{"gene":"BCOR","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2000,"finding":"BCOR (BCoR) was identified as a novel corepressor that interacts selectively with the POZ domain of BCL6 but not with eight other POZ proteins tested. BCOR can function as a corepressor when tethered to DNA, potentiates BCL6 repression when overexpressed, and interacts in vivo with specific class I and II histone deacetylases (HDACs). The BCL6/BCOR interaction is mutually exclusive with BCL6 interactions with SMRT and N-CoR.","method":"Co-immunoprecipitation, DNA-tethering repression assay, overexpression, in vivo interaction studies","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, functional tethering assay, selectivity demonstrated against 8 control POZ proteins; replicated in subsequent studies","pmids":["10898795"],"is_preprint":false},{"year":2006,"finding":"BCOR forms a novel complex containing Polycomb group (PcG) proteins (RING1, RYBP, NSPC1, RNF2) and SCF ubiquitin ligase components (SKP1, FBXL10/JHDM1B). RNF2 in the complex is an E3 ligase for mono-ubiquitylation of H2A. BCOR also coimmunoprecipitates isoforms of FBXL10 containing a JmjC domain with histone H3K36 demethylase activity. BCOR complex components and mono-ubiquitylated H2A co-localize to BCL6 target genes, indicating the complex recruits PcG proteins and two distinct E3 ubiquitin ligases plus a histone demethylase to BCL6 targets.","method":"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), complex purification/mass spectrometry","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP at endogenous targets, multiple orthogonal methods in one study, replicated by subsequent work on PRC1.1","pmids":["16943429"],"is_preprint":false},{"year":2009,"finding":"BCOR mutation in mesenchymal stem cells (MSCs) from an OFCD patient increased osteo-dentinogenic potential. AP-2alpha was identified as a repressive target of BCOR; BCOR mutation caused abnormal activation of AP-2alpha. Gain- and loss-of-function assays demonstrated AP-2alpha mediates the increased osteo-dentinogenic capacity. BCOR maintained gene silencing through epigenetic mechanisms; its mutation increased histone H3K4 and H3K36 methylation at silenced target genes in MSCs, reactivating their transcription.","method":"Patient-derived MSC culture, gain/loss-of-function assays, ChIP for histone modifications, gene expression analysis","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — gain and loss-of-function with defined molecular readout (H3K4/H3K36 methylation changes by ChIP), patient-derived cells, multiple orthogonal methods","pmids":["19578371"],"is_preprint":false},{"year":2007,"finding":"Left-sided expression of BCOR (xtBcor) in Xenopus tropicalis is required for vertebrate laterality determination. Morpholino knockdown of xtBcor caused reversed cardiac orientation and disorganized gut patterning specifically when injected into the left side of embryos, demonstrating a left-sided requirement. xtBcor knockdown also caused ocular defects (microphthalmia, coloboma) and downregulated xtPitx2c expression, placing BCOR upstream of Pitx2c in a laterality specification pathway.","method":"Morpholino antisense knockdown in Xenopus tropicalis, in situ hybridization for Pitx2c, phenotypic analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — morpholino KD with specific laterality phenotype and downstream target (Pitx2c) identified, single lab but orthogonal readouts","pmids":["17517692"],"is_preprint":false},{"year":2008,"finding":"Loss-of-function Bcor alleles in mouse embryonic stem cells result in altered expression of key developmental genes (Oct3/4, Nanog, Fgf5, Bmp4, Brachyury, Flk1) during differentiation into ectoderm, mesoderm and hematopoietic lineages, with normal expression restored upon re-expression of Bcor. Bcor loss of function shows a strong parent-of-origin effect, suggesting a requirement in extraembryonic development. Chimeric animals show reduced contribution to B and T cells and erythrocytes, and kinked/shortened tails consistent with reduced Brachyury expression.","method":"ES cell loss-of-function alleles, in vitro differentiation assays, rescue by re-expression, chimeric mouse analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal loss-of-function alleles with in vitro differentiation and in vivo chimeric rescue, single lab","pmids":["18795143"],"is_preprint":false},{"year":2014,"finding":"BCL6, BCOR, and SIRT1 form a complex that directly represses Gli1 and Gli2 effectors of the Sonic Hedgehog (SHH) pathway. BCL6 recruits BCOR corepressor and SIRT1 deacetylase to Gli1/Gli2 promoters to suppress SHH signaling. This BCL6/BCOR/SIRT1 complex is required for neurogenesis and tumor suppression of granule neuron progenitor (GNP)-derived medulloblastoma in mice.","method":"Co-immunoprecipitation, ChIP, gain/loss-of-function in mouse GNPs and human MB cells, in vivo mouse medulloblastoma model","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP at target promoters, in vivo genetic mouse model with fully penetrant tumor suppression phenotype, multiple orthogonal methods","pmids":["25490446"],"is_preprint":false},{"year":2016,"finding":"BCOR regulates myeloid cell proliferation and differentiation as a component of variant PRC1 (PRC1.1). Conditional Bcor loss-of-function in mouse bone marrow increased proliferation and differentiation of myeloid cells with upregulation of Hox genes. Bcor mutation reduced protein levels of RING1B (H2A ubiquitin E3 ligase subunit of PRC1) and reduced H2AK119 ubiquitination upstream of upregulated HoxA genes.","method":"Conditional mouse knockout, bone marrow assays, global RNA expression profiling, ChIP for H2AK119ub, protein analysis","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mouse model with ChIP demonstrating H2AK119ub loss at HoxA loci, global expression profiling, confirmed in patient AML samples","pmids":["26847029"],"is_preprint":false},{"year":2017,"finding":"BCOR acts as a tumor suppressor in T lymphocyte malignancies. Mice with deletion of Bcor exon 4 (removing the BCL6-binding domain) showed augmented thymocyte proliferative capacity and strong propensity to induce acute T-cell lymphoblastic leukemia (T-ALL), mostly in a Notch-dependent manner. ChIP-seq analysis revealed BCOR is recruited to the Myc promoter and restrains its activation in thymocytes. BCOR also targeted other NOTCH1 target genes. BCL6-deficient thymocytes behaved similarly to Bcor-deficient thymocytes.","method":"Conditional Bcor exon 4 deletion mouse model, ChIP-seq, gene expression profiling, in vitro proliferation assay","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mouse, ChIP-seq establishing direct BCOR occupancy at Myc promoter, Notch-dependence demonstrated, corroborated by BCL6 KO parallel experiment","pmids":["28827447"],"is_preprint":false},{"year":2017,"finding":"Bcor loss-of-function mutations are frequently found in spontaneous Eμ-Myc mouse lymphomas. Disruptive Bcor mutations cooperate with Myc overexpression (and with Cdkn2a loss, Nras, Kras) in lymphomagenesis, demonstrating a functional tumor suppressor role for Bcor in vivo in a MYC-driven malignancy.","method":"Whole-genome sequencing of spontaneous Eμ-Myc lymphomas, somatic mutation analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — sequencing of spontaneous tumors establishes in vivo cooperativity, but no functional rescue or in vitro reconstitution; single study","pmids":["28262675"],"is_preprint":false},{"year":2018,"finding":"BCOR is a critical component of the non-canonical PRC1.1 complex required for maintaining primed pluripotency in human embryonic stem cells (ESCs). BCOR depletion leads to erosion of Polycomb domains at key developmental loci and initiation of differentiation along endoderm and mesoderm lineages. The C-terminus of BCOR regulates assembly and targeting of the PRC1.1 complex, while the N-terminus contributes to BCOR-PRC1.1 repressor function.","method":"BCOR depletion (siRNA/shRNA) in human ESCs, ChIP-seq, ATAC-seq, RNA-seq, domain deletion mapping","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — KD in human ESCs with ChIP-seq and RNA-seq revealing Polycomb domain erosion; domain-mapping of N- and C-terminus functions; multiple orthogonal methods","pmids":["29337181"],"is_preprint":false},{"year":2018,"finding":"Bcor truncation (deletion of exons 9-10) in hematopoietic cells leads to carboxyl-terminal truncated BCOR that fails to interact with core effector components of PRC1.1. This cooperates with Tet2 deletion to cause lethal myelodysplastic syndrome (MDS) with anemia, leukocytopenia, and morphological dysplasia. Transcriptional profiling showed derepression of Cebp family myeloid regulators and HoxA cluster genes in Bcor mutant progenitors.","method":"Conditional Bcor exon 9-10 deletion mouse model, secondary transplantation, transcriptional profiling, protein interaction studies","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO mouse with defined molecular mechanism (loss of PRC1.1 core interaction), cooperativity with Tet2 loss, transplantation confirming clonal disease","pmids":["30228234"],"is_preprint":false},{"year":2019,"finding":"Bcor inactivation in hematopoietic stem cells (HSCs) expands myeloid progenitors and cooperates with oncogenic KrasG12D to initiate fully transplantable acute leukemia. ChIP-seq reveals differential regulation of a subset of PRC1-target genes including HSC-associated transcription factors Hoxa7/9, establishing BCOR's role in regulating cell fate decisions through PRC1 target gene control.","method":"Conditional mouse knockout, bone marrow transplantation, ChIP-seq, gene expression analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, ChIP-seq at PRC1 targets, fully transplantable leukemia model, genetic epistasis with KrasG12D","pmids":["30902969"],"is_preprint":false},{"year":2019,"finding":"BCOR interacts with androgen receptor (AR) in a hormone-dependent manner in castration-resistant prostate cancer (CRPC) cells. Genome-wide analysis shows BCOR is recruited to the majority of AR-binding chromatin sites in an androgen-dependent fashion. BCOR depletion decreases H2A K119 monoubiquitination and increases mRNA expression at androgen-repressed genes including HOX genes. BCOR depletion impairs proliferation and viability of CRPC cells, inducing apoptosis.","method":"Co-immunoprecipitation, ChIP-seq, siRNA knockdown, proliferation/apoptosis assays in CRPC cells","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP-seq, KD with H2AK119ub ChIP validation at target genes, functional phenotype in CRPC cells; single lab, multiple orthogonal methods","pmids":["31925334"],"is_preprint":false},{"year":2020,"finding":"BCOR directly regulates Igf2 through the PRC1.1 complex in granule neuron progenitors (GNPs). Deletion of Bcor exons 9/10 in GNPs leads to reduced H2AK119Ub at the Igf2 promoter and aberrant upregulation of Igf2. Combined with Ptch1 loss, this results in fully penetrant medulloblastomas. Ectopic Igf2 overexpression alone was sufficient to drive tumorigenesis in Ptch1+/- GNPs, placing BCOR-PRC1.1 repression of Igf2 as a key tumor suppressor mechanism.","method":"Genetically engineered mouse model (Bcor exon 9/10 deletion in GNPs), ChIP for H2AK119Ub at Igf2 promoter, ectopic Igf2 overexpression experiment, gene expression analysis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP demonstrating direct H2AK119Ub loss at Igf2, rescue by ectopic Igf2 overexpression, in vivo mouse tumor model with genetic epistasis","pmids":["32820036"],"is_preprint":false},{"year":2020,"finding":"NMR structure of the BCOR PUFD domain shows that its termini (critical for binding PCGF1 and KDM2B) are disordered. This suggests a hierarchical assembly: BCOR PUFD termini become structurally ordered upon binding PCGF1, which then allows stable association with KDM2B. Unlike BCORL1 PUFD, BCOR PUFD alone does not stably assemble with KDM2B; additional residues N-terminal to the PUFD are required. BCOR internal tandem duplications (ITDs) map to the PUFD termini and disrupt PRC1.1 assembly, suggesting loss of PRC1.1 assembly is a critical molecular event in ITD-driven tumorigenesis.","method":"NMR structure determination, 15N T2 relaxation measurements, in vitro binding studies with BCOR ITD mutant, protein biochemistry","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with functional validation by binding assays and ITD mutant; single lab but rigorous structural and biochemical methods","pmids":["32628469"],"is_preprint":false},{"year":2020,"finding":"BCOR mutations in myelodysplastic syndrome/AML disrupt assembly of the noncanonical PRC1.1 complex by selectively unlinking the RING-PCGF enzymatic core from the chromatin-targeting auxiliary subcomplex. BCOR-mutated PRC1.1 localizes to chromatin but lacks repressive activity, leading to epigenetic reprogramming and transcriptional activation at target loci. A set of functional PRC1.1 targets driving aberrant oncogenic signaling was defined; activation confers acquired treatment resistance while sensitizing to targeted kinase inhibition.","method":"Biochemical complex assembly studies, ChIP-seq in BCOR-mutated patient samples and cell lines, RNA-seq, kinase inhibitor sensitivity assays","journal":"Blood cancer discovery","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical reconstitution of PRC1.1 complex with BCOR mutants, ChIP-seq and RNA-seq in patient samples and cell lines, drug sensitivity rescue experiment","pmids":["35015684"],"is_preprint":false},{"year":2021,"finding":"BCOR acts as a suppressor of plasmacytoid DC (pDC) and conventional DC type 2 (cDC2) numbers during Flt3 ligand-mediated emergency DC development. BCOR restricts clonal expansion, especially for cDC2s, and suppresses clonal fate potential, especially for pDCs. This was established using CRISPR-validated SIS-seq clonal multi-omics.","method":"Clonal multi-omics (SIS-seq), CRISPR validation, paired sister-clone fate assays","journal":"Immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with clonal fate tracking and sister-clone comparison; novel method but single lab","pmids":["33862015"],"is_preprint":false},{"year":2021,"finding":"BCOR K607E mutation in T-cell lymphoma reduces binding affinity of mutant BCOR to BCL6, PCGF1, and RING1B proteins compared to wild-type BCOR. Ectopic expression of BCOR K607E significantly enhanced cell proliferation, AKT phosphorylation, and IL-2 expression with upregulated HOX and S100 protein gene expression. BCOR silencing produced similar effects, indicating the mutation acts as loss-of-function.","method":"Immunoprecipitation, western blotting, transfection/siRNA, DNA microarray, cell proliferation assay","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP showing reduced binding, functional OE and KD with proliferation/signaling readouts; single lab, multiple methods but no in vivo validation","pmids":["33468080"],"is_preprint":false},{"year":2020,"finding":"BCOR binding to the MLL fusion partner AF9 is essential for MLL-AF9 leukemogenesis. Protein structures of AF9 complexes with BCOR and CBX8 were determined, showing binding of AF4, DOT1L, BCOR, and CBX8 to AF9 is mutually exclusive. Point mutations selectively disrupting BCOR/MLL-AF9 binding caused partial differentiation, increased proliferation, and abrogated leukemogenic potential in a mouse model. MLL-AF9 mutant deficient for BCOR binding reduces EYA1 phosphatase expression and c-Myc protein level, altering MYC-driven and SIX-regulated gene expression programs.","method":"Protein structure determination (AF9 complexes), site-directed mutagenesis, bone marrow transplantation mouse leukemia model, gene expression analysis","journal":"Blood cancer discovery","confidence":"High","confidence_rationale":"Tier 1 / Strong — protein structure solved, selective point mutants, in vivo mouse leukemia model abrogation, downstream mechanism (EYA1, c-Myc) identified","pmids":["32954361"],"is_preprint":false},{"year":2013,"finding":"BCOR (BCoR) is recruited to the CDKN1A promoter by FBI-1 (ZBTB7A) via the adaptor MBD3. FBI-1 interacts with BCOR (as well as NCoR and SMRT) to repress transcription. MBD3 differentially regulates these interactions: it decreases FBI-1/NCoR-SMRT interaction but increases FBI-1/BCoR interaction. BCoR interacts with the Mi-2/NuRD-HDAC complex, DNMTs, and HP1, contributing to epigenetic repression of CDKN1A by DNA methylation.","method":"Co-immunoprecipitation, ChIP, promoter reporter assay, siRNA knockdown","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and ChIP demonstrating complex at CDKN1A promoter, siRNA functional validation, multiple interactions mapped; single lab","pmids":["23658227"],"is_preprint":false},{"year":2014,"finding":"IRF8 interacts directly with BCOR; the α-helical region of IRF8 and the BCL6-binding domain of BCOR are required for this interaction. IRF8 also interacts directly with BCL6. IRF8 knockdown represses Bcor and enhances Bcl6 transcription in mouse B cell lymphoma cells, suggesting a regulatory relationship within a BCOR-BCL6-IRF8 complex modulating germinal center B cell transcriptional regulation.","method":"Retrovirus-based protein complementation assay screen, direct interaction validation, siRNA knockdown with qPCR","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — PCA screen plus direct interaction validation, domain mapping; siRNA functional follow-up; single lab","pmids":["25331958"],"is_preprint":false},{"year":2010,"finding":"Bcor is expressed in both dental epithelium and mesenchyme during mouse molar development. Lentivirus-mediated knockdown of Bcor in dental mesenchymal cells at E14.5 causes dentinogenesis defects and retardation of tooth root development, demonstrating a functional requirement for Bcor in the mesenchyme during early tooth development.","method":"In situ hybridization for expression profiling, lentivirus-mediated RNAi knockdown in dental mesenchyme, morphological analysis","journal":"Cell and tissue research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — lentiviral KD with defined cellular phenotype (dentinogenesis defect) in primary tissue; single lab","pmids":["20563598"],"is_preprint":false},{"year":2020,"finding":"Bcor knockout in mice causes impaired erythroid development (macrocytosis, anemia) and enhanced thrombopoiesis. Double knockout of Bcor and Dnmt3a leads to fully penetrant acute erythroid leukemia (AEL) characterized by expansion of c-Kit+/Ter119+ blasts. Transcriptomic analysis revealed aberrant erythroid skewing driven by epigenetic changes affecting GATA1-2 transcription factors and cell-cycle regulators (Mdm2, Tp53). Demethylating agents significantly impacted leukemic burden and survival in these mice.","method":"Conditional mouse KO, secondary transplantation, transcriptomic analysis, demethylating agent treatment in vivo","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — double KO mouse model with defined AEL phenotype and transcriptomic mechanism; drug response confirms epigenetic dependency; single lab","pmids":["33159179"],"is_preprint":false}],"current_model":"BCOR is a transcriptional corepressor that selectively binds the BCL6 POZ domain and recruits class I/II HDACs, Polycomb group proteins, and SCF ubiquitin ligase components to form the non-canonical PRC1.1 complex, which deposits H2AK119 monoubiquitination at target loci (including HOX genes, Gli1/Gli2, Igf2, and AR-repressed genes) to silence them; disease-causing mutations or ITDs in the BCOR PUFD domain disrupt PRC1.1 complex assembly, abolishing repressive chromatin function and leading to epigenetic reprogramming, aberrant activation of oncogenic signaling programs, and malignant transformation across hematopoietic, neural, mesenchymal, and epithelial lineages."},"narrative":{"mechanistic_narrative":"BCOR is a transcriptional corepressor that nucleates a non-canonical Polycomb repressive complex (PRC1.1) to silence developmental and oncogenic gene programs across hematopoietic, neural, mesenchymal, and epithelial lineages [PMID:10898795, PMID:26847029, PMID:29337181]. It was first defined as a selective binding partner of the BCL6 POZ domain — an interaction mutually exclusive with BCL6's association with SMRT/N-CoR — that potentiates BCL6-mediated repression and recruits class I/II HDACs [PMID:10898795]. BCOR assembles PRC1.1 by linking the RING1/RNF2-PCGF1 catalytic core, which monoubiquitinates histone H2A at K119, to the chromatin-targeting subunit KDM2B/FBXL10 (a JmjC H3K36 demethylase) together with RYBP, NSPC1, and SKP1; these components and H2AK119ub co-occupy BCL6 target genes [PMID:16943429]. The BCOR C-terminal PUFD domain mediates this assembly: its termini are disordered and become ordered upon binding PCGF1, enabling stable KDM2B association, and internal tandem duplications mapping to the PUFD termini disrupt PRC1.1 assembly [PMID:32628469]. Through deposition of H2AK119ub, BCOR-PRC1.1 represses HOX genes, Myc, Gli1/Gli2, Igf2, and androgen-repressed loci, and loss of BCOR or its truncation reduces RING1B levels and H2AK119ub at these targets, driving their derepression [PMID:26847029, PMID:28827447, PMID:32820036, PMID:31925334]. BCOR functions as a tumor suppressor: disruptive mutations or C-terminal truncations that unlink the enzymatic core from the chromatin-targeting subcomplex leave PRC1.1 chromatin-bound but transcriptionally inactive, causing epigenetic reprogramming, and cooperate with Tet2 loss, Dnmt3a loss, oncogenic Kras, and Myc to produce myelodysplastic syndrome, acute leukemias, and medulloblastoma [PMID:30228234, PMID:35015684, PMID:30902969, PMID:33159179, PMID:32820036]. BCOR also has developmental roles in vertebrate laterality, embryonic stem cell pluripotency, and tooth development [PMID:17517692, PMID:29337181, PMID:20563598].","teleology":[{"year":2000,"claim":"Established BCOR as a dedicated corepressor for BCL6, answering how the BCL6 POZ domain enacts transcriptional silencing through a partner distinct from canonical SMRT/N-CoR.","evidence":"Reciprocal Co-IP, DNA-tethering repression assay, and selectivity screen against eight other POZ proteins","pmids":["10898795"],"confidence":"High","gaps":["HDAC recruitment shown by in vivo interaction but not biochemically reconstituted","Genome-wide target loci not defined at this stage"]},{"year":2006,"claim":"Defined the molecular composition of the BCOR complex, revealing it recruits Polycomb proteins and two E3 ubiquitin ligases to deposit H2A monoubiquitination at BCL6 targets — the basis of PRC1.1.","evidence":"Complex purification/mass spectrometry, reciprocal Co-IP, and ChIP at endogenous BCL6 targets","pmids":["16943429"],"confidence":"High","gaps":["Hierarchy of subunit assembly not resolved","Functional consequence of H2A ubiquitination on transcription not directly demonstrated"]},{"year":2007,"claim":"Showed BCOR has a developmental role beyond corepression by acting upstream of Pitx2c in vertebrate laterality determination.","evidence":"Side-specific morpholino knockdown in Xenopus tropicalis with in situ hybridization and phenotypic analysis","pmids":["17517692"],"confidence":"Medium","gaps":["Molecular mechanism linking BCOR to Pitx2c not defined","Morpholino-based, single-organism evidence"]},{"year":2008,"claim":"Demonstrated BCOR controls developmental gene expression during stem cell differentiation and is required for normal hematopoietic and embryonic lineage contribution.","evidence":"ES cell loss-of-function alleles, in vitro differentiation, rescue by re-expression, and chimeric mouse analysis","pmids":["18795143"],"confidence":"Medium","gaps":["Direct chromatin targets in ES cells not mapped","Parent-of-origin effect mechanism unexplained"]},{"year":2009,"claim":"Linked BCOR mutation to OFCD-associated phenotypes mechanistically, showing it maintains gene silencing via histone methylation control and represses AP-2alpha to restrain osteo-dentinogenic potential.","evidence":"Patient-derived MSCs, gain/loss-of-function, and ChIP for H3K4/H3K36 methylation at silenced targets","pmids":["19578371"],"confidence":"High","gaps":["Relationship between histone methylation changes and PRC1.1 ubiquitination activity not connected","Single patient genetic background"]},{"year":2014,"claim":"Extended the BCOR repressive module to SHH signaling, showing a BCL6/BCOR/SIRT1 complex silences Gli1/Gli2 to suppress medulloblastoma.","evidence":"Reciprocal Co-IP, ChIP at Gli promoters, and an in vivo GNP-derived medulloblastoma mouse model","pmids":["25490446"],"confidence":"High","gaps":["Interplay between SIRT1 deacetylation and PRC1.1 ubiquitination not dissected"]},{"year":2016,"claim":"Established that BCOR controls myeloid proliferation/differentiation as a PRC1.1 component by maintaining RING1B levels and H2AK119ub at HoxA loci.","evidence":"Conditional mouse knockout, expression profiling, and ChIP for H2AK119ub at HoxA, confirmed in patient AML","pmids":["26847029"],"confidence":"High","gaps":["How BCOR loss lowers RING1B protein not mechanistically explained"]},{"year":2017,"claim":"Defined BCOR as a tumor suppressor in T-lymphocyte malignancy by restraining Myc and Notch target genes through direct promoter occupancy.","evidence":"Conditional Bcor exon 4 deletion mouse, ChIP-seq at Myc promoter, with parallel BCL6 knockout","pmids":["28827447","28262675"],"confidence":"High","gaps":["Whether Myc repression requires PRC1.1 catalytic activity not tested directly"]},{"year":2018,"claim":"Mapped BCOR domain functions and showed C-terminal truncations sever PRC1.1 core interactions, driving Polycomb domain erosion in pluripotency and cooperating with Tet2 loss in MDS.","evidence":"Domain-deletion ChIP-seq/ATAC-seq in human ESCs and conditional Bcor exon 9-10 deletion mouse with transcriptional profiling","pmids":["29337181","30228234"],"confidence":"High","gaps":["Precise structural basis of PRC1.1 core loss not yet resolved at this stage"]},{"year":2019,"claim":"Demonstrated BCOR loss expands myeloid progenitors and cooperates with oncogenic Kras to initiate leukemia through dysregulation of PRC1 targets including Hoxa7/9, and extended PRC1.1 function to androgen-repressed genes in prostate cancer.","evidence":"Conditional mouse knockout with transplantation and ChIP-seq; Co-IP, ChIP-seq, and knockdown in castration-resistant prostate cancer cells","pmids":["30902969","31925334"],"confidence":"High","gaps":["Tissue-specific determinants of which PRC1.1 targets are derepressed not defined"]},{"year":2020,"claim":"Resolved the structural mechanism of PRC1.1 assembly and showed disease ITDs map to the PUFD termini to disrupt it, while defining a direct BCOR-PRC1.1/Igf2 tumor-suppressor axis in medulloblastoma.","evidence":"NMR structure with relaxation measurements and ITD-mutant binding assays; GNP mouse model with ChIP for H2AK119ub at Igf2 and rescue by ectopic Igf2","pmids":["32628469","32820036"],"confidence":"High","gaps":["Full-length assembled PRC1.1 structure not determined","Generality of single-effector (Igf2) sufficiency across tumor types unknown"]},{"year":2020,"claim":"Showed BCOR's role through additional protein interactions: binding the MLL fusion partner AF9 is required for MLL-AF9 leukemogenesis, and Bcor/Dnmt3a co-loss drives erythroid leukemia via GATA factor dysregulation.","evidence":"AF9 complex structures with selective point mutants in a mouse leukemia model; conditional double-knockout mouse with transcriptomics and demethylating-agent response","pmids":["32954361","33159179"],"confidence":"High","gaps":["Relationship between AF9-binding and PRC1.1 corepressor functions not integrated","Dnmt3a-cooperation experiments at Medium confidence (single lab)"]},{"year":2021,"claim":"Clarified that BCOR mutations produce a chromatin-bound but catalytically inert PRC1.1 by unlinking the RING-PCGF core from the chromatin-targeting subcomplex, defining a druggable signaling-resistance program.","evidence":"Biochemical complex assembly with BCOR mutants, ChIP-seq/RNA-seq in patient samples, and kinase-inhibitor sensitivity assays","pmids":["35015684","33468080","33862015"],"confidence":"High","gaps":["Which targeted-kinase dependencies generalize across BCOR-mutant cancers not established","Point mutation K607E effects at Medium confidence without in vivo validation"]},{"year":null,"claim":"How BCOR-PRC1.1 target selectivity is encoded across tissues, and whether restoring PRC1.1 catalytic engagement can reverse the epigenetic reprogramming of BCOR-mutant tumors, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No therapeutic strategy to re-couple mutant PRC1.1 enzymatic core to chromatin","Lineage-specific recruitment cofactors not comprehensively defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,5,7,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,14,15]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,7]}],"localization":[{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[1,6,12,13]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,6,9,13]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,7,12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,11,15,18]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,4,9,21]}],"complexes":["PRC1.1 (non-canonical PRC1)","BCL6/BCOR/SIRT1 corepressor complex"],"partners":["BCL6","RNF2","RYBP","NSPC1","PCGF1","KDM2B","SKP1","AF9"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6W2J9","full_name":"BCL-6 corepressor","aliases":[],"length_aa":1755,"mass_kda":192.2,"function":"Transcriptional corepressor. May specifically inhibit gene expression when recruited to promoter regions by sequence-specific DNA-binding proteins such as BCL6 and MLLT3. This repression may be mediated at least in part by histone deacetylase activities which can associate with this corepressor. Involved in the repression of TFAP2A; impairs binding of BCL6 and KDM2B to TFAP2A promoter regions. Via repression of TFAP2A acts as a negative regulator of osteo-dentiogenic capacity in adult stem cells; the function implies inhibition of methylation on histone H3 'Lys-4' (H3K4me3) and 'Lys-36' (H3K36me2)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q6W2J9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BCOR","classification":"Not 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pathology","url":"https://pubmed.ncbi.nlm.nih.gov/32011345","citation_count":19,"is_preprint":false},{"pmid":"33630701","id":"PMC_33630701","title":"Meta-analysis of BCOR rearranged sarcomas: challenging the therapeutic approach.","date":"2021","source":"Acta oncologica (Stockholm, Sweden)","url":"https://pubmed.ncbi.nlm.nih.gov/33630701","citation_count":18,"is_preprint":false},{"pmid":"30126017","id":"PMC_30126017","title":"Preoperative diagnosis of clear cell sarcoma of the kidney by detection of BCOR internal tandem duplication in circulating tumor DNA.","date":"2018","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30126017","citation_count":17,"is_preprint":false},{"pmid":"32628469","id":"PMC_32628469","title":"Structure and Role of BCOR PUFD in Noncanonical PRC1 Assembly and Disease.","date":"2020","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32628469","citation_count":16,"is_preprint":false},{"pmid":"34333045","id":"PMC_34333045","title":"Loss-of-function mutations in BCOR contribute to chemotherapy resistance in acute myeloid leukemia.","date":"2021","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/34333045","citation_count":16,"is_preprint":false},{"pmid":"33159179","id":"PMC_33159179","title":"Bcor deficiency perturbs erythro-megakaryopoiesis and cooperates with Dnmt3a loss in acute erythroid leukemia onset in mice.","date":"2020","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/33159179","citation_count":16,"is_preprint":false},{"pmid":"30992267","id":"PMC_30992267","title":"Engineered Bcor mutations lead to acute leukemia of progenitor B-1 lymphocyte origin in a sensitized background.","date":"2019","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/30992267","citation_count":15,"is_preprint":false},{"pmid":"36853789","id":"PMC_36853789","title":"Pediatric BCOR-Altered Tumors From Soft Tissue/Kidney Display Specific DNA Methylation Profiles.","date":"2023","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/36853789","citation_count":14,"is_preprint":false},{"pmid":"36279688","id":"PMC_36279688","title":"BCOR variants are associated with X-linked recessive partial epilepsy.","date":"2022","source":"Epilepsy research","url":"https://pubmed.ncbi.nlm.nih.gov/36279688","citation_count":14,"is_preprint":false},{"pmid":"24694763","id":"PMC_24694763","title":"Oculofaciocardiodental syndrome: novel BCOR mutations and expression in dental cells.","date":"2014","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24694763","citation_count":14,"is_preprint":false},{"pmid":"31925334","id":"PMC_31925334","title":"BCOR-coupled H2A monoubiquitination represses a subset of androgen receptor target genes regulating prostate cancer proliferation.","date":"2020","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/31925334","citation_count":14,"is_preprint":false},{"pmid":"20563598","id":"PMC_20563598","title":"Function analysis of mesenchymal Bcor in tooth development by using RNA interference.","date":"2010","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/20563598","citation_count":14,"is_preprint":false},{"pmid":"33388948","id":"PMC_33388948","title":"Imaging of bone and soft tissue BCOR-rearranged sarcoma.","date":"2021","source":"Skeletal radiology","url":"https://pubmed.ncbi.nlm.nih.gov/33388948","citation_count":13,"is_preprint":false},{"pmid":"33468080","id":"PMC_33468080","title":"The mutation of BCOR is highly recurrent and oncogenic in mature T-cell lymphoma.","date":"2021","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/33468080","citation_count":13,"is_preprint":false},{"pmid":"35537005","id":"PMC_35537005","title":"Soft Tissue and Visceral Organ Sarcomas With BCOR Alterations.","date":"2022","source":"Journal of pediatric hematology/oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35537005","citation_count":13,"is_preprint":false},{"pmid":"35681795","id":"PMC_35681795","title":"Mutations in KMT2C, BCOR and KDM5C Predict Response to Immune Checkpoint Blockade Therapy in Non-Small Cell Lung Cancer.","date":"2022","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/35681795","citation_count":13,"is_preprint":false},{"pmid":"36591870","id":"PMC_36591870","title":"Spectrum of Histopathological, Immunohistochemical, Molecular and Radiological Features in 12 Cases of BCOR::CCNB3-positive Sarcomas With Literature Review.","date":"2023","source":"International journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/36591870","citation_count":13,"is_preprint":false},{"pmid":"36782314","id":"PMC_36782314","title":"CNS tumor with EP300::BCOR fusion: discussing its prevalence in adult population.","date":"2023","source":"Acta neuropathologica communications","url":"https://pubmed.ncbi.nlm.nih.gov/36782314","citation_count":12,"is_preprint":false},{"pmid":"34103053","id":"PMC_34103053","title":"Detection of BCOR gene rearrangement in Ewing-like sarcoma: an important diagnostic tool.","date":"2021","source":"Diagnostic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/34103053","citation_count":12,"is_preprint":false},{"pmid":"31876361","id":"PMC_31876361","title":"BCOR-CCNB3 fusion-positive clear cell sarcoma of the kidney.","date":"2019","source":"Pediatric blood & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31876361","citation_count":12,"is_preprint":false},{"pmid":"25331958","id":"PMC_25331958","title":"Interferon regulatory factor 8 (IRF8) interacts with the B cell lymphoma 6 (BCL6) corepressor BCOR.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25331958","citation_count":12,"is_preprint":false},{"pmid":"31679010","id":"PMC_31679010","title":"Fine-Needle Aspiration Features of BCOR-CCNB3 Sarcoma.","date":"2020","source":"American journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31679010","citation_count":11,"is_preprint":false},{"pmid":"34325058","id":"PMC_34325058","title":"Assessment of BCOR Internal Tandem Duplications in Pediatric Cancers by Targeted RNA Sequencing.","date":"2021","source":"The Journal of molecular diagnostics : JMD","url":"https://pubmed.ncbi.nlm.nih.gov/34325058","citation_count":11,"is_preprint":false},{"pmid":"24146931","id":"PMC_24146931","title":"Overexpression of the transcriptional repressor complex BCL-6/BCoR leads to nuclear aggregates distinct from classical aggresomes.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24146931","citation_count":11,"is_preprint":false},{"pmid":"33718245","id":"PMC_33718245","title":"Specific and Sensitive Diagnosis of BCOR-ITD in Various Cancers by Digital PCR.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33718245","citation_count":10,"is_preprint":false},{"pmid":"38299584","id":"PMC_38299584","title":"Genetic landscape and clinical outcomes of patients with BCOR mutated myeloid neoplasms.","date":"2024","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/38299584","citation_count":9,"is_preprint":false},{"pmid":"37634866","id":"PMC_37634866","title":"KDM2B-Rearranged Soft Tissue Sarcomas Expand the Concept of BCOR-Associated Sarcoma.","date":"2023","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/37634866","citation_count":9,"is_preprint":false},{"pmid":"31900635","id":"PMC_31900635","title":"Primary bone sarcoma with BCOR internal tandem duplication.","date":"2020","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31900635","citation_count":9,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":55994,"output_tokens":6741,"usd":0.134548,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15753,"output_tokens":4618,"usd":0.097107,"stage2_stop_reason":"end_turn"},"total_usd":0.231655,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"BCOR (BCoR) was identified as a novel corepressor that interacts selectively with the POZ domain of BCL6 but not with eight other POZ proteins tested. BCOR can function as a corepressor when tethered to DNA, potentiates BCL6 repression when overexpressed, and interacts in vivo with specific class I and II histone deacetylases (HDACs). The BCL6/BCOR interaction is mutually exclusive with BCL6 interactions with SMRT and N-CoR.\",\n      \"method\": \"Co-immunoprecipitation, DNA-tethering repression assay, overexpression, in vivo interaction studies\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, functional tethering assay, selectivity demonstrated against 8 control POZ proteins; replicated in subsequent studies\",\n      \"pmids\": [\"10898795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"BCOR forms a novel complex containing Polycomb group (PcG) proteins (RING1, RYBP, NSPC1, RNF2) and SCF ubiquitin ligase components (SKP1, FBXL10/JHDM1B). RNF2 in the complex is an E3 ligase for mono-ubiquitylation of H2A. BCOR also coimmunoprecipitates isoforms of FBXL10 containing a JmjC domain with histone H3K36 demethylase activity. BCOR complex components and mono-ubiquitylated H2A co-localize to BCL6 target genes, indicating the complex recruits PcG proteins and two distinct E3 ubiquitin ligases plus a histone demethylase to BCL6 targets.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), complex purification/mass spectrometry\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP at endogenous targets, multiple orthogonal methods in one study, replicated by subsequent work on PRC1.1\",\n      \"pmids\": [\"16943429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"BCOR mutation in mesenchymal stem cells (MSCs) from an OFCD patient increased osteo-dentinogenic potential. AP-2alpha was identified as a repressive target of BCOR; BCOR mutation caused abnormal activation of AP-2alpha. Gain- and loss-of-function assays demonstrated AP-2alpha mediates the increased osteo-dentinogenic capacity. BCOR maintained gene silencing through epigenetic mechanisms; its mutation increased histone H3K4 and H3K36 methylation at silenced target genes in MSCs, reactivating their transcription.\",\n      \"method\": \"Patient-derived MSC culture, gain/loss-of-function assays, ChIP for histone modifications, gene expression analysis\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain and loss-of-function with defined molecular readout (H3K4/H3K36 methylation changes by ChIP), patient-derived cells, multiple orthogonal methods\",\n      \"pmids\": [\"19578371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Left-sided expression of BCOR (xtBcor) in Xenopus tropicalis is required for vertebrate laterality determination. Morpholino knockdown of xtBcor caused reversed cardiac orientation and disorganized gut patterning specifically when injected into the left side of embryos, demonstrating a left-sided requirement. xtBcor knockdown also caused ocular defects (microphthalmia, coloboma) and downregulated xtPitx2c expression, placing BCOR upstream of Pitx2c in a laterality specification pathway.\",\n      \"method\": \"Morpholino antisense knockdown in Xenopus tropicalis, in situ hybridization for Pitx2c, phenotypic analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — morpholino KD with specific laterality phenotype and downstream target (Pitx2c) identified, single lab but orthogonal readouts\",\n      \"pmids\": [\"17517692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Loss-of-function Bcor alleles in mouse embryonic stem cells result in altered expression of key developmental genes (Oct3/4, Nanog, Fgf5, Bmp4, Brachyury, Flk1) during differentiation into ectoderm, mesoderm and hematopoietic lineages, with normal expression restored upon re-expression of Bcor. Bcor loss of function shows a strong parent-of-origin effect, suggesting a requirement in extraembryonic development. Chimeric animals show reduced contribution to B and T cells and erythrocytes, and kinked/shortened tails consistent with reduced Brachyury expression.\",\n      \"method\": \"ES cell loss-of-function alleles, in vitro differentiation assays, rescue by re-expression, chimeric mouse analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal loss-of-function alleles with in vitro differentiation and in vivo chimeric rescue, single lab\",\n      \"pmids\": [\"18795143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BCL6, BCOR, and SIRT1 form a complex that directly represses Gli1 and Gli2 effectors of the Sonic Hedgehog (SHH) pathway. BCL6 recruits BCOR corepressor and SIRT1 deacetylase to Gli1/Gli2 promoters to suppress SHH signaling. This BCL6/BCOR/SIRT1 complex is required for neurogenesis and tumor suppression of granule neuron progenitor (GNP)-derived medulloblastoma in mice.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, gain/loss-of-function in mouse GNPs and human MB cells, in vivo mouse medulloblastoma model\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP at target promoters, in vivo genetic mouse model with fully penetrant tumor suppression phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"25490446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BCOR regulates myeloid cell proliferation and differentiation as a component of variant PRC1 (PRC1.1). Conditional Bcor loss-of-function in mouse bone marrow increased proliferation and differentiation of myeloid cells with upregulation of Hox genes. Bcor mutation reduced protein levels of RING1B (H2A ubiquitin E3 ligase subunit of PRC1) and reduced H2AK119 ubiquitination upstream of upregulated HoxA genes.\",\n      \"method\": \"Conditional mouse knockout, bone marrow assays, global RNA expression profiling, ChIP for H2AK119ub, protein analysis\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mouse model with ChIP demonstrating H2AK119ub loss at HoxA loci, global expression profiling, confirmed in patient AML samples\",\n      \"pmids\": [\"26847029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BCOR acts as a tumor suppressor in T lymphocyte malignancies. Mice with deletion of Bcor exon 4 (removing the BCL6-binding domain) showed augmented thymocyte proliferative capacity and strong propensity to induce acute T-cell lymphoblastic leukemia (T-ALL), mostly in a Notch-dependent manner. ChIP-seq analysis revealed BCOR is recruited to the Myc promoter and restrains its activation in thymocytes. BCOR also targeted other NOTCH1 target genes. BCL6-deficient thymocytes behaved similarly to Bcor-deficient thymocytes.\",\n      \"method\": \"Conditional Bcor exon 4 deletion mouse model, ChIP-seq, gene expression profiling, in vitro proliferation assay\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mouse, ChIP-seq establishing direct BCOR occupancy at Myc promoter, Notch-dependence demonstrated, corroborated by BCL6 KO parallel experiment\",\n      \"pmids\": [\"28827447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Bcor loss-of-function mutations are frequently found in spontaneous Eμ-Myc mouse lymphomas. Disruptive Bcor mutations cooperate with Myc overexpression (and with Cdkn2a loss, Nras, Kras) in lymphomagenesis, demonstrating a functional tumor suppressor role for Bcor in vivo in a MYC-driven malignancy.\",\n      \"method\": \"Whole-genome sequencing of spontaneous Eμ-Myc lymphomas, somatic mutation analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — sequencing of spontaneous tumors establishes in vivo cooperativity, but no functional rescue or in vitro reconstitution; single study\",\n      \"pmids\": [\"28262675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BCOR is a critical component of the non-canonical PRC1.1 complex required for maintaining primed pluripotency in human embryonic stem cells (ESCs). BCOR depletion leads to erosion of Polycomb domains at key developmental loci and initiation of differentiation along endoderm and mesoderm lineages. The C-terminus of BCOR regulates assembly and targeting of the PRC1.1 complex, while the N-terminus contributes to BCOR-PRC1.1 repressor function.\",\n      \"method\": \"BCOR depletion (siRNA/shRNA) in human ESCs, ChIP-seq, ATAC-seq, RNA-seq, domain deletion mapping\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KD in human ESCs with ChIP-seq and RNA-seq revealing Polycomb domain erosion; domain-mapping of N- and C-terminus functions; multiple orthogonal methods\",\n      \"pmids\": [\"29337181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Bcor truncation (deletion of exons 9-10) in hematopoietic cells leads to carboxyl-terminal truncated BCOR that fails to interact with core effector components of PRC1.1. This cooperates with Tet2 deletion to cause lethal myelodysplastic syndrome (MDS) with anemia, leukocytopenia, and morphological dysplasia. Transcriptional profiling showed derepression of Cebp family myeloid regulators and HoxA cluster genes in Bcor mutant progenitors.\",\n      \"method\": \"Conditional Bcor exon 9-10 deletion mouse model, secondary transplantation, transcriptional profiling, protein interaction studies\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO mouse with defined molecular mechanism (loss of PRC1.1 core interaction), cooperativity with Tet2 loss, transplantation confirming clonal disease\",\n      \"pmids\": [\"30228234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Bcor inactivation in hematopoietic stem cells (HSCs) expands myeloid progenitors and cooperates with oncogenic KrasG12D to initiate fully transplantable acute leukemia. ChIP-seq reveals differential regulation of a subset of PRC1-target genes including HSC-associated transcription factors Hoxa7/9, establishing BCOR's role in regulating cell fate decisions through PRC1 target gene control.\",\n      \"method\": \"Conditional mouse knockout, bone marrow transplantation, ChIP-seq, gene expression analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, ChIP-seq at PRC1 targets, fully transplantable leukemia model, genetic epistasis with KrasG12D\",\n      \"pmids\": [\"30902969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BCOR interacts with androgen receptor (AR) in a hormone-dependent manner in castration-resistant prostate cancer (CRPC) cells. Genome-wide analysis shows BCOR is recruited to the majority of AR-binding chromatin sites in an androgen-dependent fashion. BCOR depletion decreases H2A K119 monoubiquitination and increases mRNA expression at androgen-repressed genes including HOX genes. BCOR depletion impairs proliferation and viability of CRPC cells, inducing apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, siRNA knockdown, proliferation/apoptosis assays in CRPC cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP-seq, KD with H2AK119ub ChIP validation at target genes, functional phenotype in CRPC cells; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"31925334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BCOR directly regulates Igf2 through the PRC1.1 complex in granule neuron progenitors (GNPs). Deletion of Bcor exons 9/10 in GNPs leads to reduced H2AK119Ub at the Igf2 promoter and aberrant upregulation of Igf2. Combined with Ptch1 loss, this results in fully penetrant medulloblastomas. Ectopic Igf2 overexpression alone was sufficient to drive tumorigenesis in Ptch1+/- GNPs, placing BCOR-PRC1.1 repression of Igf2 as a key tumor suppressor mechanism.\",\n      \"method\": \"Genetically engineered mouse model (Bcor exon 9/10 deletion in GNPs), ChIP for H2AK119Ub at Igf2 promoter, ectopic Igf2 overexpression experiment, gene expression analysis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP demonstrating direct H2AK119Ub loss at Igf2, rescue by ectopic Igf2 overexpression, in vivo mouse tumor model with genetic epistasis\",\n      \"pmids\": [\"32820036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NMR structure of the BCOR PUFD domain shows that its termini (critical for binding PCGF1 and KDM2B) are disordered. This suggests a hierarchical assembly: BCOR PUFD termini become structurally ordered upon binding PCGF1, which then allows stable association with KDM2B. Unlike BCORL1 PUFD, BCOR PUFD alone does not stably assemble with KDM2B; additional residues N-terminal to the PUFD are required. BCOR internal tandem duplications (ITDs) map to the PUFD termini and disrupt PRC1.1 assembly, suggesting loss of PRC1.1 assembly is a critical molecular event in ITD-driven tumorigenesis.\",\n      \"method\": \"NMR structure determination, 15N T2 relaxation measurements, in vitro binding studies with BCOR ITD mutant, protein biochemistry\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with functional validation by binding assays and ITD mutant; single lab but rigorous structural and biochemical methods\",\n      \"pmids\": [\"32628469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BCOR mutations in myelodysplastic syndrome/AML disrupt assembly of the noncanonical PRC1.1 complex by selectively unlinking the RING-PCGF enzymatic core from the chromatin-targeting auxiliary subcomplex. BCOR-mutated PRC1.1 localizes to chromatin but lacks repressive activity, leading to epigenetic reprogramming and transcriptional activation at target loci. A set of functional PRC1.1 targets driving aberrant oncogenic signaling was defined; activation confers acquired treatment resistance while sensitizing to targeted kinase inhibition.\",\n      \"method\": \"Biochemical complex assembly studies, ChIP-seq in BCOR-mutated patient samples and cell lines, RNA-seq, kinase inhibitor sensitivity assays\",\n      \"journal\": \"Blood cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical reconstitution of PRC1.1 complex with BCOR mutants, ChIP-seq and RNA-seq in patient samples and cell lines, drug sensitivity rescue experiment\",\n      \"pmids\": [\"35015684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BCOR acts as a suppressor of plasmacytoid DC (pDC) and conventional DC type 2 (cDC2) numbers during Flt3 ligand-mediated emergency DC development. BCOR restricts clonal expansion, especially for cDC2s, and suppresses clonal fate potential, especially for pDCs. This was established using CRISPR-validated SIS-seq clonal multi-omics.\",\n      \"method\": \"Clonal multi-omics (SIS-seq), CRISPR validation, paired sister-clone fate assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with clonal fate tracking and sister-clone comparison; novel method but single lab\",\n      \"pmids\": [\"33862015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BCOR K607E mutation in T-cell lymphoma reduces binding affinity of mutant BCOR to BCL6, PCGF1, and RING1B proteins compared to wild-type BCOR. Ectopic expression of BCOR K607E significantly enhanced cell proliferation, AKT phosphorylation, and IL-2 expression with upregulated HOX and S100 protein gene expression. BCOR silencing produced similar effects, indicating the mutation acts as loss-of-function.\",\n      \"method\": \"Immunoprecipitation, western blotting, transfection/siRNA, DNA microarray, cell proliferation assay\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP showing reduced binding, functional OE and KD with proliferation/signaling readouts; single lab, multiple methods but no in vivo validation\",\n      \"pmids\": [\"33468080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BCOR binding to the MLL fusion partner AF9 is essential for MLL-AF9 leukemogenesis. Protein structures of AF9 complexes with BCOR and CBX8 were determined, showing binding of AF4, DOT1L, BCOR, and CBX8 to AF9 is mutually exclusive. Point mutations selectively disrupting BCOR/MLL-AF9 binding caused partial differentiation, increased proliferation, and abrogated leukemogenic potential in a mouse model. MLL-AF9 mutant deficient for BCOR binding reduces EYA1 phosphatase expression and c-Myc protein level, altering MYC-driven and SIX-regulated gene expression programs.\",\n      \"method\": \"Protein structure determination (AF9 complexes), site-directed mutagenesis, bone marrow transplantation mouse leukemia model, gene expression analysis\",\n      \"journal\": \"Blood cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — protein structure solved, selective point mutants, in vivo mouse leukemia model abrogation, downstream mechanism (EYA1, c-Myc) identified\",\n      \"pmids\": [\"32954361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BCOR (BCoR) is recruited to the CDKN1A promoter by FBI-1 (ZBTB7A) via the adaptor MBD3. FBI-1 interacts with BCOR (as well as NCoR and SMRT) to repress transcription. MBD3 differentially regulates these interactions: it decreases FBI-1/NCoR-SMRT interaction but increases FBI-1/BCoR interaction. BCoR interacts with the Mi-2/NuRD-HDAC complex, DNMTs, and HP1, contributing to epigenetic repression of CDKN1A by DNA methylation.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, promoter reporter assay, siRNA knockdown\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and ChIP demonstrating complex at CDKN1A promoter, siRNA functional validation, multiple interactions mapped; single lab\",\n      \"pmids\": [\"23658227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IRF8 interacts directly with BCOR; the α-helical region of IRF8 and the BCL6-binding domain of BCOR are required for this interaction. IRF8 also interacts directly with BCL6. IRF8 knockdown represses Bcor and enhances Bcl6 transcription in mouse B cell lymphoma cells, suggesting a regulatory relationship within a BCOR-BCL6-IRF8 complex modulating germinal center B cell transcriptional regulation.\",\n      \"method\": \"Retrovirus-based protein complementation assay screen, direct interaction validation, siRNA knockdown with qPCR\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — PCA screen plus direct interaction validation, domain mapping; siRNA functional follow-up; single lab\",\n      \"pmids\": [\"25331958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Bcor is expressed in both dental epithelium and mesenchyme during mouse molar development. Lentivirus-mediated knockdown of Bcor in dental mesenchymal cells at E14.5 causes dentinogenesis defects and retardation of tooth root development, demonstrating a functional requirement for Bcor in the mesenchyme during early tooth development.\",\n      \"method\": \"In situ hybridization for expression profiling, lentivirus-mediated RNAi knockdown in dental mesenchyme, morphological analysis\",\n      \"journal\": \"Cell and tissue research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — lentiviral KD with defined cellular phenotype (dentinogenesis defect) in primary tissue; single lab\",\n      \"pmids\": [\"20563598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Bcor knockout in mice causes impaired erythroid development (macrocytosis, anemia) and enhanced thrombopoiesis. Double knockout of Bcor and Dnmt3a leads to fully penetrant acute erythroid leukemia (AEL) characterized by expansion of c-Kit+/Ter119+ blasts. Transcriptomic analysis revealed aberrant erythroid skewing driven by epigenetic changes affecting GATA1-2 transcription factors and cell-cycle regulators (Mdm2, Tp53). Demethylating agents significantly impacted leukemic burden and survival in these mice.\",\n      \"method\": \"Conditional mouse KO, secondary transplantation, transcriptomic analysis, demethylating agent treatment in vivo\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — double KO mouse model with defined AEL phenotype and transcriptomic mechanism; drug response confirms epigenetic dependency; single lab\",\n      \"pmids\": [\"33159179\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BCOR is a transcriptional corepressor that selectively binds the BCL6 POZ domain and recruits class I/II HDACs, Polycomb group proteins, and SCF ubiquitin ligase components to form the non-canonical PRC1.1 complex, which deposits H2AK119 monoubiquitination at target loci (including HOX genes, Gli1/Gli2, Igf2, and AR-repressed genes) to silence them; disease-causing mutations or ITDs in the BCOR PUFD domain disrupt PRC1.1 complex assembly, abolishing repressive chromatin function and leading to epigenetic reprogramming, aberrant activation of oncogenic signaling programs, and malignant transformation across hematopoietic, neural, mesenchymal, and epithelial lineages.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"BCOR is a transcriptional corepressor that nucleates a non-canonical Polycomb repressive complex (PRC1.1) to silence developmental and oncogenic gene programs across hematopoietic, neural, mesenchymal, and epithelial lineages [#0, #6, #9]. It was first defined as a selective binding partner of the BCL6 POZ domain — an interaction mutually exclusive with BCL6's association with SMRT/N-CoR — that potentiates BCL6-mediated repression and recruits class I/II HDACs [#0]. BCOR assembles PRC1.1 by linking the RING1/RNF2-PCGF1 catalytic core, which monoubiquitinates histone H2A at K119, to the chromatin-targeting subunit KDM2B/FBXL10 (a JmjC H3K36 demethylase) together with RYBP, NSPC1, and SKP1; these components and H2AK119ub co-occupy BCL6 target genes [#1]. The BCOR C-terminal PUFD domain mediates this assembly: its termini are disordered and become ordered upon binding PCGF1, enabling stable KDM2B association, and internal tandem duplications mapping to the PUFD termini disrupt PRC1.1 assembly [#14]. Through deposition of H2AK119ub, BCOR-PRC1.1 represses HOX genes, Myc, Gli1/Gli2, Igf2, and androgen-repressed loci, and loss of BCOR or its truncation reduces RING1B levels and H2AK119ub at these targets, driving their derepression [#6, #7, #13, #12]. BCOR functions as a tumor suppressor: disruptive mutations or C-terminal truncations that unlink the enzymatic core from the chromatin-targeting subcomplex leave PRC1.1 chromatin-bound but transcriptionally inactive, causing epigenetic reprogramming, and cooperate with Tet2 loss, Dnmt3a loss, oncogenic Kras, and Myc to produce myelodysplastic syndrome, acute leukemias, and medulloblastoma [#10, #15, #11, #22, #13]. BCOR also has developmental roles in vertebrate laterality, embryonic stem cell pluripotency, and tooth development [#3, #9, #21].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established BCOR as a dedicated corepressor for BCL6, answering how the BCL6 POZ domain enacts transcriptional silencing through a partner distinct from canonical SMRT/N-CoR.\",\n      \"evidence\": \"Reciprocal Co-IP, DNA-tethering repression assay, and selectivity screen against eight other POZ proteins\",\n      \"pmids\": [\"10898795\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"HDAC recruitment shown by in vivo interaction but not biochemically reconstituted\", \"Genome-wide target loci not defined at this stage\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined the molecular composition of the BCOR complex, revealing it recruits Polycomb proteins and two E3 ubiquitin ligases to deposit H2A monoubiquitination at BCL6 targets — the basis of PRC1.1.\",\n      \"evidence\": \"Complex purification/mass spectrometry, reciprocal Co-IP, and ChIP at endogenous BCL6 targets\",\n      \"pmids\": [\"16943429\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy of subunit assembly not resolved\", \"Functional consequence of H2A ubiquitination on transcription not directly demonstrated\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed BCOR has a developmental role beyond corepression by acting upstream of Pitx2c in vertebrate laterality determination.\",\n      \"evidence\": \"Side-specific morpholino knockdown in Xenopus tropicalis with in situ hybridization and phenotypic analysis\",\n      \"pmids\": [\"17517692\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking BCOR to Pitx2c not defined\", \"Morpholino-based, single-organism evidence\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated BCOR controls developmental gene expression during stem cell differentiation and is required for normal hematopoietic and embryonic lineage contribution.\",\n      \"evidence\": \"ES cell loss-of-function alleles, in vitro differentiation, rescue by re-expression, and chimeric mouse analysis\",\n      \"pmids\": [\"18795143\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct chromatin targets in ES cells not mapped\", \"Parent-of-origin effect mechanism unexplained\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linked BCOR mutation to OFCD-associated phenotypes mechanistically, showing it maintains gene silencing via histone methylation control and represses AP-2alpha to restrain osteo-dentinogenic potential.\",\n      \"evidence\": \"Patient-derived MSCs, gain/loss-of-function, and ChIP for H3K4/H3K36 methylation at silenced targets\",\n      \"pmids\": [\"19578371\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between histone methylation changes and PRC1.1 ubiquitination activity not connected\", \"Single patient genetic background\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended the BCOR repressive module to SHH signaling, showing a BCL6/BCOR/SIRT1 complex silences Gli1/Gli2 to suppress medulloblastoma.\",\n      \"evidence\": \"Reciprocal Co-IP, ChIP at Gli promoters, and an in vivo GNP-derived medulloblastoma mouse model\",\n      \"pmids\": [\"25490446\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between SIRT1 deacetylation and PRC1.1 ubiquitination not dissected\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established that BCOR controls myeloid proliferation/differentiation as a PRC1.1 component by maintaining RING1B levels and H2AK119ub at HoxA loci.\",\n      \"evidence\": \"Conditional mouse knockout, expression profiling, and ChIP for H2AK119ub at HoxA, confirmed in patient AML\",\n      \"pmids\": [\"26847029\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How BCOR loss lowers RING1B protein not mechanistically explained\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined BCOR as a tumor suppressor in T-lymphocyte malignancy by restraining Myc and Notch target genes through direct promoter occupancy.\",\n      \"evidence\": \"Conditional Bcor exon 4 deletion mouse, ChIP-seq at Myc promoter, with parallel BCL6 knockout\",\n      \"pmids\": [\"28827447\", \"28262675\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Myc repression requires PRC1.1 catalytic activity not tested directly\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mapped BCOR domain functions and showed C-terminal truncations sever PRC1.1 core interactions, driving Polycomb domain erosion in pluripotency and cooperating with Tet2 loss in MDS.\",\n      \"evidence\": \"Domain-deletion ChIP-seq/ATAC-seq in human ESCs and conditional Bcor exon 9-10 deletion mouse with transcriptional profiling\",\n      \"pmids\": [\"29337181\", \"30228234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise structural basis of PRC1.1 core loss not yet resolved at this stage\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated BCOR loss expands myeloid progenitors and cooperates with oncogenic Kras to initiate leukemia through dysregulation of PRC1 targets including Hoxa7/9, and extended PRC1.1 function to androgen-repressed genes in prostate cancer.\",\n      \"evidence\": \"Conditional mouse knockout with transplantation and ChIP-seq; Co-IP, ChIP-seq, and knockdown in castration-resistant prostate cancer cells\",\n      \"pmids\": [\"30902969\", \"31925334\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific determinants of which PRC1.1 targets are derepressed not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved the structural mechanism of PRC1.1 assembly and showed disease ITDs map to the PUFD termini to disrupt it, while defining a direct BCOR-PRC1.1/Igf2 tumor-suppressor axis in medulloblastoma.\",\n      \"evidence\": \"NMR structure with relaxation measurements and ITD-mutant binding assays; GNP mouse model with ChIP for H2AK119ub at Igf2 and rescue by ectopic Igf2\",\n      \"pmids\": [\"32628469\", \"32820036\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length assembled PRC1.1 structure not determined\", \"Generality of single-effector (Igf2) sufficiency across tumor types unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed BCOR's role through additional protein interactions: binding the MLL fusion partner AF9 is required for MLL-AF9 leukemogenesis, and Bcor/Dnmt3a co-loss drives erythroid leukemia via GATA factor dysregulation.\",\n      \"evidence\": \"AF9 complex structures with selective point mutants in a mouse leukemia model; conditional double-knockout mouse with transcriptomics and demethylating-agent response\",\n      \"pmids\": [\"32954361\", \"33159179\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between AF9-binding and PRC1.1 corepressor functions not integrated\", \"Dnmt3a-cooperation experiments at Medium confidence (single lab)\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Clarified that BCOR mutations produce a chromatin-bound but catalytically inert PRC1.1 by unlinking the RING-PCGF core from the chromatin-targeting subcomplex, defining a druggable signaling-resistance program.\",\n      \"evidence\": \"Biochemical complex assembly with BCOR mutants, ChIP-seq/RNA-seq in patient samples, and kinase-inhibitor sensitivity assays\",\n      \"pmids\": [\"35015684\", \"33468080\", \"33862015\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which targeted-kinase dependencies generalize across BCOR-mutant cancers not established\", \"Point mutation K607E effects at Medium confidence without in vivo validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How BCOR-PRC1.1 target selectivity is encoded across tissues, and whether restoring PRC1.1 catalytic engagement can reverse the epigenetic reprogramming of BCOR-mutant tumors, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No therapeutic strategy to re-couple mutant PRC1.1 enzymatic core to chromatin\", \"Lineage-specific recruitment cofactors not comprehensively defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 5, 7, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 14, 15]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [1, 6, 12, 13]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 6, 9, 13]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 7, 12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 11, 15, 18]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 4, 9, 21]}\n    ],\n    \"complexes\": [\n      \"PRC1.1 (non-canonical PRC1)\",\n      \"BCL6/BCOR/SIRT1 corepressor complex\"\n    ],\n    \"partners\": [\n      \"BCL6\",\n      \"RNF2\",\n      \"RYBP\",\n      \"NSPC1\",\n      \"PCGF1\",\n      \"KDM2B\",\n      \"SKP1\",\n      \"AF9\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}