binding confirmed by ChIP and reporter assay, in vivo validation","pmids":["26335051"],"is_preprint":false},{"year":2018,"finding":"ETV7 interacts with mTOR in the cytoplasm and assembles a third mTOR complex, mTORC3, which is independent of ETV7's transcriptional activity. mTORC3 is devoid of canonical mTORC1/2 components (Raptor, Rictor) but exhibits bimodal mTORC1/2 kinase activity and confers rapamycin resistance.","method":"Co-immunoprecipitation, size-exclusion chromatography, kinase activity assays, rapamycin sensitivity assays, rhabdomyosarcoma mouse model","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1-2 — complex assembly demonstrated biochemically and functionally, validated in vivo mouse model","pmids":["30258985"],"is_preprint":false},{"year":2018,"finding":"ETV7 directly binds the DNAJC15 promoter, repressing DNAJC15 transcription, which reduces Doxorubicin sensitivity in breast cancer cells by increasing Doxorubicin efflux via nuclear pumps; DNA methylation may also contribute to this repression.","method":"Chromatin immunoprecipitation, promoter binding assays, siRNA knockdown, drug efflux assays, DNAJC15 overexpression rescue","journal":"Neoplasia (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 — direct promoter binding shown by ChIP, functional rescue experiments, single lab","pmids":["30025229"],"is_preprint":false},{"year":2019,"finding":"NOTCH1 intracellular domain overexpression in OSCC cells upregulates ETV7, which in turn negatively regulates SERPINE1 expression, placing ETV7 downstream of NOTCH1 signaling in a pathway that suppresses cell proliferation and migration.","method":"Gene expression profiling, ETV7 overexpression, SERPINE1 knockdown phenocopy, pathway epistasis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2-3 — epistasis supported by expression profiling and knockdown phenocopy, single lab","pmids":["31827722"],"is_preprint":false},{"year":2021,"finding":"ETV7 promotes breast cancer stem-like cell plasticity and resistance to chemotherapy and radiotherapy by repressing a signature of Interferon-responsive genes; IFN-β treatment partially reverses the increased cancer stem cell population caused by ETV7 overexpression.","method":"Stable overexpression, transcriptome profiling, CD44+/CD24low population analysis, mammosphere formation assay, IFN-β rescue","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — transcriptome profiling with functional rescue, single lab","pmids":["34315857"],"is_preprint":false},{"year":2023,"finding":"ETV7 directly binds to intron I of TNFRSF1A (encoding TNFR1), repressing its transcription and thereby reducing NF-κB signaling activation; ETV7 also competes with STAT3 for binding to the TNFRSF1A gene and recruits repressive chromatin remodelers to suppress TNFR1 expression.","method":"ChIP assay, promoter/intron binding assays, NF-κB signaling assays, competitive binding experiments","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1-2 — direct DNA binding shown by ChIP, mechanistic competition with STAT3 demonstrated, multiple orthogonal methods","pmids":["37041130"],"is_preprint":false},{"year":2024,"finding":"ETV7 binds to mTOR via two separate interaction interfaces: the ETV7 PNT domain interacts with the mTOR FRB sequence, and the ETV7 ETS domain interacts with the mTOR LBE sequence in the kinase domain. Forced expression of the mTOR FRB domain outcompetes mTOR for ETV7 binding and renders mTORC3-expressing rapamycin-resistant cells rapamycin-sensitive in vivo.","method":"Domain mapping by co-immunoprecipitation with truncation/deletion mutants, competition assay with FRB domain overexpression, in vivo rapamycin sensitivity assay","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 1-2 — domain-level interaction mapping with functional in vivo competition experiment, multiple binding interfaces defined","pmids":["39337528"],"is_preprint":false},{"year":2024,"finding":"ETV7 transcriptionally activates IFIT3 expression in colorectal cancer cells, as demonstrated by luciferase assay and RT-qPCR; IFIT3 knockdown reverses ETV7-driven proliferation and migration, establishing an ETV7/IFIT3 transcriptional axis.","method":"Luciferase reporter assay, RT-qPCR, siRNA knockdown, rescue experiments, proliferation/migration assays","journal":"Functional & integrative genomics","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct transcriptional activation shown by reporter assay with rescue experiment, single lab","pmids":["38200280"],"is_preprint":false},{"year":2025,"finding":"ETV7 drives CD8+ T cell differentiation from memory to terminal exhaustion by binding directly to memory gene loci and exhaustion gene loci, functionally skewing transcriptional programs toward exhaustion; ETV7 depletion enhances antitumor efficacy of CD8+ T cells and CAR-T cells in solid tumors.","method":"scRNA-seq, scATAC-seq, ETV7 overexpression and depletion, in vivo tumor models, direct chromatin binding analysis","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 1-2 — multi-omic single-cell analysis with direct chromatin binding, loss- and gain-of-function, in vivo validation","pmids":["39805956"],"is_preprint":false},{"year":2026,"finding":"ETV7 transcriptionally upregulates CXCL1, leading to increased neutrophil recruitment and enhanced neutrophil extracellular trap (NET) formation in the tumor microenvironment, promoting tumor aggressiveness and 5-FU resistance in colorectal cancer; pharmacological inhibition of CXCL1 or NETs degradation attenuates ETV7-driven malignant phenotypes.","method":"Luciferase reporter assay, ChIP, CXCL1 neutralization, NETs inhibition, in vitro and in vivo functional assays","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 — transcriptional target validated by ChIP and reporter, pathway confirmed by pharmacological inhibition, single lab","pmids":["41917269"],"is_preprint":false}],"current_model":"ETV7 is an ETS-family transcriptional repressor (with some activating targets) that physically interacts with mTOR via its PNT and ETS domains to assemble a rapamycin-insensitive third mTOR complex (mTORC3) in the cytoplasm, while in the nucleus it directly binds promoters/enhancers of target genes (including SERPINE1, DNAJC15, TNFRSF1A, IFIT3, and CXCL1) to regulate cancer cell proliferation, stemness, chemoresistance, inflammation, and immune evasion, and also controls CD8+ T cell fate by binding memory and exhaustion gene loci to drive terminal exhaustion."},"narrative":{"teleology":[{"year":2000,"claim":"Establishing ETV7 as a nuclear ETS-family transcriptional repressor resolved the basic molecular identity of this gene, showing it binds the canonical GGAA motif and self-associates via its PNT domain.","evidence":"DNA binding assays, co-immunoprecipitation in transfected HeLa cells, reporter gene assays with isoform and domain deletion mutants","pmids":["10828014","11108721"],"confidence":"Medium","gaps":["No genome-wide binding profile to define the full target repertoire","Repression mechanism (corepressor recruitment, chromatin modification) not identified","Reporter-based; endogenous gene repression not shown"]},{"year":2005,"claim":"Demonstrating that ETV7 cooperates with Myc in lymphomagenesis and causes myeloproliferative disease upon forced expression established ETV7 as a bona fide oncogene that promotes proliferation while blocking myeloid differentiation.","evidence":"Eμ-Myc transgenic mouse crosses, bone marrow transplantation, retroviral overexpression, differentiation assays in U937/HL60 cells","pmids":["15743832","16234363"],"confidence":"High","gaps":["Transcriptional targets mediating oncogenicity not identified","Relationship to p53 pathway inactivation is correlative","Human relevance of mouse phenotypes not confirmed"]},{"year":2012,"claim":"Showing that ETV7's SAM domain inhibits ETS1, ETS2, and ETV6 transcriptional activities revealed a cross-regulatory mechanism among ETS factors, explaining how ETV7 can antagonize the tumor-suppressive function of ETV6.","evidence":"Transcriptional reporter assays with SAM domain constructs, cross-species comparison with Drosophila Mae","pmids":["22615925"],"confidence":"Medium","gaps":["Direct physical interaction with ETS1/ETS2 not demonstrated by co-IP","Endogenous relevance in mammalian cells not shown","Stoichiometric relationship between ETV7 and other ETS factors unknown"]},{"year":2015,"claim":"Identification of SERPINE1 as a direct transcriptional target repressed by ETV7 provided the first ChIP-validated target gene linking ETV7 to a specific cellular phenotype — suppression of metastasis.","evidence":"ChIP assay and luciferase reporter assay for direct promoter binding, migration/invasion assays, in vivo metastasis model in nasopharyngeal carcinoma","pmids":["26335051"],"confidence":"High","gaps":["Genome-wide ChIP-seq not performed to define all direct targets","Whether ETV7–SERPINE1 axis operates in other cancer types untested"]},{"year":2018,"claim":"Discovery that ETV7 assembles a rapamycin-insensitive third mTOR complex (mTORC3) in the cytoplasm, independent of its transcriptional activity, fundamentally expanded ETV7's functional repertoire beyond transcription and explained a mechanism of mTOR inhibitor resistance.","evidence":"Co-immunoprecipitation, size-exclusion chromatography, kinase activity assays, rapamycin sensitivity assays, rhabdomyosarcoma mouse model","pmids":["30258985"],"confidence":"High","gaps":["Structural basis of mTORC3 assembly unknown","Full subunit composition of mTORC3 not defined","Endogenous complex stoichiometry not established"]},{"year":2018,"claim":"Identification of DNAJC15 as a second direct transcriptional target of ETV7, whose repression mediates doxorubicin resistance via increased drug efflux, linked ETV7's repressor activity to chemoresistance.","evidence":"ChIP, siRNA knockdown, drug efflux assays, DNAJC15 overexpression rescue in breast cancer cells","pmids":["30025229"],"confidence":"Medium","gaps":["Relative contribution of DNA methylation vs. ETV7 binding to DNAJC15 repression not delineated","Generalizability beyond breast cancer not tested"]},{"year":2023,"claim":"Demonstrating that ETV7 binds TNFRSF1A intron I and competes with STAT3 for binding, repressing TNFR1 and dampening NF-κB signaling, revealed a mechanism by which ETV7 modulates inflammatory signaling through direct chromatin competition.","evidence":"ChIP assay, NF-κB signaling assays, competitive binding experiments with STAT3","pmids":["37041130"],"confidence":"High","gaps":["Whether STAT3 displacement is direct or allosteric is unresolved","Identity of recruited chromatin remodelers not specified"]},{"year":2024,"claim":"Mapping the dual ETV7–mTOR interaction interfaces (PNT–FRB and ETS–LBE) and showing that FRB domain overexpression restores rapamycin sensitivity in vivo provided a structural rationale and a potential therapeutic strategy to disrupt mTORC3.","evidence":"Domain mapping by co-immunoprecipitation with truncation/deletion mutants, in vivo competition assay with FRB overexpression","pmids":["39337528"],"confidence":"High","gaps":["No high-resolution structural data for the ETV7–mTOR interfaces","Whether pharmacological small molecules can mimic FRB competition unknown"]},{"year":2024,"claim":"Establishing that ETV7 acts as a transcriptional activator of IFIT3 in colorectal cancer demonstrated that ETV7 is not exclusively a repressor, and that an ETV7–IFIT3 axis drives proliferation.","evidence":"Luciferase reporter assay, RT-qPCR, siRNA knockdown and rescue in colorectal cancer cells","pmids":["38200280"],"confidence":"Medium","gaps":["Mechanism switching ETV7 from repressor to activator at specific loci not explained","Single cancer type studied"]},{"year":2025,"claim":"Revealing that ETV7 drives CD8+ T cell terminal exhaustion by binding memory and exhaustion gene loci established ETV7 as a key immune checkpoint transcription factor, with its depletion enhancing antitumor T cell and CAR-T efficacy.","evidence":"scRNA-seq, scATAC-seq, ETV7 overexpression and depletion, in vivo tumor models, direct chromatin binding analysis","pmids":["39805956"],"confidence":"High","gaps":["Cofactors mediating ETV7's chromatin remodeling at exhaustion loci unknown","Whether ETV7's T cell role is mTORC3-dependent not addressed","Clinical translation to CAR-T engineering not validated in patients"]},{"year":2026,"claim":"Showing that ETV7 transcriptionally activates CXCL1, promoting neutrophil recruitment and NET formation in the tumor microenvironment, connected ETV7 to immune cell remodeling and 5-FU resistance in colorectal cancer.","evidence":"ChIP, luciferase reporter assay, CXCL1 neutralization, NETs inhibition, in vivo and in vitro functional assays","pmids":["41917269"],"confidence":"Medium","gaps":["Whether ETV7 directly regulates other chemokines is unexplored","Mechanism of NET-mediated chemoresistance downstream of CXCL1 not fully dissected","Single lab study"]},{"year":null,"claim":"Key unresolved questions include the structural basis of mTORC3, the cofactors and chromatin mechanisms that determine whether ETV7 acts as a repressor or activator at specific loci, and whether ETV7's cytoplasmic (mTORC3) and nuclear (transcriptional) functions are coordinated or independent.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No cryo-EM or crystal structure of mTORC3 or ETV7 in complex with mTOR","Genome-wide ChIP-seq in primary human tissues not performed","Functional interplay between mTORC3 assembly and transcriptional programs unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,1,7,9,12,14,15,16]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2,7,9,12,14,15,16]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,7,9,12,14,15]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[8,13]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,13]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[15,16]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,4,11]}],"complexes":["mTORC3"],"partners":["MTOR","ETV6","SERPINE1","DNAJC15","TNFRSF1A","STAT3"],"other_free_text":[]},"mechanistic_narrative":"ETV7 is an ETS-family transcription factor that functions as both a transcriptional repressor and activator to regulate cell differentiation, proliferation, immune signaling, and drug resistance. In the nucleus, ETV7 binds ETS consensus motifs (GGAA core) via its ETS domain and uses its PNT/SAM domain for homo- and hetero-oligomerization and transcriptional repression; it directly represses SERPINE1, DNAJC15, and TNFRSF1A to modulate metastasis, chemoresistance, and NF-κB signaling, while activating IFIT3 and CXCL1 to promote tumor proliferation and immune evasion [PMID:26335051, PMID:30025229, PMID:37041130, PMID:38200280, PMID:41917269]. In the cytoplasm, ETV7 interacts with mTOR through dual PNT–FRB and ETS–LBE interfaces to assemble mTORC3, a rapamycin-insensitive mTOR complex lacking Raptor and Rictor that confers drug resistance [PMID:30258985, PMID:39337528]. ETV7 also drives CD8+ T cell terminal exhaustion by binding memory and exhaustion gene loci, and its depletion enhances antitumor T cell and CAR-T cell efficacy in vivo [PMID:39805956]."},"prefetch_data":{"uniprot":{"accession":"Q9Y603","full_name":"Transcription factor ETV7","aliases":["ETS translocation variant 7","ETS-related protein Tel2","Tel-related Ets factor","Transcription factor Tel-2"],"length_aa":341,"mass_kda":39.0,"function":"Transcriptional repressor; binds to the DNA sequence 5'-CCGGAAGT-3'. Isoform A does not seem to have a repressor activity. Isoform C does not seem to have a repressor activity","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9Y603/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ETV7","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ETV7","total_profiled":1310},"omim":[{"mim_id":"605255","title":"ETS VARIANT TRANSCRIPTION FACTOR 7; ETV7","url":"https://www.omim.org/entry/605255"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":15.0},{"tissue":"skin 1","ntpm":14.5}],"url":"https://www.proteinatlas.org/search/ETV7"},"hgnc":{"alias_symbol":["TEL2","TEL-2"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y603","domains":[{"cath_id":"1.10.150.50","chopping":"42-121","consensus_level":"high","plddt":82.4686,"start":42,"end":121},{"cath_id":"1.10.10.10","chopping":"227-309","consensus_level":"high","plddt":89.364,"start":227,"end":309}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y603","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y603-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y603-F1-predicted_aligned_error_v6.png","plddt_mean":64.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ETV7","jax_strain_url":"https://www.jax.org/strain/search?query=ETV7"},"sequence":{"accession":"Q9Y603","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y603.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y603/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y603"}},"corpus_meta":[{"pmid":"20427287","id":"PMC_20427287","title":"Tti1 and Tel2 are critical factors in mammalian target of rapamycin complex assembly.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20427287","citation_count":204,"is_preprint":false},{"pmid":"18160036","id":"PMC_18160036","title":"Tel2 regulates the stability of PI3K-related protein kinases.","date":"2007","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/18160036","citation_count":183,"is_preprint":false},{"pmid":"20864032","id":"PMC_20864032","title":"CK2 phospho-dependent binding of R2TP complex to TEL2 is essential for mTOR and SMG1 stability.","date":"2010","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/20864032","citation_count":159,"is_preprint":false},{"pmid":"20801936","id":"PMC_20801936","title":"Tel2 structure and function in the Hsp90-dependent maturation of mTOR and ATR complexes.","date":"2010","source":"Genes & 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factor expressed in human leukemia, regulates monocytic differentiation of U937 Cells and blocks the inhibitory effect of TEL1 on ras-induced cellular transformation.","date":"2004","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/15342392","citation_count":18,"is_preprint":false},{"pmid":"35385752","id":"PMC_35385752","title":"Tel2 regulates redifferentiation of bipotential progenitor cells via Hhex during zebrafish liver regeneration.","date":"2022","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/35385752","citation_count":18,"is_preprint":false},{"pmid":"18076567","id":"PMC_18076567","title":"Tel2: a common partner of PIK-related kinases and a link between DNA checkpoint and nutritional response?","date":"2007","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/18076567","citation_count":18,"is_preprint":false},{"pmid":"24357328","id":"PMC_24357328","title":"Zebrafish ETV7 regulates red blood 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medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38282047","citation_count":8,"is_preprint":false},{"pmid":"19029808","id":"PMC_19029808","title":"Mec1 function in the DNA damage response does not require its interaction with Tel2.","date":"2008","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/19029808","citation_count":7,"is_preprint":false},{"pmid":"37175973","id":"PMC_37175973","title":"TTT (Tel2-Tti1-Tti2) Complex, the Co-Chaperone of PIKKs and a Potential Target for Cancer Chemotherapy.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37175973","citation_count":6,"is_preprint":false},{"pmid":"30478527","id":"PMC_30478527","title":"Establishment of a transgenic mouse to model ETV7 expressing human tumors.","date":"2018","source":"Transgenic 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genomics","url":"https://pubmed.ncbi.nlm.nih.gov/38200280","citation_count":5,"is_preprint":false},{"pmid":"1928758","id":"PMC_1928758","title":"Morphological analysis of the cellular interaction between thymocytes and a thymic stromal cell line (TEL-2).","date":"1991","source":"The Anatomical record","url":"https://pubmed.ncbi.nlm.nih.gov/1928758","citation_count":5,"is_preprint":false},{"pmid":"22291956","id":"PMC_22291956","title":"Genetic and physical interactions between Tel2 and the Med15 Mediator subunit in Saccharomyces cerevisiae.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22291956","citation_count":3,"is_preprint":false},{"pmid":"38791386","id":"PMC_38791386","title":"Mitigation of Breast Cancer Cells' Invasiveness via Down Regulation of ETV7, Hippo, and PI3K/mTOR Pathways by Vitamin D3 Gold-Nanoparticles.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38791386","citation_count":3,"is_preprint":false},{"pmid":"22227188","id":"PMC_22227188","title":"Saccharomyces cerevisiae Tel2 plays roles in TORC signaling and telomere maintenance that can be mutationally separated.","date":"2011","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/22227188","citation_count":3,"is_preprint":false},{"pmid":"8742694","id":"PMC_8742694","title":"Morphological study of thymus stromal cells (TEL-2 cell) which play a role in the elimination of double positive immature thymocytes by phagocytosis.","date":"1996","source":"The Anatomical record","url":"https://pubmed.ncbi.nlm.nih.gov/8742694","citation_count":3,"is_preprint":false},{"pmid":"31323273","id":"PMC_31323273","title":"The effects of Tel2 on cardiomyocyte survival.","date":"2019","source":"Life 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/41917269","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":25550,"output_tokens":3764,"usd":0.066555},"stage2":{"model":"claude-opus-4-6","input_tokens":7215,"output_tokens":3044,"usd":0.168263},"total_usd":0.234818,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"ETV7 (TEL2) localizes to the nucleus, binds the same consensus ETS DNA-binding sequence (GGAA core motif) as TEL1/ETV6, and associates with itself and with TEL1 through the PNT (pointed) domain of TEL1 in doubly transfected HeLa cells.\",\n      \"method\": \"DNA binding assays, co-immunoprecipitation in transfected HeLa cells, antibody-based nuclear localization\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reciprocal interactions shown by Co-IP and DNA binding assay, single lab\",\n      \"pmids\": [\"10828014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"ETV7 (Tel-2) functions as a transcriptional repressor; only the isoform containing both the Pointed domain and the DNA-binding domain acts as a strong repressor. It represses the retinoic acid receptor alpha and BMP-6 gene promoters, suggesting a role as an inhibitor of differentiation.\",\n      \"method\": \"Reporter gene assays with isoform-specific constructs, domain deletion mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional dissection with multiple isoforms and domain mutants, single lab\",\n      \"pmids\": [\"11108721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ETV7 inhibits monocytic differentiation of U937 cells induced by vitamin D3; domain mutants lacking the PNT or functional ETS domain act as dominant negatives, inducing differentiation and blocking ETV7-mediated transcriptional repression. ETV7 also blocks the inhibitory effect of TEL1 on Ras-induced cellular transformation.\",\n      \"method\": \"Overexpression of wild-type and domain-deletion mutants, in vitro and in vivo growth assays, transcriptional reporter assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mutant functional dissection with multiple readouts, single lab\",\n      \"pmids\": [\"15342392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ETV7 augments proliferation and survival of mouse B cells and accelerates lymphoma development in Eμ-Myc transgenic mice, cooperating with Myc in B lymphomagenesis, with inactivation of the p53 pathway as a hallmark of TEL2/Eμ-Myc lymphomas.\",\n      \"method\": \"Transgenic mouse model (Eμ-Myc cross), bone marrow transplantation, in vivo tumor studies\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic epistasis with defined phenotypic readout in mouse model\",\n      \"pmids\": [\"15743832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Forced expression of ETV7 alone in mouse bone marrow causes myeloproliferative disease and blocks vitamin D3-induced differentiation of U937 and HL60 myeloid cells, identifying ETV7 as a bona fide oncogene that promotes proliferation while TEL1 inhibits it.\",\n      \"method\": \"Bone marrow transplantation, retroviral overexpression, chemical carcinogen (ENU) acceleration, differentiation assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo loss/gain-of-function with defined cellular phenotypes, replicated across cell lines and mouse model\",\n      \"pmids\": [\"16234363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The SAM domain of human ETV7 (TEL2) can inhibit the transcriptional activities of ETS1/ETS2 and TEL1 (ETV6), providing a mechanism by which ETV7 modulates output from these oncogenes via SAM domain-mediated interactions.\",\n      \"method\": \"Transcriptional reporter assays, SAM domain constructs, cross-species comparison with Drosophila Mae\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional reporter assays with domain-specific constructs, single lab\",\n      \"pmids\": [\"22615925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ETV7 regulates red blood cell development in zebrafish by controlling transcription of the lanosterol synthase (lss) gene in the cholesterol synthesis pathway; etv7 morpholino knockdown causes loss of hemoglobin-containing red blood cells, rescued by exogenous cholesterol.\",\n      \"method\": \"Morpholino knockdown in zebrafish, cholesterol rescue experiment, gene expression analysis\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with rescue experiment in zebrafish model, single lab\",\n      \"pmids\": [\"24357328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ETV7 (TEL2) inhibits cell migration and invasion in vitro and metastasis in vivo in nasopharyngeal carcinoma by directly suppressing the SERPINE1 promoter, as demonstrated by chromatin immunoprecipitation and luciferase assays showing direct ETV7 binding.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, migration/invasion assays, in vivo metastasis model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct promoter binding confirmed by ChIP and reporter assay, in vivo validation\",\n      \"pmids\": [\"26335051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ETV7 interacts with mTOR in the cytoplasm and assembles a third mTOR complex, mTORC3, which is independent of ETV7's transcriptional activity. mTORC3 is devoid of canonical mTORC1/2 components (Raptor, Rictor) but exhibits bimodal mTORC1/2 kinase activity and confers rapamycin resistance.\",\n      \"method\": \"Co-immunoprecipitation, size-exclusion chromatography, kinase activity assays, rapamycin sensitivity assays, rhabdomyosarcoma mouse model\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — complex assembly demonstrated biochemically and functionally, validated in vivo mouse model\",\n      \"pmids\": [\"30258985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ETV7 directly binds the DNAJC15 promoter, repressing DNAJC15 transcription, which reduces Doxorubicin sensitivity in breast cancer cells by increasing Doxorubicin efflux via nuclear pumps; DNA methylation may also contribute to this repression.\",\n      \"method\": \"Chromatin immunoprecipitation, promoter binding assays, siRNA knockdown, drug efflux assays, DNAJC15 overexpression rescue\",\n      \"journal\": \"Neoplasia (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct promoter binding shown by ChIP, functional rescue experiments, single lab\",\n      \"pmids\": [\"30025229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NOTCH1 intracellular domain overexpression in OSCC cells upregulates ETV7, which in turn negatively regulates SERPINE1 expression, placing ETV7 downstream of NOTCH1 signaling in a pathway that suppresses cell proliferation and migration.\",\n      \"method\": \"Gene expression profiling, ETV7 overexpression, SERPINE1 knockdown phenocopy, pathway epistasis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — epistasis supported by expression profiling and knockdown phenocopy, single lab\",\n      \"pmids\": [\"31827722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ETV7 promotes breast cancer stem-like cell plasticity and resistance to chemotherapy and radiotherapy by repressing a signature of Interferon-responsive genes; IFN-β treatment partially reverses the increased cancer stem cell population caused by ETV7 overexpression.\",\n      \"method\": \"Stable overexpression, transcriptome profiling, CD44+/CD24low population analysis, mammosphere formation assay, IFN-β rescue\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transcriptome profiling with functional rescue, single lab\",\n      \"pmids\": [\"34315857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ETV7 directly binds to intron I of TNFRSF1A (encoding TNFR1), repressing its transcription and thereby reducing NF-κB signaling activation; ETV7 also competes with STAT3 for binding to the TNFRSF1A gene and recruits repressive chromatin remodelers to suppress TNFR1 expression.\",\n      \"method\": \"ChIP assay, promoter/intron binding assays, NF-κB signaling assays, competitive binding experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct DNA binding shown by ChIP, mechanistic competition with STAT3 demonstrated, multiple orthogonal methods\",\n      \"pmids\": [\"37041130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ETV7 binds to mTOR via two separate interaction interfaces: the ETV7 PNT domain interacts with the mTOR FRB sequence, and the ETV7 ETS domain interacts with the mTOR LBE sequence in the kinase domain. Forced expression of the mTOR FRB domain outcompetes mTOR for ETV7 binding and renders mTORC3-expressing rapamycin-resistant cells rapamycin-sensitive in vivo.\",\n      \"method\": \"Domain mapping by co-immunoprecipitation with truncation/deletion mutants, competition assay with FRB domain overexpression, in vivo rapamycin sensitivity assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — domain-level interaction mapping with functional in vivo competition experiment, multiple binding interfaces defined\",\n      \"pmids\": [\"39337528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ETV7 transcriptionally activates IFIT3 expression in colorectal cancer cells, as demonstrated by luciferase assay and RT-qPCR; IFIT3 knockdown reverses ETV7-driven proliferation and migration, establishing an ETV7/IFIT3 transcriptional axis.\",\n      \"method\": \"Luciferase reporter assay, RT-qPCR, siRNA knockdown, rescue experiments, proliferation/migration assays\",\n      \"journal\": \"Functional & integrative genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct transcriptional activation shown by reporter assay with rescue experiment, single lab\",\n      \"pmids\": [\"38200280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ETV7 drives CD8+ T cell differentiation from memory to terminal exhaustion by binding directly to memory gene loci and exhaustion gene loci, functionally skewing transcriptional programs toward exhaustion; ETV7 depletion enhances antitumor efficacy of CD8+ T cells and CAR-T cells in solid tumors.\",\n      \"method\": \"scRNA-seq, scATAC-seq, ETV7 overexpression and depletion, in vivo tumor models, direct chromatin binding analysis\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multi-omic single-cell analysis with direct chromatin binding, loss- and gain-of-function, in vivo validation\",\n      \"pmids\": [\"39805956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ETV7 transcriptionally upregulates CXCL1, leading to increased neutrophil recruitment and enhanced neutrophil extracellular trap (NET) formation in the tumor microenvironment, promoting tumor aggressiveness and 5-FU resistance in colorectal cancer; pharmacological inhibition of CXCL1 or NETs degradation attenuates ETV7-driven malignant phenotypes.\",\n      \"method\": \"Luciferase reporter assay, ChIP, CXCL1 neutralization, NETs inhibition, in vitro and in vivo functional assays\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transcriptional target validated by ChIP and reporter, pathway confirmed by pharmacological inhibition, single lab\",\n      \"pmids\": [\"41917269\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ETV7 is an ETS-family transcriptional repressor (with some activating targets) that physically interacts with mTOR via its PNT and ETS domains to assemble a rapamycin-insensitive third mTOR complex (mTORC3) in the cytoplasm, while in the nucleus it directly binds promoters/enhancers of target genes (including SERPINE1, DNAJC15, TNFRSF1A, IFIT3, and CXCL1) to regulate cancer cell proliferation, stemness, chemoresistance, inflammation, and immune evasion, and also controls CD8+ T cell fate by binding memory and exhaustion gene loci to drive terminal exhaustion.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ETV7 is an ETS-family transcription factor that functions as both a transcriptional repressor and activator to regulate cell differentiation, proliferation, immune signaling, and drug resistance. In the nucleus, ETV7 binds ETS consensus motifs (GGAA core) via its ETS domain and uses its PNT/SAM domain for homo- and hetero-oligomerization and transcriptional repression; it directly represses SERPINE1, DNAJC15, and TNFRSF1A to modulate metastasis, chemoresistance, and NF-κB signaling, while activating IFIT3 and CXCL1 to promote tumor proliferation and immune evasion [PMID:26335051, PMID:30025229, PMID:37041130, PMID:38200280, PMID:41917269]. In the cytoplasm, ETV7 interacts with mTOR through dual PNT–FRB and ETS–LBE interfaces to assemble mTORC3, a rapamycin-insensitive mTOR complex lacking Raptor and Rictor that confers drug resistance [PMID:30258985, PMID:39337528]. ETV7 also drives CD8+ T cell terminal exhaustion by binding memory and exhaustion gene loci, and its depletion enhances antitumor T cell and CAR-T cell efficacy in vivo [PMID:39805956].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing ETV7 as a nuclear ETS-family transcriptional repressor resolved the basic molecular identity of this gene, showing it binds the canonical GGAA motif and self-associates via its PNT domain.\",\n      \"evidence\": \"DNA binding assays, co-immunoprecipitation in transfected HeLa cells, reporter gene assays with isoform and domain deletion mutants\",\n      \"pmids\": [\"10828014\", \"11108721\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No genome-wide binding profile to define the full target repertoire\", \"Repression mechanism (corepressor recruitment, chromatin modification) not identified\", \"Reporter-based; endogenous gene repression not shown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrating that ETV7 cooperates with Myc in lymphomagenesis and causes myeloproliferative disease upon forced expression established ETV7 as a bona fide oncogene that promotes proliferation while blocking myeloid differentiation.\",\n      \"evidence\": \"Eμ-Myc transgenic mouse crosses, bone marrow transplantation, retroviral overexpression, differentiation assays in U937/HL60 cells\",\n      \"pmids\": [\"15743832\", \"16234363\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional targets mediating oncogenicity not identified\", \"Relationship to p53 pathway inactivation is correlative\", \"Human relevance of mouse phenotypes not confirmed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showing that ETV7's SAM domain inhibits ETS1, ETS2, and ETV6 transcriptional activities revealed a cross-regulatory mechanism among ETS factors, explaining how ETV7 can antagonize the tumor-suppressive function of ETV6.\",\n      \"evidence\": \"Transcriptional reporter assays with SAM domain constructs, cross-species comparison with Drosophila Mae\",\n      \"pmids\": [\"22615925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interaction with ETS1/ETS2 not demonstrated by co-IP\", \"Endogenous relevance in mammalian cells not shown\", \"Stoichiometric relationship between ETV7 and other ETS factors unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of SERPINE1 as a direct transcriptional target repressed by ETV7 provided the first ChIP-validated target gene linking ETV7 to a specific cellular phenotype — suppression of metastasis.\",\n      \"evidence\": \"ChIP assay and luciferase reporter assay for direct promoter binding, migration/invasion assays, in vivo metastasis model in nasopharyngeal carcinoma\",\n      \"pmids\": [\"26335051\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide ChIP-seq not performed to define all direct targets\", \"Whether ETV7–SERPINE1 axis operates in other cancer types untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovery that ETV7 assembles a rapamycin-insensitive third mTOR complex (mTORC3) in the cytoplasm, independent of its transcriptional activity, fundamentally expanded ETV7's functional repertoire beyond transcription and explained a mechanism of mTOR inhibitor resistance.\",\n      \"evidence\": \"Co-immunoprecipitation, size-exclusion chromatography, kinase activity assays, rapamycin sensitivity assays, rhabdomyosarcoma mouse model\",\n      \"pmids\": [\"30258985\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of mTORC3 assembly unknown\", \"Full subunit composition of mTORC3 not defined\", \"Endogenous complex stoichiometry not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of DNAJC15 as a second direct transcriptional target of ETV7, whose repression mediates doxorubicin resistance via increased drug efflux, linked ETV7's repressor activity to chemoresistance.\",\n      \"evidence\": \"ChIP, siRNA knockdown, drug efflux assays, DNAJC15 overexpression rescue in breast cancer cells\",\n      \"pmids\": [\"30025229\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of DNA methylation vs. ETV7 binding to DNAJC15 repression not delineated\", \"Generalizability beyond breast cancer not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating that ETV7 binds TNFRSF1A intron I and competes with STAT3 for binding, repressing TNFR1 and dampening NF-κB signaling, revealed a mechanism by which ETV7 modulates inflammatory signaling through direct chromatin competition.\",\n      \"evidence\": \"ChIP assay, NF-κB signaling assays, competitive binding experiments with STAT3\",\n      \"pmids\": [\"37041130\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether STAT3 displacement is direct or allosteric is unresolved\", \"Identity of recruited chromatin remodelers not specified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapping the dual ETV7–mTOR interaction interfaces (PNT–FRB and ETS–LBE) and showing that FRB domain overexpression restores rapamycin sensitivity in vivo provided a structural rationale and a potential therapeutic strategy to disrupt mTORC3.\",\n      \"evidence\": \"Domain mapping by co-immunoprecipitation with truncation/deletion mutants, in vivo competition assay with FRB overexpression\",\n      \"pmids\": [\"39337528\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structural data for the ETV7–mTOR interfaces\", \"Whether pharmacological small molecules can mimic FRB competition unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Establishing that ETV7 acts as a transcriptional activator of IFIT3 in colorectal cancer demonstrated that ETV7 is not exclusively a repressor, and that an ETV7–IFIT3 axis drives proliferation.\",\n      \"evidence\": \"Luciferase reporter assay, RT-qPCR, siRNA knockdown and rescue in colorectal cancer cells\",\n      \"pmids\": [\"38200280\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism switching ETV7 from repressor to activator at specific loci not explained\", \"Single cancer type studied\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealing that ETV7 drives CD8+ T cell terminal exhaustion by binding memory and exhaustion gene loci established ETV7 as a key immune checkpoint transcription factor, with its depletion enhancing antitumor T cell and CAR-T efficacy.\",\n      \"evidence\": \"scRNA-seq, scATAC-seq, ETV7 overexpression and depletion, in vivo tumor models, direct chromatin binding analysis\",\n      \"pmids\": [\"39805956\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cofactors mediating ETV7's chromatin remodeling at exhaustion loci unknown\", \"Whether ETV7's T cell role is mTORC3-dependent not addressed\", \"Clinical translation to CAR-T engineering not validated in patients\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showing that ETV7 transcriptionally activates CXCL1, promoting neutrophil recruitment and NET formation in the tumor microenvironment, connected ETV7 to immune cell remodeling and 5-FU resistance in colorectal cancer.\",\n      \"evidence\": \"ChIP, luciferase reporter assay, CXCL1 neutralization, NETs inhibition, in vivo and in vitro functional assays\",\n      \"pmids\": [\"41917269\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ETV7 directly regulates other chemokines is unexplored\", \"Mechanism of NET-mediated chemoresistance downstream of CXCL1 not fully dissected\", \"Single lab study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of mTORC3, the cofactors and chromatin mechanisms that determine whether ETV7 acts as a repressor or activator at specific loci, and whether ETV7's cytoplasmic (mTORC3) and nuclear (transcriptional) functions are coordinated or independent.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No cryo-EM or crystal structure of mTORC3 or ETV7 in complex with mTOR\", \"Genome-wide ChIP-seq in primary human tissues not performed\", \"Functional interplay between mTORC3 assembly and transcriptional programs unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 1, 7, 9, 12, 14, 15, 16]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2, 7, 9, 12, 14, 15, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 7, 9, 12, 14, 15]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0074160\", \"supporting_discovery_ids\": [1, 7, 9, 12, 14, 16]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [15, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 4, 11]}\n    ],\n    \"complexes\": [\n      \"mTORC3\"\n    ],\n    \"partners\": [\n      \"MTOR\",\n      \"ETV6\",\n      \"SERPINE1\",\n      \"DNAJC15\",\n      \"TNFRSF1A\",\n      \"STAT3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}