{"gene":"HOXB6","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1995,"finding":"Hoxb-5 and Hoxb-6 function together (genetic nonallelic noncomplementation) to specify the cervicothoracic vertebral region (C6–T1); hoxb-6 homozygous knockouts show missing first rib, bifid second rib, and anteriorizing homeotic transformation of cervicothoracic vertebrae, establishing Hoxb-6's role in anteroposterior axial patterning of brachiocervicothoracic structures.","method":"Targeted gene disruption (knockout mice), genetic complementation test (transheterozygote analysis)","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean loss-of-function knockouts with specific skeletal phenotypes, replicated by nonallelic noncomplementation cross, multiple independent mutant alleles","pmids":["7828847"],"is_preprint":false},{"year":2000,"finding":"Disruption of Hoxb-6 in mice results in increased numbers of early erythroid progenitor cells in bone marrow and fetal liver, while mature hematopoietic cell types and differentiation of other lineages remain normal, establishing a role for Hoxb-6 in controlling the generation, proliferation, or survival of erythroid progenitor cells.","method":"Targeted gene disruption (knockout mice), clonogenic progenitor cell assays","journal":"American journal of hematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with specific cellular phenotype, single lab, two orthogonal assay methods","pmids":["10996827"],"is_preprint":false},{"year":2000,"finding":"HOXB6 protein subcellular localization shifts from cytoplasmic in fetal epidermis to substantially nuclear in adult skin. GFP-fusion protein experiments demonstrated that full-length HOXB6 localizes to the nucleus while a truncated isoform lacking the homeodomain is largely cytoplasmic. Neither full-length nor truncated HOXB6 co-localizes with PBX proteins in epidermis, suggesting HOXB6 acts without PBX co-factors in skin.","method":"Immunohistochemistry, GFP-fusion protein live imaging, subcellular fractionation, Western blot (protein isoform detection)","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with GFP fusions and fractionation, functional consequence inferred, single lab","pmids":["10906782"],"is_preprint":false},{"year":1999,"finding":"Hoxb-6 is phosphorylated in vivo at serine-214 by casein kinase II (CK-II); this phosphorylation site is conserved across multiple homeodomain proteins and species. In vitro, Hoxb-6 is also phosphorylated by cAMP-dependent protein kinase. In vivo phosphorylation of the same CK-II peptide was confirmed from mouse embryonic spinal cords.","method":"Baculovirus expression system (Sf9 cells), two-dimensional tryptic phosphopeptide mapping, in vitro kinase assays with purified CK-II and PKA, immunoprecipitation from mouse embryonic spinal cords","journal":"The Journal of experimental zoology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus in vivo phosphopeptide mapping, site mapped to Ser-214, two orthogonal methods","pmids":["10327653"],"is_preprint":false},{"year":2004,"finding":"HOXB6 represses alpha- and gamma-globin mRNA levels in a DNA-binding-dependent manner in K562 cells; this activity does not require cooperative DNA-binding with PBX1 co-factor, nor the N-terminal conserved region, polyglutamic acid C-terminus, or Ser-214 CK-II phosphorylation site. Endogenous CBP (CREB-binding protein) co-precipitates with exogenous HOXB6 from nuclear and cytoplasmic fractions of transfected K562 cells, and endogenous CBP co-precipitates with endogenous HOXB6 in day 14.5 murine fetal liver cells. The CBP interaction motif was localized to the homeodomain but does not require helix 3.","method":"Stable transfection in K562 cells, RT-PCR (globin mRNA measurement), structure-function mutagenesis (homeodomain and interaction mutants), co-immunoprecipitation (endogenous and exogenous proteins)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro activity assay with mutagenesis plus reciprocal co-IP of endogenous proteins, multiple orthogonal methods in single lab","pmids":["15269212"],"is_preprint":false},{"year":2004,"finding":"HOXB6 overexpression in murine bone marrow expands hematopoietic stem cells and myeloid precursors while inhibiting erythropoiesis and lymphopoiesis, and causes AML in vivo (median latency 223 days). These effects are largely dependent on DNA binding but independent of direct interaction with PBX1. Coexpression of MEIS1 dramatically shortens AML onset. In vitro, HOXB6 immortalizes a factor-dependent myelomonocytic precursor.","method":"Retrovirus-mediated gene transfer in murine bone marrow, in vivo transplantation, in vitro immortalization assay, structure-function analysis with DNA-binding and PBX1-interaction mutants, cytogenetics","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo and in vitro functional assays with structure-function mutants, multiple orthogonal readouts, single lab with comprehensive approach","pmids":["15522959"],"is_preprint":false},{"year":2002,"finding":"Enforced expression of HOXB6 in promyelocytic NB4 cells inhibits granulocytic maturation, and in myeloblastic HL60 cells inhibits monocytic maturation, establishing that HOXB6 blocks myeloid differentiation. Endogenous HOXB6 expression is transiently induced during normal granulocytopoiesis and monocytopoiesis.","method":"Forced overexpression in NB4 and HL60 cell lines, differentiation assays (morphology, surface markers)","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function in two different cell lines with specific differentiation phenotype, single lab","pmids":["12094253"],"is_preprint":false},{"year":2015,"finding":"The linker region (LR) connecting the homeodomain and hexapeptide of Hoxb6 is essential for its rib-promoting activity in mice. An LR-defective Hoxb6 protein retains the ability to bind a target enhancer together with Pax3, acting as a dominant negative, indicating the LR recruits additional regulatory factors to target DNA. Hoxb6 also regulates somitogenesis by dysregulating Lfng expression in a mechanism independent of its rib-promoting activity.","method":"Transgenic/knock-in mouse models with LR-deletion mutant, ChIP/enhancer binding assays, analysis of Lfng expression, skeletal phenotype analysis","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo structure-function with domain mutant, dominant-negative demonstrated by enhancer binding assay, single lab","pmids":["26718008"],"is_preprint":false},{"year":1993,"finding":"Three distinct cis-acting regulatory elements control Hoxb-6 expression: a limb/LPM enhancer (directing expression to limb buds and ventrolateral mesenchyme, functioning in a promoter- and orientation-independent manner), a spinal cord element (for ventral spinal cord expression), and a mesonephric element (for mesonephric tubules and ducts). The limb/LPM element functions as a bona fide enhancer.","method":"LacZ reporter gene transgenic mouse embryos, multiple deletion constructs across 13.2 kb of genomic DNA","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple transgenic reporter lines with systematic deletion analysis in vivo, single lab","pmids":["8104549"],"is_preprint":false},{"year":1996,"finding":"Nuclear protein extracts from embryonic tissues form specific DNA-protein complexes with sequences in the Hoxb6 limb/LPM enhancer, as detected by electromobility shift assay, suggesting these interactions are important for tissue-specific regulation of Hoxb6 expression.","method":"Electromobility shift assay (EMSA) with nuclear extracts from embryonic tissues, LacZ reporter transgenic embryos","journal":"Pharmaceutica acta Helvetiae","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single EMSA-based pulldown without protein identification, no functional validation of specific binding partners","pmids":["8786996"],"is_preprint":false},{"year":2020,"finding":"HOXB6 directly binds to the promoter of Sox9 to inhibit Sox9 expression in liver progenitor cells, as demonstrated by chromatin immunoprecipitation/promoter binding assay. miR-126 suppresses HOXB6 translation, thereby de-repressing Sox9 and promoting SOX9+ liver progenitor cell proliferation and differentiation during CCl4-induced liver injury.","method":"Luciferase reporter assay (Sox9 promoter), ChIP/promoter binding, miRNA overexpression/knockdown, CCl4-induced liver injury model","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding demonstrated, functional rescue experiments, single lab with multiple orthogonal methods","pmids":["32763157"],"is_preprint":false}],"current_model":"HOXB6 is a homeodomain transcription factor that (1) binds DNA via its homeodomain (with the linker region providing additional regulatory activity) independently of PBX1 co-factor interaction in blood cells; (2) is phosphorylated at Ser-214 by casein kinase II in vivo; (3) interacts with CREB-binding protein (CBP) through its homeodomain to repress globin and other target genes; (4) directly binds the Sox9 promoter to repress Sox9 expression; (5) controls axial patterning of cervicothoracic vertebrae, rib formation, and somitogenesis (via Lfng dysregulation) in vivo; and (6) in hematopoiesis, expands myeloid progenitors while blocking erythroid and lymphoid differentiation, with MEIS1 cooperativity accelerating leukemogenesis."},"narrative":{"mechanistic_narrative":"HOXB6 is a homeodomain transcription factor that controls anteroposterior axial patterning during development and regulates differentiation decisions in hematopoietic and progenitor cell compartments [PMID:7828847, PMID:15522959]. In the embryo it specifies the cervicothoracic vertebral region and promotes rib formation, with loss of function producing missing first ribs, bifid second ribs, and anteriorizing homeotic transformations [PMID:7828847]; the linker region connecting the homeodomain and hexapeptide is essential for rib-promoting activity and recruits additional factors (e.g., Pax3) to target enhancers, while HOXB6 separately governs somitogenesis through dysregulation of Lfng [PMID:26718008]. As a transcriptional repressor, HOXB6 binds DNA through its homeodomain and acts independently of cooperative DNA binding with the PBX1 co-factor [PMID:15269212, PMID:15522959]; it interacts via its homeodomain with CREB-binding protein (CBP) to repress alpha- and gamma-globin genes, and directly binds the Sox9 promoter to repress Sox9 in liver progenitor cells [PMID:15269212, PMID:32763157]. In hematopoiesis, HOXB6 expands hematopoietic stem cells and myeloid precursors while blocking erythroid, lymphoid, and granulocytic/monocytic differentiation, and its enforced expression causes AML in vivo with latency dramatically shortened by MEIS1 co-expression [PMID:15522959, PMID:12094253]. HOXB6 is phosphorylated in vivo at Ser-214 by casein kinase II, though this site is dispensable for globin repression [PMID:10327653, PMID:15269212].","teleology":[{"year":1993,"claim":"Before any functional role was assigned, it was unknown how Hoxb-6 expression is spatially restricted; dissecting its regulatory landscape established the tissue-specific control elements driving its developmental expression.","evidence":"LacZ reporter transgenic mouse embryos with systematic deletion across 13.2 kb of genomic DNA","pmids":["8104549"],"confidence":"Medium","gaps":["The trans-acting factors binding each element were not identified","Does not address HOXB6 protein function, only its regulation"]},{"year":1995,"claim":"The in vivo developmental requirement was unknown; knockout and noncomplementation analysis established Hoxb-6 as a specifier of cervicothoracic axial identity acting together with Hoxb-5.","evidence":"Targeted gene disruption in mice and transheterozygote genetic complementation test","pmids":["7828847"],"confidence":"High","gaps":["Direct transcriptional targets driving the skeletal phenotype not identified","Molecular basis of Hoxb-5/Hoxb-6 cooperativity not resolved"]},{"year":1996,"claim":"Following enhancer mapping, it remained unknown what nuclear proteins act through the limb/LPM enhancer; EMSA detected tissue-specific DNA-protein complexes implicating sequence-specific factors.","evidence":"EMSA with embryonic nuclear extracts plus LacZ reporter transgenics","pmids":["8786996"],"confidence":"Low","gaps":["Single EMSA-based pulldown without identification of the bound proteins","No functional validation of the specific binding partners"]},{"year":1999,"claim":"Whether HOXB6 is post-translationally modified was unknown; phosphopeptide mapping identified a conserved CK-II phosphorylation site at Ser-214 modified in vivo.","evidence":"Baculovirus expression, 2D tryptic phosphopeptide mapping, in vitro kinase assays, and IP from mouse embryonic spinal cords","pmids":["10327653"],"confidence":"High","gaps":["Functional consequence of Ser-214 phosphorylation not defined","Whether PKA phosphorylation occurs in vivo not established"]},{"year":2000,"claim":"The hematopoietic role was unknown; knockout analysis revealed Hoxb-6 controls the generation, proliferation, or survival of early erythroid progenitors.","evidence":"Knockout mice with clonogenic progenitor assays in bone marrow and fetal liver","pmids":["10996827"],"confidence":"Medium","gaps":["Whether the effect is on generation versus proliferation versus survival not distinguished","Molecular targets in erythroid progenitors not identified"]},{"year":2000,"claim":"It was unclear whether HOXB6 requires PBX co-factors and how its localization is controlled; isoform and GFP-fusion experiments showed homeodomain-dependent nuclear localization that does not co-localize with PBX in epidermis.","evidence":"Immunohistochemistry, GFP-fusion live imaging, subcellular fractionation, and Western blot of protein isoforms","pmids":["10906782"],"confidence":"Medium","gaps":["Functional consequence of cytoplasmic-to-nuclear shift inferred, not directly tested","Regulator of the developmental localization switch unknown"]},{"year":2002,"claim":"Whether HOXB6 affects myeloid maturation was unknown; enforced expression in promyelocytic and myeloblastic lines established that it blocks granulocytic and monocytic differentiation.","evidence":"Forced overexpression in NB4 and HL60 cells with morphology and surface-marker differentiation assays","pmids":["12094253"],"confidence":"Medium","gaps":["Target genes mediating the differentiation block not identified","Based on cell lines rather than primary cells"]},{"year":2004,"claim":"The transcriptional mechanism and co-factor dependence were unresolved; structure-function and reciprocal co-IP showed HOXB6 represses globin genes via a DNA-binding-dependent, PBX1-independent mechanism using a homeodomain interaction with CBP.","evidence":"Stable K562 transfection, RT-PCR, structure-function mutagenesis, and reciprocal endogenous co-IP including fetal liver","pmids":["15269212"],"confidence":"High","gaps":["How CBP recruitment yields repression rather than activation not mechanistically explained","N-terminal region, polyGlu C-terminus, and Ser-214 shown dispensable but their functions elsewhere unknown"]},{"year":2004,"claim":"Whether HOXB6 dysregulation is oncogenic was unknown; bone marrow overexpression established that it expands HSCs and myeloid precursors and causes AML, with MEIS1 as a cooperating accelerator.","evidence":"Retroviral transduction of murine bone marrow, transplantation, immortalization assay, and DNA-binding/PBX1-interaction mutants","pmids":["15522959"],"confidence":"High","gaps":["Direct transcriptional targets driving leukemogenesis not defined","Mechanism of MEIS1 cooperativity not resolved"]},{"year":2015,"claim":"The domain requirements for axial function were unknown; an LR-deletion knock-in showed the linker region is essential for rib promotion by recruiting co-factors, and that somitogenesis control via Lfng is a separable activity.","evidence":"Knock-in mice with linker-region deletion, enhancer/ChIP binding assays with Pax3, and Lfng expression analysis","pmids":["26718008"],"confidence":"Medium","gaps":["Identity of the additional factors recruited by the LR (beyond Pax3) not fully resolved","How Lfng dysregulation is mechanistically linked to HOXB6 not detailed"]},{"year":2020,"claim":"A direct transcriptional target in tissue regeneration was unknown; promoter-binding and rescue experiments established that HOXB6 directly represses Sox9 and is itself suppressed by miR-126 to de-repress liver progenitor expansion.","evidence":"Sox9 luciferase reporter, ChIP/promoter binding, miR-126 overexpression/knockdown, and CCl4-induced liver injury model","pmids":["32763157"],"confidence":"Medium","gaps":["Whether co-factors are required for Sox9 promoter repression not addressed","Generality of the miR-126/HOXB6/Sox9 axis beyond liver injury unknown"]},{"year":null,"claim":"The genome-wide direct target repertoire of HOXB6 and the structural basis by which its homeodomain and linker region select repressive co-factors (CBP versus Pax3) across different tissues remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unbiased genome-wide binding map across developmental and hematopoietic contexts","No structural model of the homeodomain-CBP or LR-Pax3 interfaces","Functional role of Ser-214 phosphorylation still undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[4,5,10]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[4,5,10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,7]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5]}],"complexes":[],"partners":["CBP","PAX3","MEIS1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P17509","full_name":"Homeobox protein Hox-B6","aliases":["Homeobox protein Hox-2.2","Homeobox protein Hox-2B","Homeobox protein Hu-2"],"length_aa":224,"mass_kda":25.4,"function":"Sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P17509/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HOXB6","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":[{"gene":"ANKRD17","stoichiometry":4.0},{"gene":"CANX","stoichiometry":0.2},{"gene":"DDOST","stoichiometry":0.2},{"gene":"OST4","stoichiometry":0.2},{"gene":"PSME3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/HOXB6","total_profiled":1310},"omim":[{"mim_id":"615162","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 35; MRT35","url":"https://www.omim.org/entry/615162"},{"mim_id":"607759","title":"INTEGRIN, ALPHA-2B; ITGA2B","url":"https://www.omim.org/entry/607759"},{"mim_id":"249000","title":"MECKEL SYNDROME, TYPE 1; MKS1","url":"https://www.omim.org/entry/249000"},{"mim_id":"173470","title":"INTEGRIN, BETA-3; ITGB3","url":"https://www.omim.org/entry/173470"},{"mim_id":"142962","title":"HOMEOBOX B7; HOXB7","url":"https://www.omim.org/entry/142962"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"epididymis","ntpm":38.0},{"tissue":"kidney","ntpm":57.8}],"url":"https://www.proteinatlas.org/search/HOXB6"},"hgnc":{"alias_symbol":[],"prev_symbol":["HOX2","HOX2B"]},"alphafold":{"accession":"P17509","domains":[{"cath_id":"1.10.10.60","chopping":"153-214","consensus_level":"medium","plddt":93.5619,"start":153,"end":214}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P17509","model_url":"https://alphafold.ebi.ac.uk/files/AF-P17509-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P17509-F1-predicted_aligned_error_v6.png","plddt_mean":64.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HOXB6","jax_strain_url":"https://www.jax.org/strain/search?query=HOXB6"},"sequence":{"accession":"P17509","fasta_url":"https://rest.uniprot.org/uniprotkb/P17509.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P17509/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P17509"}},"corpus_meta":[{"pmid":"7828847","id":"PMC_7828847","title":"Genetic interaction between hoxb-5 and hoxb-6 is revealed by nonallelic noncomplementation.","date":"1995","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/7828847","citation_count":235,"is_preprint":false},{"pmid":"15522959","id":"PMC_15522959","title":"HOXB6 overexpression in murine bone marrow immortalizes a myelomonocytic precursor in vitro and causes hematopoietic stem cell expansion and acute myeloid leukemia in vivo.","date":"2004","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/15522959","citation_count":100,"is_preprint":false},{"pmid":"32745807","id":"PMC_32745807","title":"An epigenome-wide association study of Alzheimer's disease blood highlights robust DNA hypermethylation in the HOXB6 gene.","date":"2020","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/32745807","citation_count":54,"is_preprint":false},{"pmid":"10833444","id":"PMC_10833444","title":"Deregulated expression of homeobox-containing genes, HOXB6, B8, C8, C9, and Cdx-1, in human colon cancer cell lines.","date":"2000","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/10833444","citation_count":48,"is_preprint":false},{"pmid":"10996827","id":"PMC_10996827","title":"Disruption of the homeobox gene Hoxb-6 in mice results in increased numbers of early erythrocyte progenitors.","date":"2000","source":"American journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/10996827","citation_count":48,"is_preprint":false},{"pmid":"17003840","id":"PMC_17003840","title":"Mutation screening of BMP4, BMP7, HOXA4 and HOXB6 genes in Chinese patients with hypospadias.","date":"2006","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/17003840","citation_count":46,"is_preprint":false},{"pmid":"10330333","id":"PMC_10330333","title":"Evolution of a HOXB6 intergenic region within the great apes and humans.","date":"1999","source":"Journal of human evolution","url":"https://pubmed.ncbi.nlm.nih.gov/10330333","citation_count":46,"is_preprint":false},{"pmid":"10906782","id":"PMC_10906782","title":"Changes in HOXB6 homeodomain protein structure and localization during human epidermal development and differentiation.","date":"2000","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/10906782","citation_count":38,"is_preprint":false},{"pmid":"32420798","id":"PMC_32420798","title":"ST8SIA6-AS1 promotes hepatocellular carcinoma by absorbing miR-5195-3p to regulate HOXB6.","date":"2020","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32420798","citation_count":35,"is_preprint":false},{"pmid":"8104549","id":"PMC_8104549","title":"Analysis of LacZ reporter genes in transgenic embryos suggests the presence of several cis-acting regulatory elements in the murine Hoxb-6 gene.","date":"1993","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/8104549","citation_count":33,"is_preprint":false},{"pmid":"12094253","id":"PMC_12094253","title":"Expression pattern of HOXB6 homeobox gene in myelomonocytic differentiation and acute myeloid leukemia.","date":"2002","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/12094253","citation_count":29,"is_preprint":false},{"pmid":"15269212","id":"PMC_15269212","title":"HOXB6 protein is bound to CREB-binding protein and represses globin expression in a DNA binding-dependent, PBX interaction-independent process.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15269212","citation_count":28,"is_preprint":false},{"pmid":"26718008","id":"PMC_26718008","title":"Hoxb6 can interfere with somitogenesis in the posterior embryo through a mechanism independent of its rib-promoting activity.","date":"2015","source":"Development (Cambridge, 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Part A, Clinical and molecular teratology","url":"https://pubmed.ncbi.nlm.nih.gov/18553509","citation_count":17,"is_preprint":false},{"pmid":"32763157","id":"PMC_32763157","title":"MiR-126 Regulates Properties of SOX9+ Liver Progenitor Cells during Liver Repair by Targeting Hoxb6.","date":"2020","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/32763157","citation_count":14,"is_preprint":false},{"pmid":"10327653","id":"PMC_10327653","title":"Phylogenetically conserved CK-II phosphorylation site of the murine homeodomain protein Hoxb-6.","date":"1999","source":"The Journal of experimental zoology","url":"https://pubmed.ncbi.nlm.nih.gov/10327653","citation_count":12,"is_preprint":false},{"pmid":"37356630","id":"PMC_37356630","title":"Hsa_circ_0007031 promotes the proliferation and migration of osteosarcoma cells by sponging miR-196a-5p to regulate the HOXB6.","date":"2023","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37356630","citation_count":10,"is_preprint":false},{"pmid":"8786996","id":"PMC_8786996","title":"The limb/LPM enhancer of the murine Hoxb6 gene: reporter gene analysis in transgenic embryos and studies of DNA-protein interactions.","date":"1996","source":"Pharmaceutica acta Helvetiae","url":"https://pubmed.ncbi.nlm.nih.gov/8786996","citation_count":8,"is_preprint":false},{"pmid":"26800342","id":"PMC_26800342","title":"Developmental Patterning as a Quantitative Trait: Genetic Modulation of the Hoxb6 Mutant Skeletal Phenotype.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26800342","citation_count":8,"is_preprint":false},{"pmid":"12536483","id":"PMC_12536483","title":"[Influence of human cytomegalovirus infection on the expression of HOXB5, HOXB6, HOXB7, and HOXB8 genes in gliomaous cells].","date":"2001","source":"Hunan yi ke da xue xue bao = Hunan yike daxue xuebao = Bulletin of Hunan Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/12536483","citation_count":0,"is_preprint":false},{"pmid":"12536675","id":"PMC_12536675","title":"[Influence of human cytomegalovirus infection on the expressions of HOXB1, HOXB5, HOXB6, and HOXB9 genes in human embryo lung cells].","date":"2001","source":"Hunan yi ke da xue xue bao = Hunan yike daxue xuebao = Bulletin of Hunan Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/12536675","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.09.06.611619","title":"HOXB6 and HOXB8 control immune-cancer cell interactions in pancreatic cancer","date":"2024-09-06","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.06.611619","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11942,"output_tokens":3077,"usd":0.04099,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10459,"output_tokens":3622,"usd":0.071422,"stage2_stop_reason":"end_turn"},"total_usd":0.112412,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"Hoxb-5 and Hoxb-6 function together (genetic nonallelic noncomplementation) to specify the cervicothoracic vertebral region (C6–T1); hoxb-6 homozygous knockouts show missing first rib, bifid second rib, and anteriorizing homeotic transformation of cervicothoracic vertebrae, establishing Hoxb-6's role in anteroposterior axial patterning of brachiocervicothoracic structures.\",\n      \"method\": \"Targeted gene disruption (knockout mice), genetic complementation test (transheterozygote analysis)\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean loss-of-function knockouts with specific skeletal phenotypes, replicated by nonallelic noncomplementation cross, multiple independent mutant alleles\",\n      \"pmids\": [\"7828847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Disruption of Hoxb-6 in mice results in increased numbers of early erythroid progenitor cells in bone marrow and fetal liver, while mature hematopoietic cell types and differentiation of other lineages remain normal, establishing a role for Hoxb-6 in controlling the generation, proliferation, or survival of erythroid progenitor cells.\",\n      \"method\": \"Targeted gene disruption (knockout mice), clonogenic progenitor cell assays\",\n      \"journal\": \"American journal of hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with specific cellular phenotype, single lab, two orthogonal assay methods\",\n      \"pmids\": [\"10996827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"HOXB6 protein subcellular localization shifts from cytoplasmic in fetal epidermis to substantially nuclear in adult skin. GFP-fusion protein experiments demonstrated that full-length HOXB6 localizes to the nucleus while a truncated isoform lacking the homeodomain is largely cytoplasmic. Neither full-length nor truncated HOXB6 co-localizes with PBX proteins in epidermis, suggesting HOXB6 acts without PBX co-factors in skin.\",\n      \"method\": \"Immunohistochemistry, GFP-fusion protein live imaging, subcellular fractionation, Western blot (protein isoform detection)\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with GFP fusions and fractionation, functional consequence inferred, single lab\",\n      \"pmids\": [\"10906782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Hoxb-6 is phosphorylated in vivo at serine-214 by casein kinase II (CK-II); this phosphorylation site is conserved across multiple homeodomain proteins and species. In vitro, Hoxb-6 is also phosphorylated by cAMP-dependent protein kinase. In vivo phosphorylation of the same CK-II peptide was confirmed from mouse embryonic spinal cords.\",\n      \"method\": \"Baculovirus expression system (Sf9 cells), two-dimensional tryptic phosphopeptide mapping, in vitro kinase assays with purified CK-II and PKA, immunoprecipitation from mouse embryonic spinal cords\",\n      \"journal\": \"The Journal of experimental zoology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus in vivo phosphopeptide mapping, site mapped to Ser-214, two orthogonal methods\",\n      \"pmids\": [\"10327653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"HOXB6 represses alpha- and gamma-globin mRNA levels in a DNA-binding-dependent manner in K562 cells; this activity does not require cooperative DNA-binding with PBX1 co-factor, nor the N-terminal conserved region, polyglutamic acid C-terminus, or Ser-214 CK-II phosphorylation site. Endogenous CBP (CREB-binding protein) co-precipitates with exogenous HOXB6 from nuclear and cytoplasmic fractions of transfected K562 cells, and endogenous CBP co-precipitates with endogenous HOXB6 in day 14.5 murine fetal liver cells. The CBP interaction motif was localized to the homeodomain but does not require helix 3.\",\n      \"method\": \"Stable transfection in K562 cells, RT-PCR (globin mRNA measurement), structure-function mutagenesis (homeodomain and interaction mutants), co-immunoprecipitation (endogenous and exogenous proteins)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro activity assay with mutagenesis plus reciprocal co-IP of endogenous proteins, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"15269212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"HOXB6 overexpression in murine bone marrow expands hematopoietic stem cells and myeloid precursors while inhibiting erythropoiesis and lymphopoiesis, and causes AML in vivo (median latency 223 days). These effects are largely dependent on DNA binding but independent of direct interaction with PBX1. Coexpression of MEIS1 dramatically shortens AML onset. In vitro, HOXB6 immortalizes a factor-dependent myelomonocytic precursor.\",\n      \"method\": \"Retrovirus-mediated gene transfer in murine bone marrow, in vivo transplantation, in vitro immortalization assay, structure-function analysis with DNA-binding and PBX1-interaction mutants, cytogenetics\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo and in vitro functional assays with structure-function mutants, multiple orthogonal readouts, single lab with comprehensive approach\",\n      \"pmids\": [\"15522959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Enforced expression of HOXB6 in promyelocytic NB4 cells inhibits granulocytic maturation, and in myeloblastic HL60 cells inhibits monocytic maturation, establishing that HOXB6 blocks myeloid differentiation. Endogenous HOXB6 expression is transiently induced during normal granulocytopoiesis and monocytopoiesis.\",\n      \"method\": \"Forced overexpression in NB4 and HL60 cell lines, differentiation assays (morphology, surface markers)\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function in two different cell lines with specific differentiation phenotype, single lab\",\n      \"pmids\": [\"12094253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The linker region (LR) connecting the homeodomain and hexapeptide of Hoxb6 is essential for its rib-promoting activity in mice. An LR-defective Hoxb6 protein retains the ability to bind a target enhancer together with Pax3, acting as a dominant negative, indicating the LR recruits additional regulatory factors to target DNA. Hoxb6 also regulates somitogenesis by dysregulating Lfng expression in a mechanism independent of its rib-promoting activity.\",\n      \"method\": \"Transgenic/knock-in mouse models with LR-deletion mutant, ChIP/enhancer binding assays, analysis of Lfng expression, skeletal phenotype analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo structure-function with domain mutant, dominant-negative demonstrated by enhancer binding assay, single lab\",\n      \"pmids\": [\"26718008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Three distinct cis-acting regulatory elements control Hoxb-6 expression: a limb/LPM enhancer (directing expression to limb buds and ventrolateral mesenchyme, functioning in a promoter- and orientation-independent manner), a spinal cord element (for ventral spinal cord expression), and a mesonephric element (for mesonephric tubules and ducts). The limb/LPM element functions as a bona fide enhancer.\",\n      \"method\": \"LacZ reporter gene transgenic mouse embryos, multiple deletion constructs across 13.2 kb of genomic DNA\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple transgenic reporter lines with systematic deletion analysis in vivo, single lab\",\n      \"pmids\": [\"8104549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Nuclear protein extracts from embryonic tissues form specific DNA-protein complexes with sequences in the Hoxb6 limb/LPM enhancer, as detected by electromobility shift assay, suggesting these interactions are important for tissue-specific regulation of Hoxb6 expression.\",\n      \"method\": \"Electromobility shift assay (EMSA) with nuclear extracts from embryonic tissues, LacZ reporter transgenic embryos\",\n      \"journal\": \"Pharmaceutica acta Helvetiae\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single EMSA-based pulldown without protein identification, no functional validation of specific binding partners\",\n      \"pmids\": [\"8786996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HOXB6 directly binds to the promoter of Sox9 to inhibit Sox9 expression in liver progenitor cells, as demonstrated by chromatin immunoprecipitation/promoter binding assay. miR-126 suppresses HOXB6 translation, thereby de-repressing Sox9 and promoting SOX9+ liver progenitor cell proliferation and differentiation during CCl4-induced liver injury.\",\n      \"method\": \"Luciferase reporter assay (Sox9 promoter), ChIP/promoter binding, miRNA overexpression/knockdown, CCl4-induced liver injury model\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding demonstrated, functional rescue experiments, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32763157\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HOXB6 is a homeodomain transcription factor that (1) binds DNA via its homeodomain (with the linker region providing additional regulatory activity) independently of PBX1 co-factor interaction in blood cells; (2) is phosphorylated at Ser-214 by casein kinase II in vivo; (3) interacts with CREB-binding protein (CBP) through its homeodomain to repress globin and other target genes; (4) directly binds the Sox9 promoter to repress Sox9 expression; (5) controls axial patterning of cervicothoracic vertebrae, rib formation, and somitogenesis (via Lfng dysregulation) in vivo; and (6) in hematopoiesis, expands myeloid progenitors while blocking erythroid and lymphoid differentiation, with MEIS1 cooperativity accelerating leukemogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HOXB6 is a homeodomain transcription factor that controls anteroposterior axial patterning during development and regulates differentiation decisions in hematopoietic and progenitor cell compartments [#0, #5]. In the embryo it specifies the cervicothoracic vertebral region and promotes rib formation, with loss of function producing missing first ribs, bifid second ribs, and anteriorizing homeotic transformations [#0]; the linker region connecting the homeodomain and hexapeptide is essential for rib-promoting activity and recruits additional factors (e.g., Pax3) to target enhancers, while HOXB6 separately governs somitogenesis through dysregulation of Lfng [#7]. As a transcriptional repressor, HOXB6 binds DNA through its homeodomain and acts independently of cooperative DNA binding with the PBX1 co-factor [#4, #5]; it interacts via its homeodomain with CREB-binding protein (CBP) to repress alpha- and gamma-globin genes, and directly binds the Sox9 promoter to repress Sox9 in liver progenitor cells [#4, #10]. In hematopoiesis, HOXB6 expands hematopoietic stem cells and myeloid precursors while blocking erythroid, lymphoid, and granulocytic/monocytic differentiation, and its enforced expression causes AML in vivo with latency dramatically shortened by MEIS1 co-expression [#5, #6]. HOXB6 is phosphorylated in vivo at Ser-214 by casein kinase II, though this site is dispensable for globin repression [#3, #4].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Before any functional role was assigned, it was unknown how Hoxb-6 expression is spatially restricted; dissecting its regulatory landscape established the tissue-specific control elements driving its developmental expression.\",\n      \"evidence\": \"LacZ reporter transgenic mouse embryos with systematic deletion across 13.2 kb of genomic DNA\",\n      \"pmids\": [\"8104549\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The trans-acting factors binding each element were not identified\", \"Does not address HOXB6 protein function, only its regulation\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"The in vivo developmental requirement was unknown; knockout and noncomplementation analysis established Hoxb-6 as a specifier of cervicothoracic axial identity acting together with Hoxb-5.\",\n      \"evidence\": \"Targeted gene disruption in mice and transheterozygote genetic complementation test\",\n      \"pmids\": [\"7828847\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets driving the skeletal phenotype not identified\", \"Molecular basis of Hoxb-5/Hoxb-6 cooperativity not resolved\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Following enhancer mapping, it remained unknown what nuclear proteins act through the limb/LPM enhancer; EMSA detected tissue-specific DNA-protein complexes implicating sequence-specific factors.\",\n      \"evidence\": \"EMSA with embryonic nuclear extracts plus LacZ reporter transgenics\",\n      \"pmids\": [\"8786996\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single EMSA-based pulldown without identification of the bound proteins\", \"No functional validation of the specific binding partners\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Whether HOXB6 is post-translationally modified was unknown; phosphopeptide mapping identified a conserved CK-II phosphorylation site at Ser-214 modified in vivo.\",\n      \"evidence\": \"Baculovirus expression, 2D tryptic phosphopeptide mapping, in vitro kinase assays, and IP from mouse embryonic spinal cords\",\n      \"pmids\": [\"10327653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of Ser-214 phosphorylation not defined\", \"Whether PKA phosphorylation occurs in vivo not established\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"The hematopoietic role was unknown; knockout analysis revealed Hoxb-6 controls the generation, proliferation, or survival of early erythroid progenitors.\",\n      \"evidence\": \"Knockout mice with clonogenic progenitor assays in bone marrow and fetal liver\",\n      \"pmids\": [\"10996827\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the effect is on generation versus proliferation versus survival not distinguished\", \"Molecular targets in erythroid progenitors not identified\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"It was unclear whether HOXB6 requires PBX co-factors and how its localization is controlled; isoform and GFP-fusion experiments showed homeodomain-dependent nuclear localization that does not co-localize with PBX in epidermis.\",\n      \"evidence\": \"Immunohistochemistry, GFP-fusion live imaging, subcellular fractionation, and Western blot of protein isoforms\",\n      \"pmids\": [\"10906782\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of cytoplasmic-to-nuclear shift inferred, not directly tested\", \"Regulator of the developmental localization switch unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Whether HOXB6 affects myeloid maturation was unknown; enforced expression in promyelocytic and myeloblastic lines established that it blocks granulocytic and monocytic differentiation.\",\n      \"evidence\": \"Forced overexpression in NB4 and HL60 cells with morphology and surface-marker differentiation assays\",\n      \"pmids\": [\"12094253\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Target genes mediating the differentiation block not identified\", \"Based on cell lines rather than primary cells\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"The transcriptional mechanism and co-factor dependence were unresolved; structure-function and reciprocal co-IP showed HOXB6 represses globin genes via a DNA-binding-dependent, PBX1-independent mechanism using a homeodomain interaction with CBP.\",\n      \"evidence\": \"Stable K562 transfection, RT-PCR, structure-function mutagenesis, and reciprocal endogenous co-IP including fetal liver\",\n      \"pmids\": [\"15269212\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CBP recruitment yields repression rather than activation not mechanistically explained\", \"N-terminal region, polyGlu C-terminus, and Ser-214 shown dispensable but their functions elsewhere unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Whether HOXB6 dysregulation is oncogenic was unknown; bone marrow overexpression established that it expands HSCs and myeloid precursors and causes AML, with MEIS1 as a cooperating accelerator.\",\n      \"evidence\": \"Retroviral transduction of murine bone marrow, transplantation, immortalization assay, and DNA-binding/PBX1-interaction mutants\",\n      \"pmids\": [\"15522959\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets driving leukemogenesis not defined\", \"Mechanism of MEIS1 cooperativity not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The domain requirements for axial function were unknown; an LR-deletion knock-in showed the linker region is essential for rib promotion by recruiting co-factors, and that somitogenesis control via Lfng is a separable activity.\",\n      \"evidence\": \"Knock-in mice with linker-region deletion, enhancer/ChIP binding assays with Pax3, and Lfng expression analysis\",\n      \"pmids\": [\"26718008\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the additional factors recruited by the LR (beyond Pax3) not fully resolved\", \"How Lfng dysregulation is mechanistically linked to HOXB6 not detailed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A direct transcriptional target in tissue regeneration was unknown; promoter-binding and rescue experiments established that HOXB6 directly represses Sox9 and is itself suppressed by miR-126 to de-repress liver progenitor expansion.\",\n      \"evidence\": \"Sox9 luciferase reporter, ChIP/promoter binding, miR-126 overexpression/knockdown, and CCl4-induced liver injury model\",\n      \"pmids\": [\"32763157\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether co-factors are required for Sox9 promoter repression not addressed\", \"Generality of the miR-126/HOXB6/Sox9 axis beyond liver injury unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The genome-wide direct target repertoire of HOXB6 and the structural basis by which its homeodomain and linker region select repressive co-factors (CBP versus Pax3) across different tissues remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unbiased genome-wide binding map across developmental and hematopoietic contexts\", \"No structural model of the homeodomain-CBP or LR-Pax3 interfaces\", \"Functional role of Ser-214 phosphorylation still undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4, 5, 10]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [4, 5, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CBP\", \"PAX3\", \"MEIS1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}