{"gene":"CBFB","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":1995,"finding":"CBF-C (encoded by CBFB) is required together with CBF-A and CBF-B to form a CBF-DNA complex binding to CCAAT motifs; CBF-A and CBF-C interact to form a heterodimer, and CBF-B does not interact individually with either subunit but associates with the CBF-A/CBF-C complex.","method":"Recombinant protein reconstitution, electrophoretic mobility shift assay (EMSA), immunoprecipitation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro with purified recombinant subunits and direct protein-DNA complex demonstrated","pmids":["7878029"],"is_preprint":false},{"year":1996,"finding":"CBF-B interacts simultaneously with both CBF-A and CBF-C subunits to form a heterotrimeric CBF molecule; the histone-fold motif of CBF-C (similar to histone H2A) is necessary for CBF-DNA complex formation and for interaction with CBF-A, and two separate CBF-B interaction domains were identified flanking the CBF-A interaction domain in CBF-C.","method":"Cross-linking, immunoprecipitation, mutational analysis, in vitro binding assays, yeast two-hybrid","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal methods including mutagenesis, in vitro assay, and two-hybrid in a single study","pmids":["8754798"],"is_preprint":false},{"year":1996,"finding":"The heterotrimeric CBF (NF-Y) transcription factor has two distinct transcriptional activation domains: one in the CBF-B subunit (N-terminal residues 1–224) and one in the CBF-C subunit (C-terminal residues 114–309), and these two domains act additively to stimulate transcription.","method":"In vitro transcription reconstitution with purified recombinant CBF subunits and deletion mutants in nuclear extracts depleted of CBF","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro transcription with purified deletion mutants","pmids":["8662945"],"is_preprint":false},{"year":1996,"finding":"The CBFB-MYH11 fusion oncogene acts as a dominant negative for CBF function: embryos heterozygous for Cbfb-MYH11 knock-in lack definitive hematopoiesis and develop fatal hemorrhages, a phenotype similar to homozygous deletion of Cbfb or Cbfa2 (AML1), indicating dominant negative suppression of CBF-dependent hematopoiesis.","method":"Knock-in mouse model (homologous recombination), embryonic analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — genetic loss-of-function knock-in with defined hematopoietic phenotype, highly cited foundational paper","pmids":["8929537"],"is_preprint":false},{"year":1996,"finding":"The CBFB-MYH11 fusion protein (CBFβ-SMMHC) is produced in leukemic cells, is located primarily in the nuclei, and forms a very high molecular weight protein-DNA complex in nuclear extracts as detected by EMSA; immunofluorescence shows the fusion protein organizes into novel structures within cell nuclei.","method":"Western blot with anti-CBFB and anti-MYH11 C-terminus antibodies, immunofluorescence, EMSA with nuclear extracts from patient cells","journal":"Genes, chromosomes & cancer","confidence":"High","confidence_rationale":"Tier 2 — direct protein detection in patient cells with multiple complementary methods","pmids":["8818654"],"is_preprint":false},{"year":2001,"finding":"In vitro studies demonstrated that expression of CBFB-MYH11 leads to sequestration of CBFα2 (RUNX1) in the cytoplasm, inhibits CBF-mediated transactivation, slows cell cycle progression, delays the apoptotic response to DNA-damaging agents, and protects CBFα2 from degradation.","method":"Review summarizing in vitro cell-based assays (transfection, transactivation reporter, cell cycle analysis, apoptosis assays)","journal":"Current opinion in hematology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple mechanistic findings summarized from in vitro studies; review rather than primary data paper","pmids":["11561156"],"is_preprint":false},{"year":2002,"finding":"Cbfb is expressed in hematopoietic stem and progenitor cells in midgestation embryos and in adult stem/progenitor as well as mature myeloid and lymphoid cells, but not during terminal erythropoiesis; Cbfb-MYH11 blocks embryonic hematopoiesis at the stem-progenitor cell level by eliminating this population.","method":"Cbfb-GFP knock-in mouse model, flow cytometry, comparison with Cbfb-MYH11 knock-in mice","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — knock-in mouse with GFP reporter provides direct localization and functional characterization of Cbfb expression in hematopoietic hierarchy","pmids":["12239155"],"is_preprint":false},{"year":2003,"finding":"Cbfb is required for the functions of Runx1 and Runx2 in skeletal development; Runx2/Cbfb heterodimers play essential roles in osteoblast differentiation and chondrocyte maturation.","method":"Genetic analysis of Cbfb-deficient mice with partial hematopoietic rescue, phenotypic analysis of skeletal development","journal":"Journal of bone and mineral metabolism","confidence":"Medium","confidence_rationale":"Tier 2 — mouse genetic loss-of-function with skeletal phenotypic readout; review article summarizing mouse model data","pmids":["12811622"],"is_preprint":false},{"year":2005,"finding":"CBFB-SMMHC (CBFβ-SMMHC) suppresses CEBPA protein expression and binding activity without altering CEBPA mRNA levels by inducing calreticulin, an inhibitor of CEBPA translation; siRNA knockdown of calreticulin restored CEBPA levels.","method":"Conditional expression system (U937 cells), Western blot, EMSA, siRNA knockdown, patient sample analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — mechanistic pathway defined with conditional expression, siRNA rescue, and patient samples using multiple methods","pmids":["15855281"],"is_preprint":false},{"year":2007,"finding":"Cbfb enhances osteogenic differentiation of mesenchymal stem cells induced by Cbfa-1 (RUNX2) by reducing ubiquitination-mediated proteasomal degradation of RUNX2, thereby increasing RUNX2 protein stability.","method":"Adenoviral overexpression, alkaline phosphatase activity assay, osteocalcin measurement, ubiquitination assay in C3H10T1/2 and human MSCs","journal":"Stem cells (Dayton, Ohio)","confidence":"High","confidence_rationale":"Tier 2 — direct ubiquitination assay demonstrating mechanism of RUNX2 stabilization by CBFB with functional osteogenic readout","pmids":["17379770"],"is_preprint":false},{"year":2009,"finding":"Cbfb-MYH11 causes hematopoietic defects (delayed differentiation with sustained expression of Gata2, Il1rl1, and Csf2rb) that are independent of Cbfb/Runx1 repression, indicating the fusion protein has RUNX1-repression-independent leukemogenic activities.","method":"Knock-in mouse model, gene expression analysis, comparison with Cbfb and Runx1 knockout phenotypes","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis using knock-in and knockout mice with defined molecular and cellular phenotypes","pmids":["20007544"],"is_preprint":false},{"year":2009,"finding":"GATA-1 represses Cbfb transcription in erythroleukemia cells by co-occupying PU.1 binding sites near the Cbfb locus; activation of PU.1 or knockdown of GATA-1 derepresses Cbfb expression with accompanying increases in H3K9 acetylation at the Cbfb locus.","method":"Conditional PU.1 activation (PUER), siRNA knockdown of GATA-1, chromatin immunoprecipitation (ChIP), reporter assays, gene expression arrays","journal":"Molecular cancer research : MCR","confidence":"High","confidence_rationale":"Tier 2 — ChIP, reporter assay, and siRNA rescue provide mechanistic definition of CBFB transcriptional regulation","pmids":["19825991"],"is_preprint":false},{"year":2013,"finding":"CBFβ-MYH11 localizes to RUNX1-occupied promoters genome-wide and interacts with TAL1, FLI1, TBP-associated factors (TAFs), ERG, GATA2, PU.1, EP300, and HDAC1; the fusion protein maintains active transcription of self-renewal genes (ID1, LMO1, JAG1) and represses only a subset of RUNX1 target genes.","method":"Genome-wide ChIP-seq, quantitative interaction proteomics (mass spectrometry), RNA-seq upon fusion protein knockdown","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 1/2 — genome-wide binding analysis combined with quantitative proteomics interactome and transcriptional analysis","pmids":["24002588"],"is_preprint":false},{"year":2015,"finding":"Cbfb stabilizes Runx1, Runx2, and Runx3 proteins in skeletal cells; conditional deletion of Cbfb in mesenchymal cells led to reduced Runx family protein levels (without corresponding mRNA reduction) and decreased Runx2 protein stability, causing dwarfism, impaired ossification, and inhibited chondrocyte and osteoblast differentiation.","method":"Conditional knockout (Cbfb-floxed × Dermo1-Cre), protein/mRNA analysis, in vitro differentiation assays, promoter reporter assays","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 — conditional knockout with protein stability analysis and functional differentiation assays","pmids":["25262822"],"is_preprint":false},{"year":2015,"finding":"Loss of Runx1 activity rescued the hematopoietic differentiation defects induced by Cbfb-MYH11 during primitive and definitive hematopoiesis, and significantly delayed Cbfb-MYH11-induced leukemia, demonstrating that Runx1 activity is critical for Cbfb-MYH11-induced leukemogenesis.","method":"Genetic epistasis — Cbfb-MYH11 knock-in combined with Runx1 null or dominant-negative alleles in mice, leukemia latency analysis","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 — classical genetic epistasis in mouse model with clear phenotypic and survival readouts","pmids":["25742748"],"is_preprint":false},{"year":2017,"finding":"p53 induced by RUNX1 depletion directly binds to the CBFB promoter and stimulates its transcription and translation; the resulting CBFB protein then stabilizes RUNX1, creating a compensatory RUNX1-p53-CBFB feedback loop in AML cells.","method":"Gene silencing (siRNA), chromatin immunoprecipitation, luciferase reporter assay, Western blot, patient sample analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and reporter assay define direct p53-CBFB promoter interaction; single lab","pmids":["29192243"],"is_preprint":false},{"year":2017,"finding":"CHD7 interacts with CBFβ-SMMHC through RUNX1, enhances transcriptional activity of RUNX1 and CBFβ-SMMHC on target genes (e.g., Csf1r), and Chd7 deficiency delayed Cbfb-MYH11-induced leukemia in mice.","method":"Co-immunoprecipitation, transcriptional reporter assay, conditional Chd7 knockout combined with Cbfb-MYH11 knock-in, RNA-seq","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — Co-IP, reporter assay, and in vivo genetic epistasis with leukemia latency readout","pmids":["29018080"],"is_preprint":false},{"year":2019,"finding":"CBFB has a noncanonical cytoplasmic role in translation regulation: cytoplasmic CBFB binds to hundreds of mRNA transcripts (including RUNX1 mRNA) via hnRNPK and enhances their translation through eIF4B; nuclear CBFB/RUNX1 complex transcriptionally represses NOTCH signaling in breast cancer.","method":"RNA immunoprecipitation followed by deep sequencing (RIP-seq), polysome profiling, co-immunoprecipitation, knockdown/rescue experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1/2 — RIP-seq plus functional translation assays plus nuclear transcription analysis; multiple orthogonal methods","pmids":["31061501"],"is_preprint":false},{"year":2019,"finding":"In anterior palatogenesis, Cbfb acts as an obligatory cofactor for Runx1 in a Runx1/Cbfb-Stat3-Tgfb3 signaling axis; Cbfb mutant mice develop anterior cleft palate with disrupted TGFB3 expression and reduced Stat3 phosphorylation, and folic acid rescues the cleft by activating Stat3 and Tgfb3.","method":"Conditional Cbfb knockout mouse model, immunofluorescence, in vitro palatal fusion assay, TGFB3 rescue experiment, pharmaceutical Stat3 activation","journal":"Disease models & mechanisms","confidence":"High","confidence_rationale":"Tier 2 — genetic loss-of-function with defined molecular pathway (Runx1/Cbfb-Stat3-Tgfb3) and pharmacological rescue","pmids":["31171577"],"is_preprint":false},{"year":2021,"finding":"CBFB-MYH11 fusion sequesters RUNX1 in the cytoplasm, preventing RUNX1 from interacting with and recruiting DNMT3A to RUNX1 target genes, resulting in DNA hypomethylation at those loci similar to DNMT3A loss-of-function; RUNX1 directly interacts with DNMT3A and this interaction is disrupted by CBFB-MYH11.","method":"Co-immunoprecipitation, methylation analysis (bisulfite sequencing), gene expression analysis, comparison with DNMT3A-inhibited cells, mutual exclusivity analysis in patient datasets","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 2 — direct Co-IP of RUNX1-DNMT3A interaction, functional methylation assay, and genetic mutual exclusivity supporting mechanism","pmids":["34336831"],"is_preprint":false},{"year":2021,"finding":"CBFB cooperates with p53 to maintain TAp73 expression as a shared transcriptional target; loss of either CBFB or p53 leads to TAp73 depletion, and TAp73 re-expression abrogates the tumorigenic effect of CBFB deletion in breast cancer.","method":"Integrated genomic analysis, gene expression experiments, ChIP, rescue experiments (TAp73 re-expression), xenograft mouse model, immunohistochemistry","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — ChIP, transcriptional analysis, and functional rescue with multiple orthogonal approaches","pmids":["33945523"],"is_preprint":false},{"year":2023,"finding":"CBFB localizes to mitochondria and enhances the binding of mitochondrial mRNAs to TUFM (a mitochondrial translation elongation factor), thereby promoting mitochondrial genome translation; CBFB loss of function causes mitochondrial translation defects, leading to defective oxidative phosphorylation, the Warburg effect, and autophagy/mitophagy addiction.","method":"Subcellular fractionation showing mitochondrial CBFB localization, co-immunoprecipitation of CBFB with TUFM and mitochondrial mRNAs, proteomics interactome, metabolic assays, mouse tumor models, patient-derived xenografts","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1/2 — direct localization to mitochondria plus protein-mRNA interaction data plus functional metabolic readouts in multiple models","pmids":["36799863"],"is_preprint":false},{"year":2023,"finding":"The CBFB::MYH11 oncofusion protein sequesters RUNX1 in cytoplasmic aggregates via the CBFB domain interacting with the MYH11 domain that also binds cytoplasmic myosin-related proteins; this cytoplasmic sequestration is associated with increased RUNX1/2 transcription suggesting a feedback sensor for reduced functional RUNX1.","method":"TurboID proximity biotinylation proteomics in primary murine hematopoietic cells, immunofluorescence, subcellular fractionation, validation in primary human AML cells","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1/2 — unbiased proximity proteomics plus multiple validation methods in primary mouse and human cells","pmids":["38061017"],"is_preprint":false},{"year":2020,"finding":"miR-27b targets CBFB to inhibit differentiation of human bone marrow mesenchymal stem cells into hypertrophic chondrocytes; CBFB forms a complex with RUNX2, and CBFB knockdown by shRNA increases COL2/SOX9 expression while decreasing COL10/RUNX2 levels.","method":"Luciferase reporter assay (CBFB 3'-UTR), co-immunoprecipitation (CBFB-RUNX2 complex), shRNA knockdown, in vivo cartilage repair model","journal":"Stem cell research & therapy","confidence":"High","confidence_rationale":"Tier 2 — luciferase reporter and Co-IP with functional differentiation readout in vitro and in vivo","pmids":["32917285"],"is_preprint":false}],"current_model":"CBFB encodes the β subunit of Core Binding Factor, which heterodimerizes with RUNX family proteins (RUNX1/2/3) through histone-fold domain interactions to enhance their DNA binding and stabilize them against ubiquitin-mediated proteasomal degradation; in addition to this canonical nuclear transcriptional co-activator role (where the CBFB/RUNX1 complex recruits DNMT3A and represses oncogenic NOTCH signaling), CBFB functions non-canonically in the cytoplasm—binding mRNAs via hnRNPK to promote translation through eIF4B, and in mitochondria where it enhances mitochondrial genome translation by binding mitochondrial mRNAs to the elongation factor TUFM; the leukemia-associated CBFB-MYH11 fusion protein sequesters RUNX1 in cytoplasmic aggregates via myosin-related protein interactions, blocks CBF-dependent hematopoietic differentiation in a partly RUNX1-dependent and partly RUNX1-independent manner, and suppresses CEBPA protein through calreticulin-mediated translational inhibition."},"narrative":{"teleology":[{"year":1995,"claim":"Establishing CBFβ as an obligate component of a DNA-binding transcription factor complex resolved the question of whether CBFB contributes directly to CCAAT-motif recognition or acts only as a cofactor.","evidence":"Recombinant protein reconstitution and EMSA showing CBF-C (CBFβ) is required with CBF-A and CBF-B to form the CBF-DNA complex","pmids":["7878029"],"confidence":"High","gaps":["Exact DNA-contact residues of CBFβ not mapped","Role in vivo not yet established"]},{"year":1996,"claim":"Identification of the histone-fold motif as the structural basis for CBFβ heterodimerization and demonstration that CBFβ harbors a transcriptional activation domain defined how each subunit contributes to CBF function.","evidence":"Cross-linking, mutagenesis, yeast two-hybrid, and in vitro transcription with purified deletion mutants","pmids":["8754798","8662945"],"confidence":"High","gaps":["Crystal structure of the heterotrimer not yet available","In vivo relevance of each activation domain not tested"]},{"year":1996,"claim":"The Cbfb-MYH11 knock-in mouse proved that the fusion protein acts as a dominant-negative for CBF-dependent hematopoiesis, establishing its causal role in leukemogenesis.","evidence":"Knock-in mouse with heterozygous Cbfb-MYH11 phenocopying Cbfb and Cbfa2 nulls — lethal hemorrhage, absent definitive hematopoiesis","pmids":["8929537"],"confidence":"High","gaps":["Mechanism of dominant-negative action (sequestration vs. active repression) not resolved","Additional cooperating mutations for full leukemia not defined"]},{"year":2002,"claim":"Mapping Cbfb expression across the hematopoietic hierarchy revealed its requirement at the stem/progenitor level and showed Cbfb-MYH11 eliminates this population, pinpointing the cellular target of the fusion.","evidence":"Cbfb-GFP knock-in reporter combined with flow cytometry in embryonic and adult hematopoietic cells","pmids":["12239155"],"confidence":"High","gaps":["Whether Cbfb has distinct functions in lymphoid vs. myeloid lineages not resolved","Dose-dependence of Cbfb in stem cell self-renewal unknown"]},{"year":2005,"claim":"Discovery that CBFβ-SMMHC suppresses CEBPA protein through calreticulin-mediated translational inhibition identified a RUNX-independent oncogenic mechanism of the fusion.","evidence":"Conditional expression in U937 cells, Western blot, siRNA knockdown of calreticulin restoring CEBPA","pmids":["15855281"],"confidence":"High","gaps":["Whether calreticulin induction is direct or indirect not clarified","Relevance to non-hematopoietic contexts unknown"]},{"year":2007,"claim":"Demonstrating that CBFβ stabilizes RUNX2 by reducing its ubiquitin-mediated proteasomal degradation established protein stabilization as a core mechanism through which CBFβ promotes osteogenic differentiation.","evidence":"Ubiquitination assays and overexpression in mesenchymal stem cells with osteogenic differentiation readouts","pmids":["17379770"],"confidence":"High","gaps":["Identity of the E3 ligase counteracted by CBFβ not determined","Whether the same stabilization mechanism applies to RUNX1 and RUNX3 not directly tested"]},{"year":2009,"claim":"Genetic epistasis revealed that Cbfb-MYH11 causes hematopoietic defects independent of RUNX1 repression, broadening the fusion's oncogenic mechanism beyond simple dominant-negative CBF inhibition.","evidence":"Comparison of Cbfb-MYH11 knock-in with Cbfb and Runx1 knockouts showing distinct gene expression changes (Gata2, Il1rl1, Csf2rb)","pmids":["20007544"],"confidence":"High","gaps":["Molecular basis for RUNX1-independent activities not defined","Direct fusion protein targets mediating these effects unknown"]},{"year":2013,"claim":"Genome-wide binding and interactome analyses of CBFβ-MYH11 showed it co-occupies RUNX1 target promoters, interacts with hematopoietic transcription factors and chromatin regulators, and maintains self-renewal gene expression rather than globally repressing RUNX1 targets.","evidence":"ChIP-seq, quantitative interaction proteomics (mass spectrometry), and RNA-seq upon fusion knockdown in leukemia cells","pmids":["24002588"],"confidence":"High","gaps":["Which chromatin remodeling complexes are essential for fusion-driven transcription not established","Whether the fusion redirects vs. maintains pre-existing RUNX1 programs unclear"]},{"year":2015,"claim":"Conditional deletion of Cbfb in mesenchymal cells confirmed that CBFβ stabilizes all three RUNX proteins at the post-translational level in vivo, causing dwarfism and impaired skeletal development.","evidence":"Cbfb conditional knockout (Dermo1-Cre), protein and mRNA analysis showing reduced RUNX protein without mRNA change","pmids":["25262822"],"confidence":"High","gaps":["Relative contribution of RUNX1 vs. RUNX2 vs. RUNX3 stabilization to each skeletal phenotype not separated"]},{"year":2015,"claim":"Loss of Runx1 delayed Cbfb-MYH11-induced leukemia, proving that RUNX1 activity is paradoxically required for leukemogenesis driven by the fusion.","evidence":"Genetic epistasis combining Cbfb-MYH11 knock-in with Runx1 null or dominant-negative alleles; leukemia latency analysis","pmids":["25742748"],"confidence":"High","gaps":["Whether residual Runx2/Runx3 compensate for Runx1 loss not assessed","Mechanism by which Runx1 enables fusion-driven transformation not defined"]},{"year":2019,"claim":"Discovery of a noncanonical cytoplasmic role for CBFβ in translational regulation — binding mRNAs via hnRNPK and promoting translation through eIF4B — fundamentally expanded CBFβ function beyond transcription.","evidence":"RIP-seq identifying hundreds of CBFβ-bound mRNAs, polysome profiling, co-immunoprecipitation of CBFβ-hnRNPK-eIF4B in breast cancer cells","pmids":["31061501"],"confidence":"High","gaps":["Structural basis of CBFβ-RNA interaction unknown","Whether cytoplasmic CBFβ function is conserved across all cell types not established"]},{"year":2019,"claim":"Cbfb was shown to be required for anterior palatogenesis through a Runx1/Cbfb-Stat3-Tgfb3 axis, linking CBFβ loss to cleft palate and identifying folic acid rescue via Stat3 activation.","evidence":"Conditional Cbfb knockout mice with cleft palate, reduced Stat3 phosphorylation and Tgfb3 expression, folic acid and Tgfb3 rescue experiments","pmids":["31171577"],"confidence":"High","gaps":["Direct vs. indirect mechanism of Stat3 activation by RUNX1/CBFβ not resolved","Relevance to human cleft palate genetics not confirmed"]},{"year":2021,"claim":"Demonstration that CBFB-MYH11 disrupts the RUNX1-DNMT3A interaction, causing DNA hypomethylation at RUNX1 target loci, connected the fusion to epigenetic dysregulation analogous to DNMT3A loss-of-function.","evidence":"Co-immunoprecipitation of RUNX1-DNMT3A, bisulfite sequencing showing hypomethylation, mutual exclusivity of CBFB-MYH11 and DNMT3A mutations in patients","pmids":["34336831"],"confidence":"High","gaps":["Whether CBFβ itself is needed for the RUNX1-DNMT3A interaction not tested","Genome-wide methylation consequences in primary leukemia not fully mapped"]},{"year":2023,"claim":"Identification of CBFβ in mitochondria where it promotes mitochondrial genome translation by enhancing mRNA binding to TUFM revealed a third subcellular compartment of CBFβ function and linked its loss to defective oxidative phosphorylation and metabolic reprogramming.","evidence":"Subcellular fractionation, co-immunoprecipitation of CBFβ-TUFM-mitochondrial mRNAs, metabolic assays in mouse tumor models and patient-derived xenografts","pmids":["36799863"],"confidence":"High","gaps":["Mechanism of CBFβ import into mitochondria not defined","Relative contribution of mitochondrial vs. nuclear/cytoplasmic CBFβ to tumor suppression not quantified"]},{"year":2023,"claim":"Proximity proteomics defined the mechanism of RUNX1 cytoplasmic sequestration by CBFβ-MYH11 — the MYH11 moiety interacts with cytoplasmic myosin-related proteins to form aggregates, with compensatory upregulation of RUNX1/2 transcription.","evidence":"TurboID proximity biotinylation in primary murine hematopoietic cells, validated by immunofluorescence and subcellular fractionation in primary human AML samples","pmids":["38061017"],"confidence":"High","gaps":["Whether preventing aggregate formation rescues leukemia phenotype not tested","Specific myosin interactors mediating aggregation not fully characterized"]},{"year":null,"claim":"Key unresolved questions include how CBFβ is partitioned among nuclear, cytoplasmic, and mitochondrial pools, the structural basis of its RNA-binding activity, and whether therapeutic disruption of CBFβ-RUNX interaction or CBFβ-MYH11 aggregation is achievable.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of CBFβ bound to mRNA or mitochondrial mRNA-TUFM complex","Mechanism governing subcellular distribution of CBFβ unknown","Therapeutic targeting of the CBFβ-MYH11 fusion protein not yet validated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,12,17]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[17,21]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[17,21]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,13]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,12,17]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[17,22]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[21]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,11,12,17]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,13,18,23]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,8,10,14,22]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[9,13,17,21]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[21]}],"complexes":["Core Binding Factor (CBF/NF-Y heterotrimer)","CBFβ-RUNX1 heterodimer","CBFβ-RUNX2 heterodimer"],"partners":["RUNX1","RUNX2","RUNX3","HNRNPK","EIF4B","TUFM","DNMT3A","CHD7"],"other_free_text":[]},"mechanistic_narrative":"CBFB encodes the β subunit of Core Binding Factor (CBF), a transcriptional regulator essential for definitive hematopoiesis, skeletal development, and tumor suppression. In the nucleus, CBFβ heterodimerizes with RUNX family proteins (RUNX1/2/3) via histone-fold domain interactions, stabilizing them against ubiquitin-mediated proteasomal degradation and enhancing their DNA-binding activity to regulate target genes including those controlling hematopoietic differentiation, osteoblast maturation, chondrocyte development, and palatogenesis [PMID:25262822, PMID:17379770, PMID:31171577]; the nuclear CBFβ/RUNX1 complex also recruits DNMT3A to maintain DNA methylation at target loci and represses NOTCH signaling [PMID:34336831, PMID:31061501]. Beyond its canonical nuclear role, cytoplasmic CBFβ binds hundreds of mRNAs via hnRNPK and promotes their translation through eIF4B, and mitochondrial CBFβ enhances mitochondrial genome translation by facilitating mRNA binding to the elongation factor TUFM, linking CBFβ loss to defective oxidative phosphorylation [PMID:31061501, PMID:36799863]. The leukemia-associated CBFB-MYH11 fusion protein acts as a dominant-negative by sequestering RUNX1 in cytoplasmic aggregates, blocking CBF-dependent differentiation, suppressing CEBPA translation via calreticulin induction, and maintaining self-renewal gene expression, establishing this fusion as a driver of inv(16) acute myeloid leukemia [PMID:8929537, PMID:15855281, PMID:24002588, PMID:38061017]."},"prefetch_data":{"uniprot":{"accession":"Q13951","full_name":"Core-binding factor subunit beta","aliases":["Polyomavirus enhancer-binding protein 2 beta subunit","PEA2-beta","PEBP2-beta","SL3-3 enhancer factor 1 subunit beta","SL3/AKV core-binding factor beta subunit"],"length_aa":182,"mass_kda":21.5,"function":"Forms the heterodimeric complex core-binding factor (CBF) with RUNX family proteins (RUNX1, RUNX2, and RUNX3). RUNX members modulate the transcription of their target genes through recognizing the core consensus binding sequence 5'-TGTGGT-3', or very rarely, 5'-TGCGGT-3', within their regulatory regions via their runt domain, while CBFB is a non-DNA-binding regulatory subunit that allosterically enhances the sequence-specific DNA-binding capacity of RUNX. The heterodimers bind to the core site of a number of enhancers and promoters, including murine leukemia virus, polyomavirus enhancer, T-cell receptor enhancers, LCK, IL3 and GM-CSF promoters. CBF complexes repress ZBTB7B transcription factor during cytotoxic (CD8+) T cell development. They bind to RUNX-binding sequence within the ZBTB7B locus acting as transcriptional silencer and allowing for cytotoxic T cell differentiation (Microbial infection) Following infection, hijacked by the HIV-1 Vif protein, leading to the formation a cullin-5-RING E3 ubiquitin-protein ligase complex (ECS complex) that catalyzes ubiquitination and degradation of APOBEC3F and APOBEC3G (PubMed:22190037, PubMed:31792451, PubMed:36598981, PubMed:36754086, PubMed:37419875). The complex can also ubiquitinate APOBEC3H to some extent (PubMed:37640699). Association with HIV-1 Vif protein also inhibits the transcription coactivator activity of CBFB/CBF-beta (PubMed:22190037)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q13951/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CBFB","classification":"Not Classified","n_dependent_lines":288,"n_total_lines":1208,"dependency_fraction":0.23841059602649006},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CBFB","total_profiled":1310},"omim":[{"mim_id":"620099","title":"CLEIDOCRANIAL DYSPLASIA 2; CLCD2","url":"https://www.omim.org/entry/620099"},{"mim_id":"614541","title":"CHROMOSOME 16q22 DELETION SYNDROME","url":"https://www.omim.org/entry/614541"},{"mim_id":"611614","title":"UTP3 SMALL SUBUNIT PROCESSOME COMPONENT; 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A Case Report and Review of Literature.","date":"2020","source":"Case reports in hematology","url":"https://pubmed.ncbi.nlm.nih.gov/33489389","citation_count":7,"is_preprint":false},{"pmid":"37807922","id":"PMC_37807922","title":"Multiple roles of LncRNA-BMNCR on cell proliferation and apoptosis by targeting miR-145/CBFB axis in BMECs.","date":"2023","source":"The veterinary quarterly","url":"https://pubmed.ncbi.nlm.nih.gov/37807922","citation_count":6,"is_preprint":false},{"pmid":"36241386","id":"PMC_36241386","title":"Heterozygous pathogenic variants involving CBFB cause a new skeletal disorder resembling cleidocranial dysplasia.","date":"2022","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36241386","citation_count":6,"is_preprint":false},{"pmid":"32711101","id":"PMC_32711101","title":"The transcription factor CBFB mutations indicate an improved survival in HR+/HER2- breast 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Cancer Progression.","date":"2022","source":"Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/35903297","citation_count":5,"is_preprint":false},{"pmid":"8847901","id":"PMC_8847901","title":"Clinical aspects of expression of inversion 16 chromosomal fusion transcript CBFB/MYH11 in acute myelogenous leukemia subtype M1 with abnormal bone marrow eosinophilia.","date":"1996","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/8847901","citation_count":5,"is_preprint":false},{"pmid":"17981216","id":"PMC_17981216","title":"Gain of multiple copies of the CBFB gene: a new genetic aberration in a case of granulocytic sarcoma.","date":"2007","source":"Cancer genetics and cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/17981216","citation_count":5,"is_preprint":false},{"pmid":"40304077","id":"PMC_40304077","title":"Clinical characteristics and therapeutic determinants of RUNX1::RUNX1T1 differ from those of CBFB::MYH11 acute myeloid leukemia.","date":"2025","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/40304077","citation_count":4,"is_preprint":false},{"pmid":"35184217","id":"PMC_35184217","title":"3'CBFB deletion in CBFB-rearranged acute myeloid leukemia retains morphological features associated with inv(16), but patients have higher risk of relapse and may require stem cell transplant.","date":"2022","source":"Annals of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/35184217","citation_count":3,"is_preprint":false},{"pmid":"32570264","id":"PMC_32570264","title":"Sustained Complete Remission with Incomplete Hematologic Recovery (CRi) in a Patient with Relapsed AML and Concurrent BCR-ABL1 and CBFB Rearrangement Treated with a Combination of Venetoclax and 5-Azacytidine.","date":"2020","source":"Chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/32570264","citation_count":3,"is_preprint":false},{"pmid":"35647832","id":"PMC_35647832","title":"CircRIP2 aggravates the deterioration of colorectal carcinoma by negatively regulating CBFB.","date":"2022","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35647832","citation_count":2,"is_preprint":false},{"pmid":"38801226","id":"PMC_38801226","title":"Integrative immunophenotypic and genetic characterization of acute myeloid leukemia with CBFB rearrangement.","date":"2024","source":"American journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/38801226","citation_count":2,"is_preprint":false},{"pmid":"35794567","id":"PMC_35794567","title":"Molecular dissection of a hyper-aggressive CBFB-MYH11/FLT3-ITD-positive acute myeloid leukemia.","date":"2022","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35794567","citation_count":2,"is_preprint":false},{"pmid":"37115099","id":"PMC_37115099","title":"Autophagy Inhibition as a Potential Therapeutic Strategy for Breast Cancer with Mitochondrial Translation Defect Caused by CBFB-Deficiency.","date":"2023","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/37115099","citation_count":2,"is_preprint":false},{"pmid":"16502584","id":"PMC_16502584","title":"Diagnosis and monitoring of CBFB-MYH11-positive acute myeloid leukemia by qualitative and quantitative RT-PCR.","date":"2006","source":"Methods in molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16502584","citation_count":2,"is_preprint":false},{"pmid":"25786458","id":"PMC_25786458","title":"Therapy-related leukemia with Inv(16)(p13.1q22) and type D CBFB/MYH11 developing after exposure to irinotecan-containing chemoradiotherapy.","date":"2015","source":"Internal medicine (Tokyo, Japan)","url":"https://pubmed.ncbi.nlm.nih.gov/25786458","citation_count":2,"is_preprint":false},{"pmid":"40345240","id":"PMC_40345240","title":"A Case of Cryptic CBFB::MYH11 Acute Myeloid Leukemia With Noncanonical Breakpoints Detected by Optical Genome Mapping.","date":"2025","source":"Journal of the National Comprehensive Cancer Network : JNCCN","url":"https://pubmed.ncbi.nlm.nih.gov/40345240","citation_count":1,"is_preprint":false},{"pmid":"36011278","id":"PMC_36011278","title":"PPP1R7 Is a Novel Translocation Partner of CBFB via t(2;16)(q37;q22) in Acute Myeloid Leukemia.","date":"2022","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/36011278","citation_count":1,"is_preprint":false},{"pmid":"35613501","id":"PMC_35613501","title":"Jumping translocation involving chromosome 13q in a patient with Crohn's Disease and inv(16)(p13.1q22)/CBFB-MYH11 acute myeloid leukemia.","date":"2022","source":"Cancer genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35613501","citation_count":1,"is_preprint":false},{"pmid":"39894570","id":"PMC_39894570","title":"A Cryptic CBFB Deletion-Inversion Expands the Mutational Spectrum of Variants Associated With Cleidocranial Dysplasia.","date":"2025","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39894570","citation_count":1,"is_preprint":false},{"pmid":"40882571","id":"PMC_40882571","title":"Unfavorable disease progression in patients with chronic myeloid leukemia and concurrent t(6;9) translocation (DEK::NUP214 fusion) or inversion 16 (CBFB::MYH11 fusion).","date":"2025","source":"Cancer genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40882571","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51542,"output_tokens":5793,"usd":0.120761},"stage2":{"model":"claude-opus-4-6","input_tokens":9396,"output_tokens":3992,"usd":0.22017},"total_usd":0.340931,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"CBF-C (encoded by CBFB) is required together with CBF-A and CBF-B to form a CBF-DNA complex binding to CCAAT motifs; CBF-A and CBF-C interact to form a heterodimer, and CBF-B does not interact individually with either subunit but associates with the CBF-A/CBF-C complex.\",\n      \"method\": \"Recombinant protein reconstitution, electrophoretic mobility shift assay (EMSA), immunoprecipitation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro with purified recombinant subunits and direct protein-DNA complex demonstrated\",\n      \"pmids\": [\"7878029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CBF-B interacts simultaneously with both CBF-A and CBF-C subunits to form a heterotrimeric CBF molecule; the histone-fold motif of CBF-C (similar to histone H2A) is necessary for CBF-DNA complex formation and for interaction with CBF-A, and two separate CBF-B interaction domains were identified flanking the CBF-A interaction domain in CBF-C.\",\n      \"method\": \"Cross-linking, immunoprecipitation, mutational analysis, in vitro binding assays, yeast two-hybrid\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal methods including mutagenesis, in vitro assay, and two-hybrid in a single study\",\n      \"pmids\": [\"8754798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The heterotrimeric CBF (NF-Y) transcription factor has two distinct transcriptional activation domains: one in the CBF-B subunit (N-terminal residues 1–224) and one in the CBF-C subunit (C-terminal residues 114–309), and these two domains act additively to stimulate transcription.\",\n      \"method\": \"In vitro transcription reconstitution with purified recombinant CBF subunits and deletion mutants in nuclear extracts depleted of CBF\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro transcription with purified deletion mutants\",\n      \"pmids\": [\"8662945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The CBFB-MYH11 fusion oncogene acts as a dominant negative for CBF function: embryos heterozygous for Cbfb-MYH11 knock-in lack definitive hematopoiesis and develop fatal hemorrhages, a phenotype similar to homozygous deletion of Cbfb or Cbfa2 (AML1), indicating dominant negative suppression of CBF-dependent hematopoiesis.\",\n      \"method\": \"Knock-in mouse model (homologous recombination), embryonic analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function knock-in with defined hematopoietic phenotype, highly cited foundational paper\",\n      \"pmids\": [\"8929537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The CBFB-MYH11 fusion protein (CBFβ-SMMHC) is produced in leukemic cells, is located primarily in the nuclei, and forms a very high molecular weight protein-DNA complex in nuclear extracts as detected by EMSA; immunofluorescence shows the fusion protein organizes into novel structures within cell nuclei.\",\n      \"method\": \"Western blot with anti-CBFB and anti-MYH11 C-terminus antibodies, immunofluorescence, EMSA with nuclear extracts from patient cells\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct protein detection in patient cells with multiple complementary methods\",\n      \"pmids\": [\"8818654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"In vitro studies demonstrated that expression of CBFB-MYH11 leads to sequestration of CBFα2 (RUNX1) in the cytoplasm, inhibits CBF-mediated transactivation, slows cell cycle progression, delays the apoptotic response to DNA-damaging agents, and protects CBFα2 from degradation.\",\n      \"method\": \"Review summarizing in vitro cell-based assays (transfection, transactivation reporter, cell cycle analysis, apoptosis assays)\",\n      \"journal\": \"Current opinion in hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple mechanistic findings summarized from in vitro studies; review rather than primary data paper\",\n      \"pmids\": [\"11561156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Cbfb is expressed in hematopoietic stem and progenitor cells in midgestation embryos and in adult stem/progenitor as well as mature myeloid and lymphoid cells, but not during terminal erythropoiesis; Cbfb-MYH11 blocks embryonic hematopoiesis at the stem-progenitor cell level by eliminating this population.\",\n      \"method\": \"Cbfb-GFP knock-in mouse model, flow cytometry, comparison with Cbfb-MYH11 knock-in mice\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — knock-in mouse with GFP reporter provides direct localization and functional characterization of Cbfb expression in hematopoietic hierarchy\",\n      \"pmids\": [\"12239155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Cbfb is required for the functions of Runx1 and Runx2 in skeletal development; Runx2/Cbfb heterodimers play essential roles in osteoblast differentiation and chondrocyte maturation.\",\n      \"method\": \"Genetic analysis of Cbfb-deficient mice with partial hematopoietic rescue, phenotypic analysis of skeletal development\",\n      \"journal\": \"Journal of bone and mineral metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mouse genetic loss-of-function with skeletal phenotypic readout; review article summarizing mouse model data\",\n      \"pmids\": [\"12811622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CBFB-SMMHC (CBFβ-SMMHC) suppresses CEBPA protein expression and binding activity without altering CEBPA mRNA levels by inducing calreticulin, an inhibitor of CEBPA translation; siRNA knockdown of calreticulin restored CEBPA levels.\",\n      \"method\": \"Conditional expression system (U937 cells), Western blot, EMSA, siRNA knockdown, patient sample analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway defined with conditional expression, siRNA rescue, and patient samples using multiple methods\",\n      \"pmids\": [\"15855281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Cbfb enhances osteogenic differentiation of mesenchymal stem cells induced by Cbfa-1 (RUNX2) by reducing ubiquitination-mediated proteasomal degradation of RUNX2, thereby increasing RUNX2 protein stability.\",\n      \"method\": \"Adenoviral overexpression, alkaline phosphatase activity assay, osteocalcin measurement, ubiquitination assay in C3H10T1/2 and human MSCs\",\n      \"journal\": \"Stem cells (Dayton, Ohio)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct ubiquitination assay demonstrating mechanism of RUNX2 stabilization by CBFB with functional osteogenic readout\",\n      \"pmids\": [\"17379770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Cbfb-MYH11 causes hematopoietic defects (delayed differentiation with sustained expression of Gata2, Il1rl1, and Csf2rb) that are independent of Cbfb/Runx1 repression, indicating the fusion protein has RUNX1-repression-independent leukemogenic activities.\",\n      \"method\": \"Knock-in mouse model, gene expression analysis, comparison with Cbfb and Runx1 knockout phenotypes\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis using knock-in and knockout mice with defined molecular and cellular phenotypes\",\n      \"pmids\": [\"20007544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"GATA-1 represses Cbfb transcription in erythroleukemia cells by co-occupying PU.1 binding sites near the Cbfb locus; activation of PU.1 or knockdown of GATA-1 derepresses Cbfb expression with accompanying increases in H3K9 acetylation at the Cbfb locus.\",\n      \"method\": \"Conditional PU.1 activation (PUER), siRNA knockdown of GATA-1, chromatin immunoprecipitation (ChIP), reporter assays, gene expression arrays\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP, reporter assay, and siRNA rescue provide mechanistic definition of CBFB transcriptional regulation\",\n      \"pmids\": [\"19825991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CBFβ-MYH11 localizes to RUNX1-occupied promoters genome-wide and interacts with TAL1, FLI1, TBP-associated factors (TAFs), ERG, GATA2, PU.1, EP300, and HDAC1; the fusion protein maintains active transcription of self-renewal genes (ID1, LMO1, JAG1) and represses only a subset of RUNX1 target genes.\",\n      \"method\": \"Genome-wide ChIP-seq, quantitative interaction proteomics (mass spectrometry), RNA-seq upon fusion protein knockdown\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — genome-wide binding analysis combined with quantitative proteomics interactome and transcriptional analysis\",\n      \"pmids\": [\"24002588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Cbfb stabilizes Runx1, Runx2, and Runx3 proteins in skeletal cells; conditional deletion of Cbfb in mesenchymal cells led to reduced Runx family protein levels (without corresponding mRNA reduction) and decreased Runx2 protein stability, causing dwarfism, impaired ossification, and inhibited chondrocyte and osteoblast differentiation.\",\n      \"method\": \"Conditional knockout (Cbfb-floxed × Dermo1-Cre), protein/mRNA analysis, in vitro differentiation assays, promoter reporter assays\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional knockout with protein stability analysis and functional differentiation assays\",\n      \"pmids\": [\"25262822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Loss of Runx1 activity rescued the hematopoietic differentiation defects induced by Cbfb-MYH11 during primitive and definitive hematopoiesis, and significantly delayed Cbfb-MYH11-induced leukemia, demonstrating that Runx1 activity is critical for Cbfb-MYH11-induced leukemogenesis.\",\n      \"method\": \"Genetic epistasis — Cbfb-MYH11 knock-in combined with Runx1 null or dominant-negative alleles in mice, leukemia latency analysis\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — classical genetic epistasis in mouse model with clear phenotypic and survival readouts\",\n      \"pmids\": [\"25742748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"p53 induced by RUNX1 depletion directly binds to the CBFB promoter and stimulates its transcription and translation; the resulting CBFB protein then stabilizes RUNX1, creating a compensatory RUNX1-p53-CBFB feedback loop in AML cells.\",\n      \"method\": \"Gene silencing (siRNA), chromatin immunoprecipitation, luciferase reporter assay, Western blot, patient sample analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and reporter assay define direct p53-CBFB promoter interaction; single lab\",\n      \"pmids\": [\"29192243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CHD7 interacts with CBFβ-SMMHC through RUNX1, enhances transcriptional activity of RUNX1 and CBFβ-SMMHC on target genes (e.g., Csf1r), and Chd7 deficiency delayed Cbfb-MYH11-induced leukemia in mice.\",\n      \"method\": \"Co-immunoprecipitation, transcriptional reporter assay, conditional Chd7 knockout combined with Cbfb-MYH11 knock-in, RNA-seq\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, reporter assay, and in vivo genetic epistasis with leukemia latency readout\",\n      \"pmids\": [\"29018080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CBFB has a noncanonical cytoplasmic role in translation regulation: cytoplasmic CBFB binds to hundreds of mRNA transcripts (including RUNX1 mRNA) via hnRNPK and enhances their translation through eIF4B; nuclear CBFB/RUNX1 complex transcriptionally represses NOTCH signaling in breast cancer.\",\n      \"method\": \"RNA immunoprecipitation followed by deep sequencing (RIP-seq), polysome profiling, co-immunoprecipitation, knockdown/rescue experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — RIP-seq plus functional translation assays plus nuclear transcription analysis; multiple orthogonal methods\",\n      \"pmids\": [\"31061501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In anterior palatogenesis, Cbfb acts as an obligatory cofactor for Runx1 in a Runx1/Cbfb-Stat3-Tgfb3 signaling axis; Cbfb mutant mice develop anterior cleft palate with disrupted TGFB3 expression and reduced Stat3 phosphorylation, and folic acid rescues the cleft by activating Stat3 and Tgfb3.\",\n      \"method\": \"Conditional Cbfb knockout mouse model, immunofluorescence, in vitro palatal fusion assay, TGFB3 rescue experiment, pharmaceutical Stat3 activation\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with defined molecular pathway (Runx1/Cbfb-Stat3-Tgfb3) and pharmacological rescue\",\n      \"pmids\": [\"31171577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CBFB-MYH11 fusion sequesters RUNX1 in the cytoplasm, preventing RUNX1 from interacting with and recruiting DNMT3A to RUNX1 target genes, resulting in DNA hypomethylation at those loci similar to DNMT3A loss-of-function; RUNX1 directly interacts with DNMT3A and this interaction is disrupted by CBFB-MYH11.\",\n      \"method\": \"Co-immunoprecipitation, methylation analysis (bisulfite sequencing), gene expression analysis, comparison with DNMT3A-inhibited cells, mutual exclusivity analysis in patient datasets\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct Co-IP of RUNX1-DNMT3A interaction, functional methylation assay, and genetic mutual exclusivity supporting mechanism\",\n      \"pmids\": [\"34336831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CBFB cooperates with p53 to maintain TAp73 expression as a shared transcriptional target; loss of either CBFB or p53 leads to TAp73 depletion, and TAp73 re-expression abrogates the tumorigenic effect of CBFB deletion in breast cancer.\",\n      \"method\": \"Integrated genomic analysis, gene expression experiments, ChIP, rescue experiments (TAp73 re-expression), xenograft mouse model, immunohistochemistry\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP, transcriptional analysis, and functional rescue with multiple orthogonal approaches\",\n      \"pmids\": [\"33945523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CBFB localizes to mitochondria and enhances the binding of mitochondrial mRNAs to TUFM (a mitochondrial translation elongation factor), thereby promoting mitochondrial genome translation; CBFB loss of function causes mitochondrial translation defects, leading to defective oxidative phosphorylation, the Warburg effect, and autophagy/mitophagy addiction.\",\n      \"method\": \"Subcellular fractionation showing mitochondrial CBFB localization, co-immunoprecipitation of CBFB with TUFM and mitochondrial mRNAs, proteomics interactome, metabolic assays, mouse tumor models, patient-derived xenografts\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — direct localization to mitochondria plus protein-mRNA interaction data plus functional metabolic readouts in multiple models\",\n      \"pmids\": [\"36799863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The CBFB::MYH11 oncofusion protein sequesters RUNX1 in cytoplasmic aggregates via the CBFB domain interacting with the MYH11 domain that also binds cytoplasmic myosin-related proteins; this cytoplasmic sequestration is associated with increased RUNX1/2 transcription suggesting a feedback sensor for reduced functional RUNX1.\",\n      \"method\": \"TurboID proximity biotinylation proteomics in primary murine hematopoietic cells, immunofluorescence, subcellular fractionation, validation in primary human AML cells\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — unbiased proximity proteomics plus multiple validation methods in primary mouse and human cells\",\n      \"pmids\": [\"38061017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-27b targets CBFB to inhibit differentiation of human bone marrow mesenchymal stem cells into hypertrophic chondrocytes; CBFB forms a complex with RUNX2, and CBFB knockdown by shRNA increases COL2/SOX9 expression while decreasing COL10/RUNX2 levels.\",\n      \"method\": \"Luciferase reporter assay (CBFB 3'-UTR), co-immunoprecipitation (CBFB-RUNX2 complex), shRNA knockdown, in vivo cartilage repair model\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — luciferase reporter and Co-IP with functional differentiation readout in vitro and in vivo\",\n      \"pmids\": [\"32917285\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CBFB encodes the β subunit of Core Binding Factor, which heterodimerizes with RUNX family proteins (RUNX1/2/3) through histone-fold domain interactions to enhance their DNA binding and stabilize them against ubiquitin-mediated proteasomal degradation; in addition to this canonical nuclear transcriptional co-activator role (where the CBFB/RUNX1 complex recruits DNMT3A and represses oncogenic NOTCH signaling), CBFB functions non-canonically in the cytoplasm—binding mRNAs via hnRNPK to promote translation through eIF4B, and in mitochondria where it enhances mitochondrial genome translation by binding mitochondrial mRNAs to the elongation factor TUFM; the leukemia-associated CBFB-MYH11 fusion protein sequesters RUNX1 in cytoplasmic aggregates via myosin-related protein interactions, blocks CBF-dependent hematopoietic differentiation in a partly RUNX1-dependent and partly RUNX1-independent manner, and suppresses CEBPA protein through calreticulin-mediated translational inhibition.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CBFB encodes the β subunit of Core Binding Factor (CBF), a transcriptional regulator essential for definitive hematopoiesis, skeletal development, and tumor suppression. In the nucleus, CBFβ heterodimerizes with RUNX family proteins (RUNX1/2/3) via histone-fold domain interactions, stabilizing them against ubiquitin-mediated proteasomal degradation and enhancing their DNA-binding activity to regulate target genes including those controlling hematopoietic differentiation, osteoblast maturation, chondrocyte development, and palatogenesis [PMID:25262822, PMID:17379770, PMID:31171577]; the nuclear CBFβ/RUNX1 complex also recruits DNMT3A to maintain DNA methylation at target loci and represses NOTCH signaling [PMID:34336831, PMID:31061501]. Beyond its canonical nuclear role, cytoplasmic CBFβ binds hundreds of mRNAs via hnRNPK and promotes their translation through eIF4B, and mitochondrial CBFβ enhances mitochondrial genome translation by facilitating mRNA binding to the elongation factor TUFM, linking CBFβ loss to defective oxidative phosphorylation [PMID:31061501, PMID:36799863]. The leukemia-associated CBFB-MYH11 fusion protein acts as a dominant-negative by sequestering RUNX1 in cytoplasmic aggregates, blocking CBF-dependent differentiation, suppressing CEBPA translation via calreticulin induction, and maintaining self-renewal gene expression, establishing this fusion as a driver of inv(16) acute myeloid leukemia [PMID:8929537, PMID:15855281, PMID:24002588, PMID:38061017].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing CBFβ as an obligate component of a DNA-binding transcription factor complex resolved the question of whether CBFB contributes directly to CCAAT-motif recognition or acts only as a cofactor.\",\n      \"evidence\": \"Recombinant protein reconstitution and EMSA showing CBF-C (CBFβ) is required with CBF-A and CBF-B to form the CBF-DNA complex\",\n      \"pmids\": [\"7878029\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Exact DNA-contact residues of CBFβ not mapped\", \"Role in vivo not yet established\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Identification of the histone-fold motif as the structural basis for CBFβ heterodimerization and demonstration that CBFβ harbors a transcriptional activation domain defined how each subunit contributes to CBF function.\",\n      \"evidence\": \"Cross-linking, mutagenesis, yeast two-hybrid, and in vitro transcription with purified deletion mutants\",\n      \"pmids\": [\"8754798\", \"8662945\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of the heterotrimer not yet available\", \"In vivo relevance of each activation domain not tested\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"The Cbfb-MYH11 knock-in mouse proved that the fusion protein acts as a dominant-negative for CBF-dependent hematopoiesis, establishing its causal role in leukemogenesis.\",\n      \"evidence\": \"Knock-in mouse with heterozygous Cbfb-MYH11 phenocopying Cbfb and Cbfa2 nulls — lethal hemorrhage, absent definitive hematopoiesis\",\n      \"pmids\": [\"8929537\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of dominant-negative action (sequestration vs. active repression) not resolved\", \"Additional cooperating mutations for full leukemia not defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Mapping Cbfb expression across the hematopoietic hierarchy revealed its requirement at the stem/progenitor level and showed Cbfb-MYH11 eliminates this population, pinpointing the cellular target of the fusion.\",\n      \"evidence\": \"Cbfb-GFP knock-in reporter combined with flow cytometry in embryonic and adult hematopoietic cells\",\n      \"pmids\": [\"12239155\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Cbfb has distinct functions in lymphoid vs. myeloid lineages not resolved\", \"Dose-dependence of Cbfb in stem cell self-renewal unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Discovery that CBFβ-SMMHC suppresses CEBPA protein through calreticulin-mediated translational inhibition identified a RUNX-independent oncogenic mechanism of the fusion.\",\n      \"evidence\": \"Conditional expression in U937 cells, Western blot, siRNA knockdown of calreticulin restoring CEBPA\",\n      \"pmids\": [\"15855281\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether calreticulin induction is direct or indirect not clarified\", \"Relevance to non-hematopoietic contexts unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating that CBFβ stabilizes RUNX2 by reducing its ubiquitin-mediated proteasomal degradation established protein stabilization as a core mechanism through which CBFβ promotes osteogenic differentiation.\",\n      \"evidence\": \"Ubiquitination assays and overexpression in mesenchymal stem cells with osteogenic differentiation readouts\",\n      \"pmids\": [\"17379770\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the E3 ligase counteracted by CBFβ not determined\", \"Whether the same stabilization mechanism applies to RUNX1 and RUNX3 not directly tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Genetic epistasis revealed that Cbfb-MYH11 causes hematopoietic defects independent of RUNX1 repression, broadening the fusion's oncogenic mechanism beyond simple dominant-negative CBF inhibition.\",\n      \"evidence\": \"Comparison of Cbfb-MYH11 knock-in with Cbfb and Runx1 knockouts showing distinct gene expression changes (Gata2, Il1rl1, Csf2rb)\",\n      \"pmids\": [\"20007544\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for RUNX1-independent activities not defined\", \"Direct fusion protein targets mediating these effects unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Genome-wide binding and interactome analyses of CBFβ-MYH11 showed it co-occupies RUNX1 target promoters, interacts with hematopoietic transcription factors and chromatin regulators, and maintains self-renewal gene expression rather than globally repressing RUNX1 targets.\",\n      \"evidence\": \"ChIP-seq, quantitative interaction proteomics (mass spectrometry), and RNA-seq upon fusion knockdown in leukemia cells\",\n      \"pmids\": [\"24002588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which chromatin remodeling complexes are essential for fusion-driven transcription not established\", \"Whether the fusion redirects vs. maintains pre-existing RUNX1 programs unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Conditional deletion of Cbfb in mesenchymal cells confirmed that CBFβ stabilizes all three RUNX proteins at the post-translational level in vivo, causing dwarfism and impaired skeletal development.\",\n      \"evidence\": \"Cbfb conditional knockout (Dermo1-Cre), protein and mRNA analysis showing reduced RUNX protein without mRNA change\",\n      \"pmids\": [\"25262822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of RUNX1 vs. RUNX2 vs. RUNX3 stabilization to each skeletal phenotype not separated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Loss of Runx1 delayed Cbfb-MYH11-induced leukemia, proving that RUNX1 activity is paradoxically required for leukemogenesis driven by the fusion.\",\n      \"evidence\": \"Genetic epistasis combining Cbfb-MYH11 knock-in with Runx1 null or dominant-negative alleles; leukemia latency analysis\",\n      \"pmids\": [\"25742748\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether residual Runx2/Runx3 compensate for Runx1 loss not assessed\", \"Mechanism by which Runx1 enables fusion-driven transformation not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Discovery of a noncanonical cytoplasmic role for CBFβ in translational regulation — binding mRNAs via hnRNPK and promoting translation through eIF4B — fundamentally expanded CBFβ function beyond transcription.\",\n      \"evidence\": \"RIP-seq identifying hundreds of CBFβ-bound mRNAs, polysome profiling, co-immunoprecipitation of CBFβ-hnRNPK-eIF4B in breast cancer cells\",\n      \"pmids\": [\"31061501\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CBFβ-RNA interaction unknown\", \"Whether cytoplasmic CBFβ function is conserved across all cell types not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Cbfb was shown to be required for anterior palatogenesis through a Runx1/Cbfb-Stat3-Tgfb3 axis, linking CBFβ loss to cleft palate and identifying folic acid rescue via Stat3 activation.\",\n      \"evidence\": \"Conditional Cbfb knockout mice with cleft palate, reduced Stat3 phosphorylation and Tgfb3 expression, folic acid and Tgfb3 rescue experiments\",\n      \"pmids\": [\"31171577\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs. indirect mechanism of Stat3 activation by RUNX1/CBFβ not resolved\", \"Relevance to human cleft palate genetics not confirmed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstration that CBFB-MYH11 disrupts the RUNX1-DNMT3A interaction, causing DNA hypomethylation at RUNX1 target loci, connected the fusion to epigenetic dysregulation analogous to DNMT3A loss-of-function.\",\n      \"evidence\": \"Co-immunoprecipitation of RUNX1-DNMT3A, bisulfite sequencing showing hypomethylation, mutual exclusivity of CBFB-MYH11 and DNMT3A mutations in patients\",\n      \"pmids\": [\"34336831\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CBFβ itself is needed for the RUNX1-DNMT3A interaction not tested\", \"Genome-wide methylation consequences in primary leukemia not fully mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of CBFβ in mitochondria where it promotes mitochondrial genome translation by enhancing mRNA binding to TUFM revealed a third subcellular compartment of CBFβ function and linked its loss to defective oxidative phosphorylation and metabolic reprogramming.\",\n      \"evidence\": \"Subcellular fractionation, co-immunoprecipitation of CBFβ-TUFM-mitochondrial mRNAs, metabolic assays in mouse tumor models and patient-derived xenografts\",\n      \"pmids\": [\"36799863\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of CBFβ import into mitochondria not defined\", \"Relative contribution of mitochondrial vs. nuclear/cytoplasmic CBFβ to tumor suppression not quantified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Proximity proteomics defined the mechanism of RUNX1 cytoplasmic sequestration by CBFβ-MYH11 — the MYH11 moiety interacts with cytoplasmic myosin-related proteins to form aggregates, with compensatory upregulation of RUNX1/2 transcription.\",\n      \"evidence\": \"TurboID proximity biotinylation in primary murine hematopoietic cells, validated by immunofluorescence and subcellular fractionation in primary human AML samples\",\n      \"pmids\": [\"38061017\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether preventing aggregate formation rescues leukemia phenotype not tested\", \"Specific myosin interactors mediating aggregation not fully characterized\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include how CBFβ is partitioned among nuclear, cytoplasmic, and mitochondrial pools, the structural basis of its RNA-binding activity, and whether therapeutic disruption of CBFβ-RUNX interaction or CBFβ-MYH11 aggregation is achievable.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of CBFβ bound to mRNA or mitochondrial mRNA-TUFM complex\", \"Mechanism governing subcellular distribution of CBFβ unknown\", \"Therapeutic targeting of the CBFβ-MYH11 fusion protein not yet validated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 12, 17]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [17, 21]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [17, 21]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 12, 17]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [17, 22]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 11, 12, 17]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 13, 18, 23]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 8, 10, 14, 22]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [9, 13, 17, 21]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [21]}\n    ],\n    \"complexes\": [\n      \"Core Binding Factor (CBF/NF-Y heterotrimer)\",\n      \"CBFβ-RUNX1 heterodimer\",\n      \"CBFβ-RUNX2 heterodimer\"\n    ],\n    \"partners\": [\n      \"RUNX1\",\n      \"RUNX2\",\n      \"RUNX3\",\n      \"HNRNPK\",\n      \"EIF4B\",\n      \"TUFM\",\n      \"DNMT3A\",\n      \"CHD7\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}