{"gene":"ASXL1","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2006,"finding":"ASXL1 functions as a ligand-dependent coactivator for retinoic acid receptor (RAR), interacting through its C-terminal nuclear receptor box (LVMQLL) with the AF-2 AD core of RAR, and cooperates with SRC-1 to increase acetylated histone H3 on RA-responsive promoters, enhancing RAR-mediated transcription.","method":"GST pulldown, co-immunoprecipitation, chromatin IP, luciferase reporter assay, confocal microscopy","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including in vitro pulldown, in vivo IP, ChIP, and functional transcription assays in single study","pmids":["16606617"],"is_preprint":false},{"year":2006,"finding":"Murine Asxl1 protein contains two regions conserved with Drosophila Asx: an N-terminal ASX homology domain (ASXH) with nuclear receptor co-regulator binding motifs, and a C-terminal PHD domain; it is expressed ubiquitously in adult tissues and embryos.","method":"Sequence analysis, Northern blot, whole-mount RNA in situ hybridization","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 — direct characterization of domain architecture and expression; single study","pmids":["16412590"],"is_preprint":false},{"year":2009,"finding":"ASXL1 represses RAR-mediated transcription through its N-terminal region by directly interacting with HP1 (via an HP1 box, PXVXL motif) and histone demethylase LSD1, forming a ternary ASXL1-HP1-LSD1 complex that removes H3K4 methylation at RA-responsive promoters.","method":"In vitro GST pulldown, in vivo co-immunoprecipitation, chromatin IP, transcription assays, siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods, direct demonstration of complex, histone mark changes, and functional consequence","pmids":["19880879"],"is_preprint":false},{"year":2012,"finding":"ASXL1 associates with the PRC2 complex and loss of ASXL1 results in reduced H3K27 tri-methylation genome-wide, leading to derepression of posterior HOXA cluster genes and collaborating with NRASG12D to promote myeloid leukemogenesis.","method":"Co-immunoprecipitation, ChIP-Seq, microarray, in vivo mouse model","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 1-2 — Co-IP demonstrating ASXL1-PRC2 interaction, genome-wide ChIP-Seq, and in vivo epistasis; highly cited foundational study","pmids":["22897849"],"is_preprint":false},{"year":2013,"finding":"Constitutive or hematopoietic-specific deletion of Asxl1 in mice results in global reduction of H3K27 trimethylation and H3K4me3, dysregulated expression of hematopoietic regulators, progressive cytopenias and dysplasia recapitulating MDS; compound Asxl1/Tet2 deletion accelerates myeloid disease.","method":"Conditional knockout mouse model, RNA-Seq, ChIP-Seq, serial transplantation","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO with multiple orthogonal readouts including ChIP-Seq and RNA-Seq; independently replicated by multiple labs","pmids":["24218140"],"is_preprint":false},{"year":2013,"finding":"C-terminal truncating ASXL1 mutations inhibit PRC2-mediated H3K27 methylation, leading to derepression of Hoxa9 and miR-125a, which reduces Clec5a expression and blocks myeloid differentiation, inducing MDS-like disease in mice.","method":"Mouse bone marrow transplantation model, ChIP, qRT-PCR, miRNA target validation","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — in vivo mouse model with molecular pathway dissection using ChIP and miRNA functional assays","pmids":["24216483"],"is_preprint":false},{"year":2015,"finding":"ASXL1 truncation mutations confer gain-of-function on the ASXL1-BAP1 deubiquitinase complex, resulting in enhanced BAP1 activity, global erasure of H2AK119Ub, striking depletion of H3K27me3, and upregulation of bivalently marked genes, driving mast cell differentiation; effects require BAP1 catalytic activity.","method":"Stable cell line expression, genome-wide histone ChIP, functional differentiation assays, in vivo bone marrow reconstitution","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including genome-wide ChIP, functional assays, catalytic mutant controls, and in vivo studies","pmids":["26095772"],"is_preprint":false},{"year":2015,"finding":"ASXL1 is required for BAP1-mediated deubiquitylation of H2AK119ub1 at the INK4B locus; ASXL1 and BAP1 co-occupy the INK4B promoter, and ASXL1 loss prevents H2AK119 deubiquitylation and induction of p15(INK4B) in response to oncogenic signaling or anti-proliferative signals.","method":"ChIP, siRNA knockdown, luciferase reporter, primary bone marrow cell functional assays","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 — ChIP localization, functional H2AK119ub1 changes, and defined cellular phenotype with pathway placement","pmids":["26470845"],"is_preprint":false},{"year":2016,"finding":"BAP1's C-terminal extension auto-recruits BAP1 to nucleosomes in an unproductive complex; ASXL1 (or ASXL2/3) DEUBAD domains activate BAP1 by increasing its affinity for ubiquitin on H2A K119, driving deubiquitination specifically for Polycomb H2A modifications but not DNA damage-associated H2A K13/15 ubiquitination.","method":"Biochemical reconstitution, in vitro deubiquitinase assay, mutagenesis, nucleosome binding assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with mechanistic dissection, mutagenesis, and substrate specificity determination","pmids":["26739236"],"is_preprint":false},{"year":2015,"finding":"Truncated ASXL1 mutant proteins (C-terminal truncations) are detectable at the protein level in cell lines harboring homozygous ASXL1 mutations, demonstrating that ASXL1 truncation mutations produce stable expressed proteins rather than undergoing nonsense-mediated decay.","method":"Mass spectrometry, Western blot, cell lines with homozygous ASXL1 mutations","journal":"Experimental hematology","confidence":"High","confidence_rationale":"Tier 2 — two independent detection methods (MS and Western blot) directly detecting truncated protein","pmids":["26700326"],"is_preprint":false},{"year":2017,"finding":"ASXL1 truncating protein (aa1-587) acquires an interaction with BRD4 (not present with full-length ASXL1), resulting in more open chromatin at critical hematopoietic genes; expression of truncated ASXL1 drives myeloid malignancies in transgenic mice and confers hypersensitivity to BET bromodomain inhibitors.","method":"LC-MS/MS, co-immunoprecipitation, ATAC-seq, RNA-seq, transgenic mouse model, epigenetic drug screening","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 — MS-identified interaction confirmed by Co-IP, genome-wide chromatin and transcriptome analyses, in vivo model","pmids":["29113963"],"is_preprint":false},{"year":2017,"finding":"ASXL1 interacts directly with the kinase domain of AKT1 through amino acids 371-655; loss of Asxl1 prevents IGF-1-induced AKT1 phosphorylation, retains p27Kip1 in the nucleus, suppresses Rb phosphorylation and E2F target genes, and promotes cellular senescence; Asxl1 also cooperates with Ezh2 through direct interaction.","method":"Co-immunoprecipitation, domain mapping, AKT inhibitor treatment, microarray, SA-β-gal staining in Asxl1-null MEFs","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP domain mapping and functional rescue; single lab, multiple assays","pmids":["28701722"],"is_preprint":false},{"year":2018,"finding":"Physiological expression of C-terminal truncated Asxl1 mutant in knock-in mice reduces H3K4me3 and H2AK119Ub without significant reduction in H3K27me3—distinct from Asxl1 loss—and wild-type versus mutant Asxl1 have opposing effects on H3K4me3 at specific loci, altering the HSC epigenome and increasing susceptibility to leukemic transformation.","method":"Conditional knock-in mouse model, ChIP-Seq, competitive transplantation, viral insertional mutagenesis","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — genome-wide ChIP-Seq in physiological knock-in model distinguishing loss-of-function from gain-of-function effects","pmids":["29643185"],"is_preprint":false},{"year":2018,"finding":"ASXL1 forms a protein complex with HCFC1 and OGT; OGT directly stabilizes ASXL1 through O-GlcNAcylation; disruption of this ASXL1-OGT axis inhibits H3K4 methylation, H2B glycosylation, and myeloid differentiation, implicating MLL5 as the downstream H3K4 methyltransferase.","method":"Co-immunoprecipitation, mass spectrometry, O-GlcNAcylation assay, ChIP, in vivo leukemogenicity assay","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 1-2 — MS-identified complex, PTM demonstrated biochemically, functional ChIP and in vivo validation","pmids":["29556021"],"is_preprint":false},{"year":2018,"finding":"Asxl1G643fs mutant ASXL1 loses the ability to interact with BMI1 (PRC1 subunit), reducing H2AK119ub1 at the p16Ink4a promoter; derepression of p16Ink4a induces cellular senescence in HSCs, producing low-risk MDS-like phenotypes; heterozygous p16Ink4a deletion restores HSC pool.","method":"Co-immunoprecipitation, ChIP at p16Ink4a locus, knock-in mouse model, genetic rescue with p16Ink4a heterozygosity","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 1-2 — direct Co-IP showing loss of BMI1 interaction, ChIP at specific locus, genetic epistasis rescue","pmids":["29967380"],"is_preprint":false},{"year":2018,"finding":"Loss of ASXL1 in bone marrow stromal cells (BMSCs) impairs hematopoietic stem/progenitor cell maintenance; ASXL1 interacts with core subunits of RNA polymerase II complex in BMSCs and regulates RNAPII-dependent transcription of genes critical for HSC/HPC maintenance (e.g., Vcam1).","method":"Co-immunoprecipitation, ChIP-seq, RNA-seq, BMSC co-culture assays","journal":"Cell discovery","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with RNAPII, ChIP-seq and RNA-seq convergent analysis; single lab","pmids":["29423272"],"is_preprint":false},{"year":2018,"finding":"ASXL1 and SETBP1 co-mutations repress TGFβ pathway genes through reduced histone H3 and H4 acetylation at their promoters; HDAC inhibitor vorinostat restores histone acetylation, derepresses TGFβ pathway genes, and selectively inhibits growth of ASXL1-mutant cells.","method":"ChIP for H3/H4 acetylation, HDAC inhibitor treatment, gene expression analysis, in vivo mouse model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP-based mechanism and pharmacological rescue; single lab","pmids":["30367089"],"is_preprint":false},{"year":2020,"finding":"PR-DUB complex (BAP1 with ASXL1/2/3, FOXK1/2, HCFC1, OGT) is recruited to chromatin through FOXK1/2 and ASXL proteins; BAP1 is dependent on ASXL proteins and FOXK1/2 for genome-wide H2AK119ub1 removal and activation of metabolic and homeostatic genes, with minimal functional overlap with PRC2 in ESCs.","method":"ChIP-seq, genome-wide H2AK119ub1 profiling, genetic knockouts, proteomics","journal":"Genome research","confidence":"High","confidence_rationale":"Tier 2 — genome-wide ChIP-seq and genetic KO of multiple complex components; orthogonal methods","pmids":["32747411"],"is_preprint":false},{"year":2020,"finding":"Wild-type ASXL1 interacts with forkhead transcription factors FOXK1 and FOXK2 to regulate target genes; C-terminally truncated mutant ASXL1 loses FOXK1/K2 interaction and is expressed at higher levels than wild-type in heterozygous leukemia cells; specific deletion of mutant allele restores BAP1-ASXL1 association and FOXK1/K2 target gene expression.","method":"Co-immunoprecipitation, CRISPR allele-specific deletion, gene expression analysis","journal":"Protein & cell","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP showing differential interactions, allele-specific genetic rescue; single lab","pmids":["32683582"],"is_preprint":false},{"year":2021,"finding":"ASXL1-mutant (C-terminally truncated) cooperates with BAP1 to deubiquitinate and activate AKT; overactive Akt/mTOR signaling causes aberrant HSC proliferation, age-related DNA damage accumulation, and clonal expansion; mTOR inhibitor rapamycin ameliorates the phenotype in knock-in mice.","method":"Conditional knock-in mouse model, biochemical AKT deubiquitination assay, genetic mosaic model, rapamycin treatment","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical demonstration of AKT deubiquitination, in vivo genetic model, pharmacological rescue","pmids":["33758188"],"is_preprint":false},{"year":2021,"finding":"ASXL1 forms phase-separated droplets via its C-terminal intrinsically disordered region (IDR), upregulates NEAT1 expression, and increases NONO-NEAT1 interactions to support paraspeckle formation in hematopoietic cells; pathogenic truncated ASXL1 lacking the IDR fails to support paraspeckle components, causing abnormal cytoplasmic NONO localization and impaired HSPC repopulating potential.","method":"Co-immunoprecipitation, phase separation assay, knock-in mouse model, live imaging, NONO shRNA knockdown","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP, phase separation assay, and KI mouse with defined cellular phenotype; single lab","pmids":["34433054"],"is_preprint":false},{"year":2021,"finding":"Cancer-associated ASXL1 frameshift mutations encode stable truncated gain-of-function proteins that increase BAP1 protein stability, enhance BAP1 chromatin recruitment, and drive expression of a pro-leukemic transcriptional signature; BAP1 catalytic inhibitors identified by biochemical screen suppress truncated-ASXL1-driven leukemic gene expression and impair tumor progression in vivo.","method":"Protein stability assays, ChIP, RNA-seq, biochemical inhibitor screen, in vivo tumor models","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical screen, ChIP, RNA-seq, and in vivo pharmacological validation; multiple orthogonal methods","pmids":["35122023"],"is_preprint":false},{"year":2021,"finding":"Oncogenic ASXL1 truncation mutations enhance binding to the ET domain of BRD4 via a specific motif near the truncation breakpoint; ASXL1Y591X truncation markedly increases BRD4 ET-domain binding relative to full-length ASXL1, providing a molecular mechanism for aberrant BRD4 recruitment to transcriptional complexes.","method":"Binding assays (ITC, SPR), domain mapping, recombinant protein analysis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro binding assays with quantitative affinity measurements and domain-level mechanistic dissection","pmids":["34536441"],"is_preprint":false},{"year":2023,"finding":"Cryo-EM structure of human BAP1-ASXL1 DEUBAD in complex with H2AK119Ub nucleosome reveals molecular interactions of BAP1 and ASXL1 with histones and DNA that restructure the nucleosome to establish specificity for H2AK119Ub; structure explains how >50 cancer-associated mutations in BAP1 and ASXL1 dysregulate deubiquitination.","method":"Cryo-EM structure determination, biochemical deubiquitinase assays, mutagenesis, cellular complementation","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 — high-resolution cryo-EM structure with biochemical and cellular functional validation and disease mutation mapping","pmids":["37556531"],"is_preprint":false},{"year":2013,"finding":"ASXL1 interacts with WTIP (Wilms tumor 1-interacting protein) via its PHD domain; loss of Asxl1 in mice causes kidney podocyte morphology defects and up-regulation of Wt1/Wtip target genes, placing ASXL1 in a WT1 regulatory pathway during kidney development.","method":"Co-immunoprecipitation, Asxl1-null mouse analysis, gene expression assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP and KO phenotype with pathway gene expression; single lab","pmids":["26385183"],"is_preprint":false},{"year":2013,"finding":"ASXL1 suppresses LXRα-mediated transcription and lipid accumulation, while ASXL2 activates LXRα, acting through direct interaction with LXRα; ChIP shows ligand-dependent recruitment of ASXL1 to ABCA1 promoters; ASXL1 expression increases under fasting and decreases in insulin-treated or high-fat-diet conditions.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, lipid accumulation assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 — Direct binding demonstrated by Co-IP, ChIP at target promoter, physiological regulation context; single lab","pmids":["24321552"],"is_preprint":false},{"year":2020,"finding":"Asxl1 is required for transcriptional activation of Pten by facilitating H2AK119 deubiquitylation at the Pten promoter; loss of Asxl1 reduces PTEN expression, sustains PI3K/AKT signaling, and confers sensitivity to AKT inhibitor MK2206.","method":"ChIP at Pten promoter, AKT activity assays, siRNA knockdown, inhibitor sensitivity assay","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP at specific locus, functional pathway assay, and pharmacological validation; single lab","pmids":["32236560"],"is_preprint":false},{"year":2024,"finding":"Truncated ASXL1 leads to global redistribution (not simply loss) of H2AK119Ub, increased transposase-accessible chromatin, and activation of myeloid and stem cell gene-expression programs in human HSPCs; H2AK119Ub levels are tied to truncated ASXL1 expression levels, and PRC1 complex inhibition is an ASXL1-mutant-specific therapeutic vulnerability.","method":"CRISPR-edited human HSPCs, CUT&RUN for H2AK119Ub, ATAC-seq, RNA-seq, PRC1 inhibitor treatment","journal":"Blood cancer discovery","confidence":"High","confidence_rationale":"Tier 2 — human primary cell model with genome-wide chromatin and transcriptome assays and pharmacological validation","pmids":["38359087"],"is_preprint":false},{"year":2017,"finding":"BAP1 mutations in cancer act allosterically to inhibit ASXL2 ASXH-domain binding to BAP1's ULD domain; BAP1-UCH, BAP1-ULD, and ASXH form a cooperative ternary complex required for deubiquitination activity; four classes of BAP1 mutations outside the UCH domain all fail to productively recruit ASXH, abolishing enzyme activity.","method":"Computational modeling, in vitro reconstitution biochemistry, domain binding and enzymatic assays, mutagenesis","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution and mutagenesis defining allosteric mechanism; relevant to ASXL1/2 interaction with BAP1","pmids":["29284740"],"is_preprint":false},{"year":2020,"finding":"Truncated ASXL1 mutant protein expression in T cells (but not myeloid cells) promotes solid tumor progression by inducing aberrant intrathymic T-cell development, decreased CD4/CD8 ratio, naïve-memory imbalance, and PD-1 upregulation on CD8+ T cells, creating a pro-tumor immune microenvironment.","method":"Conditional knock-in mouse syngeneic tumor models, MMTV-PyMT spontaneous tumor model, intratumor T-cell analysis","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo conditional knock-in model with defined lineage-specific and cellular phenotypic readouts; single lab","pmids":["35133065"],"is_preprint":false}],"current_model":"ASXL1 functions as a scaffolding protein that regulates multiple chromatin modifications: it associates with PRC2 to promote H3K27 trimethylation, forms the catalytic PR-DUB complex with BAP1 (activated by ASXL1's DEUBAD domain) to remove H2AK119 monoubiquitination at Polycomb target sites with specificity revealed by cryo-EM structure, interacts with HP1 and LSD1 to repress RAR-target genes via H3K4 demethylation, is stabilized by OGT-mediated O-GlcNAcylation within an ASXL1-HCFC1-OGT complex that promotes H3K4 methylation, and supports paraspeckle formation via its C-terminal IDR; cancer-associated C-terminal truncation mutations produce stable proteins that gain enhanced BAP1 activity (globally erasing H2AK119Ub), acquire novel BRD4 interaction through an exposed ET-domain binding motif, lose interaction with BMI1 and FOXK1/2, activate AKT by deubiquitination, and redistribute rather than uniformly deplete H2AK119Ub to activate myeloid and stem cell transcriptional programs driving clonal hematopoiesis and myeloid malignancy."},"narrative":{"teleology":[{"year":2006,"claim":"Establishing that ASXL1 is a nuclear receptor coregulator answered how a mammalian Asx homolog participates in transcription: ASXL1 directly contacts RAR via a C-terminal NR box and cooperates with SRC-1 to increase histone H3 acetylation at RA-responsive promoters.","evidence":"GST pulldown, co-IP, ChIP, luciferase reporter in mammalian cells","pmids":["16606617"],"confidence":"High","gaps":["Whether coactivation extends to other nuclear receptors beyond RAR in vivo","Structural basis of NR box–RAR AF-2 interaction unresolved"]},{"year":2009,"claim":"Demonstrating that ASXL1 also represses RAR targets resolved an apparent paradox — the same protein acts as both coactivator and corepressor — by showing the N-terminal region recruits HP1 and LSD1 to remove H3K4 methylation, establishing ASXL1 as a context-dependent transcriptional switch.","evidence":"GST pulldown, co-IP, ChIP, siRNA knockdown, transcription assays","pmids":["19880879"],"confidence":"High","gaps":["How the switch between coactivation and corepression is regulated at specific loci","Whether the ASXL1-HP1-LSD1 complex has genome-wide targets beyond RAR"]},{"year":2012,"claim":"Linking ASXL1 to PRC2-mediated H3K27me3 established its role as a Polycomb co-factor and explained how ASXL1 loss derepresses HOXA genes to cooperate with oncogenic RAS in myeloid leukemogenesis.","evidence":"Co-IP of ASXL1–PRC2, ChIP-Seq, in vivo NRAS-G12D mouse model","pmids":["22897849"],"confidence":"High","gaps":["Whether ASXL1 is a stable PRC2 subunit or a transient recruiter","Mechanism by which ASXL1 facilitates PRC2 catalytic activity"]},{"year":2013,"claim":"In vivo knockout studies and truncation mutant mouse models demonstrated that ASXL1 loss and C-terminal truncation produce overlapping yet distinct epigenomic consequences — both reduce H3K27me3 and derepress Hoxa9/miR-125a, establishing the MDS-initiating mechanism.","evidence":"Conditional KO mice, knock-in of truncation mutant, ChIP-Seq, RNA-Seq, bone marrow transplantation","pmids":["24218140","24216483"],"confidence":"High","gaps":["Relative contributions of PRC2 loss versus PR-DUB gain-of-function in truncation mutants","Cell-intrinsic versus microenvironmental contributions to MDS phenotype"]},{"year":2015,"claim":"Biochemical reconstitution revealed that ASXL1's DEUBAD domain directly activates BAP1 by increasing its affinity for ubiquitin on H2AK119, and that truncation mutations produce stable proteins with enhanced BAP1 deubiquitinase activity that globally erases H2AK119Ub — reframing truncations as gain-of-function rather than simple loss-of-function.","evidence":"In vitro deubiquitinase reconstitution, mutagenesis, nucleosome binding assays, mass spectrometry detection of truncated protein, genome-wide histone ChIP","pmids":["26739236","26095772","26700326"],"confidence":"High","gaps":["Structural basis of how truncation enhances BAP1 activity was unknown at this stage","Whether enhanced activity is dosage-dependent in vivo"]},{"year":2017,"claim":"Identification of a neomorphic BRD4 interaction specific to truncated ASXL1 — mediated by an ET-domain binding motif exposed by truncation — explained how mutant ASXL1 opens chromatin at leukemogenic loci and established BET inhibitor sensitivity as a therapeutic vulnerability.","evidence":"LC-MS/MS, co-IP, ATAC-seq, RNA-seq, transgenic mouse model, ITC/SPR binding quantification","pmids":["29113963","34536441"],"confidence":"High","gaps":["Whether BRD4 interaction and enhanced BAP1 activity act synergistically or independently","Genome-wide sites of aberrant BRD4 recruitment by truncated ASXL1"]},{"year":2018,"claim":"Discovery of the ASXL1–HCFC1–OGT complex showed that OGT-mediated O-GlcNAcylation stabilizes ASXL1 protein and promotes H3K4 methylation, while the finding that truncated ASXL1 loses BMI1 interaction placed PRC1-mediated H2AK119Ub at the p16Ink4a locus as a key senescence checkpoint disrupted by mutation.","evidence":"Co-IP, mass spectrometry, O-GlcNAcylation assay, ChIP, knock-in mouse with p16Ink4a genetic rescue","pmids":["29556021","29967380"],"confidence":"High","gaps":["Whether OGT stabilization is disrupted by truncation mutations","How H3K4me3 reduction and H2AK119Ub loss cooperate at individual loci"]},{"year":2018,"claim":"Physiological knock-in of Asxl1 truncation revealed that mutant protein reduces H3K4me3 and H2AK119Ub without significantly reducing H3K27me3 — distinguishing gain-of-function truncation from loss-of-function and demonstrating opposing epigenomic effects of wild-type versus mutant at specific loci.","evidence":"Conditional knock-in mice, genome-wide ChIP-Seq, competitive transplantation","pmids":["29643185"],"confidence":"High","gaps":["Locus-specific rules governing which marks are affected remain incompletely defined","Whether the epigenomic signature changes during disease progression"]},{"year":2020,"claim":"Genome-wide PR-DUB mapping showed that ASXL proteins and FOXK1/2 are both required for BAP1 chromatin recruitment and H2AK119Ub removal, while truncated ASXL1 loses FOXK1/2 interaction, clarifying how the full complex is assembled and how truncation rewires its targeting.","evidence":"ChIP-seq, genetic knockouts in ESCs, proteomics, allele-specific CRISPR deletion in leukemia cells","pmids":["32747411","32683582"],"confidence":"High","gaps":["How PR-DUB target selection differs between ASXL1, ASXL2, and ASXL3","Whether FOXK1/2 loss fully explains aberrant PR-DUB targeting in mutant cells"]},{"year":2021,"claim":"Truncated ASXL1 cooperates with BAP1 to deubiquitinate and activate AKT, establishing a non-histone substrate for the hyperactive PR-DUB complex and connecting mutant ASXL1 to mTOR signaling; rapamycin rescue validated therapeutic targeting of this axis.","evidence":"Biochemical AKT deubiquitination assay, conditional knock-in mice, rapamycin treatment","pmids":["33758188"],"confidence":"High","gaps":["Full repertoire of non-histone PR-DUB substrates is unknown","Whether AKT deubiquitination contributes to leukemogenesis independently of chromatin effects"]},{"year":2021,"claim":"Discovery that ASXL1's C-terminal IDR drives phase separation supporting paraspeckle formation via NONO–NEAT1 interactions revealed a non-chromatin function lost in truncation mutants, broadening the functional consequences of pathogenic mutations beyond epigenetics.","evidence":"Phase separation assay, co-IP, knock-in mouse model, live imaging","pmids":["34433054"],"confidence":"Medium","gaps":["How paraspeckle disruption contributes quantitatively to mutant ASXL1-driven disease","Whether phase separation also modulates ASXL1's chromatin functions","Confirmation in independent systems needed"]},{"year":2023,"claim":"The cryo-EM structure of BAP1–ASXL1 DEUBAD bound to an H2AK119Ub nucleosome provided atomic-level explanation for substrate specificity and mapped >50 cancer-associated mutations onto the structure, unifying biochemical and genetic observations.","evidence":"Cryo-EM at near-atomic resolution, mutagenesis, deubiquitinase assays, cellular complementation","pmids":["37556531"],"confidence":"High","gaps":["Structure of full-length ASXL1 or truncated mutant in complex with BAP1 on nucleosomes not yet resolved","Dynamic conformational changes during catalysis remain uncharacterized"]},{"year":2024,"claim":"Genome-wide H2AK119Ub mapping in CRISPR-edited human HSPCs showed that truncated ASXL1 redistributes rather than simply depletes H2AK119Ub, activating myeloid/stem cell programs and establishing PRC1 inhibition as a mutation-specific therapeutic vulnerability.","evidence":"CUT&RUN, ATAC-seq, RNA-seq in primary human HSPCs, PRC1 inhibitor treatment","pmids":["38359087"],"confidence":"High","gaps":["Whether H2AK119Ub redistribution pattern predicts clinical progression","Which PRC1 subcomplexes are responsible for the redistributed ubiquitination"]},{"year":null,"claim":"The full-length structure of ASXL1, the mechanistic basis for switching between its activating (PRC2, OGT) and repressive (HP1-LSD1) functions at specific loci, and the relative pathogenic contributions of its multiple neomorphic interactions (enhanced BAP1, BRD4, AKT deubiquitination, paraspeckle loss) remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length ASXL1 structure","No quantitative model integrating chromatin and non-chromatin functions in disease","Therapeutic window for BAP1/PRC1 inhibition in ASXL1-mutant patients undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,6,8,17]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[3,8,23]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,15,25]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,6,13,17]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2,3,7,15]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[7,8,17,23]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[3,4,6,7,8,12,17,23,27]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,15,25]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[11,19,26]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,6,10,21,27]}],"complexes":["PR-DUB (BAP1-ASXL1)","ASXL1-HCFC1-OGT","ASXL1-HP1-LSD1"],"partners":["BAP1","HCFC1","OGT","BRD4","FOXK1","FOXK2","BMI1","LSD1"],"other_free_text":[]},"mechanistic_narrative":"ASXL1 is a chromatin scaffolding protein that orchestrates multiple histone modifications to regulate gene expression in hematopoiesis, development, and metabolism. Its DEUBAD domain activates the deubiquitinase BAP1 within the PR-DUB complex, conferring specificity for H2AK119Ub removal at Polycomb target genes through direct nucleosome contacts revealed by cryo-EM, while its N-terminal ASXH domain recruits HP1 and LSD1 to demethylate H3K4 at retinoic acid-responsive promoters, and its association with PRC2 supports H3K27 trimethylation [PMID:26739236, PMID:37556531, PMID:19880879, PMID:22897849]. ASXL1 is stabilized by OGT-mediated O-GlcNAcylation within an ASXL1–HCFC1–OGT complex that promotes H3K4 methylation and myeloid differentiation, and its C-terminal intrinsically disordered region drives phase separation required for paraspeckle formation [PMID:29556021, PMID:34433054]. Recurrent C-terminal truncation mutations in myeloid malignancies produce stable gain-of-function proteins that hyperactivate BAP1, globally redistribute H2AK119Ub, acquire a novel BRD4 interaction via an exposed ET-domain binding motif, lose FOXK1/2 and BMI1 binding, and activate AKT through BAP1-mediated deubiquitination, collectively driving clonal hematopoiesis and leukemic transcriptional programs [PMID:35122023, PMID:38359087, PMID:34536441, PMID:33758188, PMID:29967380]."},"prefetch_data":{"uniprot":{"accession":"Q8IXJ9","full_name":"Polycomb group protein ASXL1","aliases":["Additional sex combs-like protein 1"],"length_aa":1541,"mass_kda":165.4,"function":"Probable Polycomb group (PcG) protein involved in transcriptional regulation mediated by ligand-bound nuclear hormone receptors, such as retinoic acid receptors (RARs) and peroxisome proliferator-activated receptor gamma (PPARG) (PubMed:16606617). Acts as a coactivator of RARA and RXRA through association with NCOA1 (PubMed:16606617). Acts as a corepressor for PPARG and suppresses its adipocyte differentiation-inducing activity (By similarity). Non-catalytic component of the PR-DUB complex, a complex that specifically mediates deubiquitination of histone H2A monoubiquitinated at 'Lys-119' (H2AK119ub1) (PubMed:20436459, PubMed:30664650, PubMed:36180891). Acts as a sensor of N(6)-methyladenine methylation on DNA (6mA): recognizes and binds 6mA DNA, leading to its ubiquitination and degradation by TRIP12, thereby inactivating the PR-DUB complex and regulating Polycomb silencing (PubMed:30982744). The PR-DUB complex is an epigenetic regulator of gene expression and acts as a transcriptional coactivator, affecting genes involved in development, cell communication, signaling, cell proliferation and cell viability (PubMed:30664650, PubMed:36180891). ASXL1, ASXL2 and ASXL3 function redundantly in the PR-DUB complex (By similarity) (PubMed:30664650). The ASXL proteins are essential for chromatin recruitment and transcriptional activation of associated genes (By similarity). ASXL1 and ASXL2 are important for BAP1 protein stability (PubMed:30664650). Together with BAP1, negatively regulates epithelial-mesenchymal transition (EMT) of trophoblast stem cells during placental development by regulating genes involved in epithelial cell integrity, cell adhesion and cytoskeletal organization (PubMed:34170818)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q8IXJ9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ASXL1","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ASXL1","total_profiled":1310},"omim":[{"mim_id":"619626","title":"METHYLTRANSFERASE 4, N6-ADENOSINE; METTL4","url":"https://www.omim.org/entry/619626"},{"mim_id":"617190","title":"SHASHI-PENA SYNDROME; SHAPNS","url":"https://www.omim.org/entry/617190"},{"mim_id":"616604","title":"CHROMOSOME 14q32 DUPLICATION SYNDROME, 700-KB","url":"https://www.omim.org/entry/616604"},{"mim_id":"615485","title":"BAINBRIDGE-ROPERS SYNDROME; BRPS","url":"https://www.omim.org/entry/615485"},{"mim_id":"615115","title":"ASXL TRANSCRIPTIONAL REGULATOR 3; ASXL3","url":"https://www.omim.org/entry/615115"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nucleoli","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ASXL1"},"hgnc":{"alias_symbol":["KIAA0978"],"prev_symbol":[]},"alphafold":{"accession":"Q8IXJ9","domains":[{"cath_id":"-","chopping":"253-330","consensus_level":"medium","plddt":84.6214,"start":253,"end":330},{"cath_id":"1.10.10","chopping":"2-92","consensus_level":"medium","plddt":84.7411,"start":2,"end":92}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IXJ9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IXJ9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IXJ9-F1-predicted_aligned_error_v6.png","plddt_mean":42.22},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ASXL1","jax_strain_url":"https://www.jax.org/strain/search?query=ASXL1"},"sequence":{"accession":"Q8IXJ9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IXJ9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IXJ9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IXJ9"}},"corpus_meta":[{"pmid":"22897849","id":"PMC_22897849","title":"ASXL1 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it is expressed ubiquitously in adult tissues and embryos.\",\n      \"method\": \"Sequence analysis, Northern blot, whole-mount RNA in situ hybridization\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct characterization of domain architecture and expression; single study\",\n      \"pmids\": [\"16412590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ASXL1 represses RAR-mediated transcription through its N-terminal region by directly interacting with HP1 (via an HP1 box, PXVXL motif) and histone demethylase LSD1, forming a ternary ASXL1-HP1-LSD1 complex that removes H3K4 methylation at RA-responsive promoters.\",\n      \"method\": \"In vitro GST pulldown, in vivo co-immunoprecipitation, chromatin IP, transcription assays, siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods, direct demonstration of complex, histone mark changes, and functional consequence\",\n      \"pmids\": [\"19880879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ASXL1 associates with the PRC2 complex and loss of ASXL1 results in reduced H3K27 tri-methylation genome-wide, leading to derepression of posterior HOXA cluster genes and collaborating with NRASG12D to promote myeloid leukemogenesis.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-Seq, microarray, in vivo mouse model\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — Co-IP demonstrating ASXL1-PRC2 interaction, genome-wide ChIP-Seq, and in vivo epistasis; highly cited foundational study\",\n      \"pmids\": [\"22897849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Constitutive or hematopoietic-specific deletion of Asxl1 in mice results in global reduction of H3K27 trimethylation and H3K4me3, dysregulated expression of hematopoietic regulators, progressive cytopenias and dysplasia recapitulating MDS; compound Asxl1/Tet2 deletion accelerates myeloid disease.\",\n      \"method\": \"Conditional knockout mouse model, RNA-Seq, ChIP-Seq, serial transplantation\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with multiple orthogonal readouts including ChIP-Seq and RNA-Seq; independently replicated by multiple labs\",\n      \"pmids\": [\"24218140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"C-terminal truncating ASXL1 mutations inhibit PRC2-mediated H3K27 methylation, leading to derepression of Hoxa9 and miR-125a, which reduces Clec5a expression and blocks myeloid differentiation, inducing MDS-like disease in mice.\",\n      \"method\": \"Mouse bone marrow transplantation model, ChIP, qRT-PCR, miRNA target validation\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo mouse model with molecular pathway dissection using ChIP and miRNA functional assays\",\n      \"pmids\": [\"24216483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ASXL1 truncation mutations confer gain-of-function on the ASXL1-BAP1 deubiquitinase complex, resulting in enhanced BAP1 activity, global erasure of H2AK119Ub, striking depletion of H3K27me3, and upregulation of bivalently marked genes, driving mast cell differentiation; effects require BAP1 catalytic activity.\",\n      \"method\": \"Stable cell line expression, genome-wide histone ChIP, functional differentiation assays, in vivo bone marrow reconstitution\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including genome-wide ChIP, functional assays, catalytic mutant controls, and in vivo studies\",\n      \"pmids\": [\"26095772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ASXL1 is required for BAP1-mediated deubiquitylation of H2AK119ub1 at the INK4B locus; ASXL1 and BAP1 co-occupy the INK4B promoter, and ASXL1 loss prevents H2AK119 deubiquitylation and induction of p15(INK4B) in response to oncogenic signaling or anti-proliferative signals.\",\n      \"method\": \"ChIP, siRNA knockdown, luciferase reporter, primary bone marrow cell functional assays\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP localization, functional H2AK119ub1 changes, and defined cellular phenotype with pathway placement\",\n      \"pmids\": [\"26470845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BAP1's C-terminal extension auto-recruits BAP1 to nucleosomes in an unproductive complex; ASXL1 (or ASXL2/3) DEUBAD domains activate BAP1 by increasing its affinity for ubiquitin on H2A K119, driving deubiquitination specifically for Polycomb H2A modifications but not DNA damage-associated H2A K13/15 ubiquitination.\",\n      \"method\": \"Biochemical reconstitution, in vitro deubiquitinase assay, mutagenesis, nucleosome binding assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with mechanistic dissection, mutagenesis, and substrate specificity determination\",\n      \"pmids\": [\"26739236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Truncated ASXL1 mutant proteins (C-terminal truncations) are detectable at the protein level in cell lines harboring homozygous ASXL1 mutations, demonstrating that ASXL1 truncation mutations produce stable expressed proteins rather than undergoing nonsense-mediated decay.\",\n      \"method\": \"Mass spectrometry, Western blot, cell lines with homozygous ASXL1 mutations\",\n      \"journal\": \"Experimental hematology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — two independent detection methods (MS and Western blot) directly detecting truncated protein\",\n      \"pmids\": [\"26700326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ASXL1 truncating protein (aa1-587) acquires an interaction with BRD4 (not present with full-length ASXL1), resulting in more open chromatin at critical hematopoietic genes; expression of truncated ASXL1 drives myeloid malignancies in transgenic mice and confers hypersensitivity to BET bromodomain inhibitors.\",\n      \"method\": \"LC-MS/MS, co-immunoprecipitation, ATAC-seq, RNA-seq, transgenic mouse model, epigenetic drug screening\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — MS-identified interaction confirmed by Co-IP, genome-wide chromatin and transcriptome analyses, in vivo model\",\n      \"pmids\": [\"29113963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ASXL1 interacts directly with the kinase domain of AKT1 through amino acids 371-655; loss of Asxl1 prevents IGF-1-induced AKT1 phosphorylation, retains p27Kip1 in the nucleus, suppresses Rb phosphorylation and E2F target genes, and promotes cellular senescence; Asxl1 also cooperates with Ezh2 through direct interaction.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, AKT inhibitor treatment, microarray, SA-β-gal staining in Asxl1-null MEFs\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP domain mapping and functional rescue; single lab, multiple assays\",\n      \"pmids\": [\"28701722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Physiological expression of C-terminal truncated Asxl1 mutant in knock-in mice reduces H3K4me3 and H2AK119Ub without significant reduction in H3K27me3—distinct from Asxl1 loss—and wild-type versus mutant Asxl1 have opposing effects on H3K4me3 at specific loci, altering the HSC epigenome and increasing susceptibility to leukemic transformation.\",\n      \"method\": \"Conditional knock-in mouse model, ChIP-Seq, competitive transplantation, viral insertional mutagenesis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide ChIP-Seq in physiological knock-in model distinguishing loss-of-function from gain-of-function effects\",\n      \"pmids\": [\"29643185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ASXL1 forms a protein complex with HCFC1 and OGT; OGT directly stabilizes ASXL1 through O-GlcNAcylation; disruption of this ASXL1-OGT axis inhibits H3K4 methylation, H2B glycosylation, and myeloid differentiation, implicating MLL5 as the downstream H3K4 methyltransferase.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, O-GlcNAcylation assay, ChIP, in vivo leukemogenicity assay\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — MS-identified complex, PTM demonstrated biochemically, functional ChIP and in vivo validation\",\n      \"pmids\": [\"29556021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Asxl1G643fs mutant ASXL1 loses the ability to interact with BMI1 (PRC1 subunit), reducing H2AK119ub1 at the p16Ink4a promoter; derepression of p16Ink4a induces cellular senescence in HSCs, producing low-risk MDS-like phenotypes; heterozygous p16Ink4a deletion restores HSC pool.\",\n      \"method\": \"Co-immunoprecipitation, ChIP at p16Ink4a locus, knock-in mouse model, genetic rescue with p16Ink4a heterozygosity\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct Co-IP showing loss of BMI1 interaction, ChIP at specific locus, genetic epistasis rescue\",\n      \"pmids\": [\"29967380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss of ASXL1 in bone marrow stromal cells (BMSCs) impairs hematopoietic stem/progenitor cell maintenance; ASXL1 interacts with core subunits of RNA polymerase II complex in BMSCs and regulates RNAPII-dependent transcription of genes critical for HSC/HPC maintenance (e.g., Vcam1).\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, RNA-seq, BMSC co-culture assays\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with RNAPII, ChIP-seq and RNA-seq convergent analysis; single lab\",\n      \"pmids\": [\"29423272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ASXL1 and SETBP1 co-mutations repress TGFβ pathway genes through reduced histone H3 and H4 acetylation at their promoters; HDAC inhibitor vorinostat restores histone acetylation, derepresses TGFβ pathway genes, and selectively inhibits growth of ASXL1-mutant cells.\",\n      \"method\": \"ChIP for H3/H4 acetylation, HDAC inhibitor treatment, gene expression analysis, in vivo mouse model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-based mechanism and pharmacological rescue; single lab\",\n      \"pmids\": [\"30367089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PR-DUB complex (BAP1 with ASXL1/2/3, FOXK1/2, HCFC1, OGT) is recruited to chromatin through FOXK1/2 and ASXL proteins; BAP1 is dependent on ASXL proteins and FOXK1/2 for genome-wide H2AK119ub1 removal and activation of metabolic and homeostatic genes, with minimal functional overlap with PRC2 in ESCs.\",\n      \"method\": \"ChIP-seq, genome-wide H2AK119ub1 profiling, genetic knockouts, proteomics\",\n      \"journal\": \"Genome research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide ChIP-seq and genetic KO of multiple complex components; orthogonal methods\",\n      \"pmids\": [\"32747411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Wild-type ASXL1 interacts with forkhead transcription factors FOXK1 and FOXK2 to regulate target genes; C-terminally truncated mutant ASXL1 loses FOXK1/K2 interaction and is expressed at higher levels than wild-type in heterozygous leukemia cells; specific deletion of mutant allele restores BAP1-ASXL1 association and FOXK1/K2 target gene expression.\",\n      \"method\": \"Co-immunoprecipitation, CRISPR allele-specific deletion, gene expression analysis\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP showing differential interactions, allele-specific genetic rescue; single lab\",\n      \"pmids\": [\"32683582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ASXL1-mutant (C-terminally truncated) cooperates with BAP1 to deubiquitinate and activate AKT; overactive Akt/mTOR signaling causes aberrant HSC proliferation, age-related DNA damage accumulation, and clonal expansion; mTOR inhibitor rapamycin ameliorates the phenotype in knock-in mice.\",\n      \"method\": \"Conditional knock-in mouse model, biochemical AKT deubiquitination assay, genetic mosaic model, rapamycin treatment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical demonstration of AKT deubiquitination, in vivo genetic model, pharmacological rescue\",\n      \"pmids\": [\"33758188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ASXL1 forms phase-separated droplets via its C-terminal intrinsically disordered region (IDR), upregulates NEAT1 expression, and increases NONO-NEAT1 interactions to support paraspeckle formation in hematopoietic cells; pathogenic truncated ASXL1 lacking the IDR fails to support paraspeckle components, causing abnormal cytoplasmic NONO localization and impaired HSPC repopulating potential.\",\n      \"method\": \"Co-immunoprecipitation, phase separation assay, knock-in mouse model, live imaging, NONO shRNA knockdown\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP, phase separation assay, and KI mouse with defined cellular phenotype; single lab\",\n      \"pmids\": [\"34433054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cancer-associated ASXL1 frameshift mutations encode stable truncated gain-of-function proteins that increase BAP1 protein stability, enhance BAP1 chromatin recruitment, and drive expression of a pro-leukemic transcriptional signature; BAP1 catalytic inhibitors identified by biochemical screen suppress truncated-ASXL1-driven leukemic gene expression and impair tumor progression in vivo.\",\n      \"method\": \"Protein stability assays, ChIP, RNA-seq, biochemical inhibitor screen, in vivo tumor models\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical screen, ChIP, RNA-seq, and in vivo pharmacological validation; multiple orthogonal methods\",\n      \"pmids\": [\"35122023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Oncogenic ASXL1 truncation mutations enhance binding to the ET domain of BRD4 via a specific motif near the truncation breakpoint; ASXL1Y591X truncation markedly increases BRD4 ET-domain binding relative to full-length ASXL1, providing a molecular mechanism for aberrant BRD4 recruitment to transcriptional complexes.\",\n      \"method\": \"Binding assays (ITC, SPR), domain mapping, recombinant protein analysis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro binding assays with quantitative affinity measurements and domain-level mechanistic dissection\",\n      \"pmids\": [\"34536441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM structure of human BAP1-ASXL1 DEUBAD in complex with H2AK119Ub nucleosome reveals molecular interactions of BAP1 and ASXL1 with histones and DNA that restructure the nucleosome to establish specificity for H2AK119Ub; structure explains how >50 cancer-associated mutations in BAP1 and ASXL1 dysregulate deubiquitination.\",\n      \"method\": \"Cryo-EM structure determination, biochemical deubiquitinase assays, mutagenesis, cellular complementation\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution cryo-EM structure with biochemical and cellular functional validation and disease mutation mapping\",\n      \"pmids\": [\"37556531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ASXL1 interacts with WTIP (Wilms tumor 1-interacting protein) via its PHD domain; loss of Asxl1 in mice causes kidney podocyte morphology defects and up-regulation of Wt1/Wtip target genes, placing ASXL1 in a WT1 regulatory pathway during kidney development.\",\n      \"method\": \"Co-immunoprecipitation, Asxl1-null mouse analysis, gene expression assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and KO phenotype with pathway gene expression; single lab\",\n      \"pmids\": [\"26385183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ASXL1 suppresses LXRα-mediated transcription and lipid accumulation, while ASXL2 activates LXRα, acting through direct interaction with LXRα; ChIP shows ligand-dependent recruitment of ASXL1 to ABCA1 promoters; ASXL1 expression increases under fasting and decreases in insulin-treated or high-fat-diet conditions.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, lipid accumulation assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Direct binding demonstrated by Co-IP, ChIP at target promoter, physiological regulation context; single lab\",\n      \"pmids\": [\"24321552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Asxl1 is required for transcriptional activation of Pten by facilitating H2AK119 deubiquitylation at the Pten promoter; loss of Asxl1 reduces PTEN expression, sustains PI3K/AKT signaling, and confers sensitivity to AKT inhibitor MK2206.\",\n      \"method\": \"ChIP at Pten promoter, AKT activity assays, siRNA knockdown, inhibitor sensitivity assay\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP at specific locus, functional pathway assay, and pharmacological validation; single lab\",\n      \"pmids\": [\"32236560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Truncated ASXL1 leads to global redistribution (not simply loss) of H2AK119Ub, increased transposase-accessible chromatin, and activation of myeloid and stem cell gene-expression programs in human HSPCs; H2AK119Ub levels are tied to truncated ASXL1 expression levels, and PRC1 complex inhibition is an ASXL1-mutant-specific therapeutic vulnerability.\",\n      \"method\": \"CRISPR-edited human HSPCs, CUT&RUN for H2AK119Ub, ATAC-seq, RNA-seq, PRC1 inhibitor treatment\",\n      \"journal\": \"Blood cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human primary cell model with genome-wide chromatin and transcriptome assays and pharmacological validation\",\n      \"pmids\": [\"38359087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BAP1 mutations in cancer act allosterically to inhibit ASXL2 ASXH-domain binding to BAP1's ULD domain; BAP1-UCH, BAP1-ULD, and ASXH form a cooperative ternary complex required for deubiquitination activity; four classes of BAP1 mutations outside the UCH domain all fail to productively recruit ASXH, abolishing enzyme activity.\",\n      \"method\": \"Computational modeling, in vitro reconstitution biochemistry, domain binding and enzymatic assays, mutagenesis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution and mutagenesis defining allosteric mechanism; relevant to ASXL1/2 interaction with BAP1\",\n      \"pmids\": [\"29284740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Truncated ASXL1 mutant protein expression in T cells (but not myeloid cells) promotes solid tumor progression by inducing aberrant intrathymic T-cell development, decreased CD4/CD8 ratio, naïve-memory imbalance, and PD-1 upregulation on CD8+ T cells, creating a pro-tumor immune microenvironment.\",\n      \"method\": \"Conditional knock-in mouse syngeneic tumor models, MMTV-PyMT spontaneous tumor model, intratumor T-cell analysis\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo conditional knock-in model with defined lineage-specific and cellular phenotypic readouts; single lab\",\n      \"pmids\": [\"35133065\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ASXL1 functions as a scaffolding protein that regulates multiple chromatin modifications: it associates with PRC2 to promote H3K27 trimethylation, forms the catalytic PR-DUB complex with BAP1 (activated by ASXL1's DEUBAD domain) to remove H2AK119 monoubiquitination at Polycomb target sites with specificity revealed by cryo-EM structure, interacts with HP1 and LSD1 to repress RAR-target genes via H3K4 demethylation, is stabilized by OGT-mediated O-GlcNAcylation within an ASXL1-HCFC1-OGT complex that promotes H3K4 methylation, and supports paraspeckle formation via its C-terminal IDR; cancer-associated C-terminal truncation mutations produce stable proteins that gain enhanced BAP1 activity (globally erasing H2AK119Ub), acquire novel BRD4 interaction through an exposed ET-domain binding motif, lose interaction with BMI1 and FOXK1/2, activate AKT by deubiquitination, and redistribute rather than uniformly deplete H2AK119Ub to activate myeloid and stem cell transcriptional programs driving clonal hematopoiesis and myeloid malignancy.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ASXL1 is a chromatin scaffolding protein that orchestrates multiple histone modifications to regulate gene expression in hematopoiesis, development, and metabolism. Its DEUBAD domain activates the deubiquitinase BAP1 within the PR-DUB complex, conferring specificity for H2AK119Ub removal at Polycomb target genes through direct nucleosome contacts revealed by cryo-EM, while its N-terminal ASXH domain recruits HP1 and LSD1 to demethylate H3K4 at retinoic acid-responsive promoters, and its association with PRC2 supports H3K27 trimethylation [PMID:26739236, PMID:37556531, PMID:19880879, PMID:22897849]. ASXL1 is stabilized by OGT-mediated O-GlcNAcylation within an ASXL1–HCFC1–OGT complex that promotes H3K4 methylation and myeloid differentiation, and its C-terminal intrinsically disordered region drives phase separation required for paraspeckle formation [PMID:29556021, PMID:34433054]. Recurrent C-terminal truncation mutations in myeloid malignancies produce stable gain-of-function proteins that hyperactivate BAP1, globally redistribute H2AK119Ub, acquire a novel BRD4 interaction via an exposed ET-domain binding motif, lose FOXK1/2 and BMI1 binding, and activate AKT through BAP1-mediated deubiquitination, collectively driving clonal hematopoiesis and leukemic transcriptional programs [PMID:35122023, PMID:38359087, PMID:34536441, PMID:33758188, PMID:29967380].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Establishing that ASXL1 is a nuclear receptor coregulator answered how a mammalian Asx homolog participates in transcription: ASXL1 directly contacts RAR via a C-terminal NR box and cooperates with SRC-1 to increase histone H3 acetylation at RA-responsive promoters.\",\n      \"evidence\": \"GST pulldown, co-IP, ChIP, luciferase reporter in mammalian cells\",\n      \"pmids\": [\"16606617\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether coactivation extends to other nuclear receptors beyond RAR in vivo\", \"Structural basis of NR box–RAR AF-2 interaction unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrating that ASXL1 also represses RAR targets resolved an apparent paradox — the same protein acts as both coactivator and corepressor — by showing the N-terminal region recruits HP1 and LSD1 to remove H3K4 methylation, establishing ASXL1 as a context-dependent transcriptional switch.\",\n      \"evidence\": \"GST pulldown, co-IP, ChIP, siRNA knockdown, transcription assays\",\n      \"pmids\": [\"19880879\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the switch between coactivation and corepression is regulated at specific loci\", \"Whether the ASXL1-HP1-LSD1 complex has genome-wide targets beyond RAR\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linking ASXL1 to PRC2-mediated H3K27me3 established its role as a Polycomb co-factor and explained how ASXL1 loss derepresses HOXA genes to cooperate with oncogenic RAS in myeloid leukemogenesis.\",\n      \"evidence\": \"Co-IP of ASXL1–PRC2, ChIP-Seq, in vivo NRAS-G12D mouse model\",\n      \"pmids\": [\"22897849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ASXL1 is a stable PRC2 subunit or a transient recruiter\", \"Mechanism by which ASXL1 facilitates PRC2 catalytic activity\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"In vivo knockout studies and truncation mutant mouse models demonstrated that ASXL1 loss and C-terminal truncation produce overlapping yet distinct epigenomic consequences — both reduce H3K27me3 and derepress Hoxa9/miR-125a, establishing the MDS-initiating mechanism.\",\n      \"evidence\": \"Conditional KO mice, knock-in of truncation mutant, ChIP-Seq, RNA-Seq, bone marrow transplantation\",\n      \"pmids\": [\"24218140\", \"24216483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of PRC2 loss versus PR-DUB gain-of-function in truncation mutants\", \"Cell-intrinsic versus microenvironmental contributions to MDS phenotype\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Biochemical reconstitution revealed that ASXL1's DEUBAD domain directly activates BAP1 by increasing its affinity for ubiquitin on H2AK119, and that truncation mutations produce stable proteins with enhanced BAP1 deubiquitinase activity that globally erases H2AK119Ub — reframing truncations as gain-of-function rather than simple loss-of-function.\",\n      \"evidence\": \"In vitro deubiquitinase reconstitution, mutagenesis, nucleosome binding assays, mass spectrometry detection of truncated protein, genome-wide histone ChIP\",\n      \"pmids\": [\"26739236\", \"26095772\", \"26700326\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of how truncation enhances BAP1 activity was unknown at this stage\", \"Whether enhanced activity is dosage-dependent in vivo\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of a neomorphic BRD4 interaction specific to truncated ASXL1 — mediated by an ET-domain binding motif exposed by truncation — explained how mutant ASXL1 opens chromatin at leukemogenic loci and established BET inhibitor sensitivity as a therapeutic vulnerability.\",\n      \"evidence\": \"LC-MS/MS, co-IP, ATAC-seq, RNA-seq, transgenic mouse model, ITC/SPR binding quantification\",\n      \"pmids\": [\"29113963\", \"34536441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether BRD4 interaction and enhanced BAP1 activity act synergistically or independently\", \"Genome-wide sites of aberrant BRD4 recruitment by truncated ASXL1\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovery of the ASXL1–HCFC1–OGT complex showed that OGT-mediated O-GlcNAcylation stabilizes ASXL1 protein and promotes H3K4 methylation, while the finding that truncated ASXL1 loses BMI1 interaction placed PRC1-mediated H2AK119Ub at the p16Ink4a locus as a key senescence checkpoint disrupted by mutation.\",\n      \"evidence\": \"Co-IP, mass spectrometry, O-GlcNAcylation assay, ChIP, knock-in mouse with p16Ink4a genetic rescue\",\n      \"pmids\": [\"29556021\", \"29967380\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether OGT stabilization is disrupted by truncation mutations\", \"How H3K4me3 reduction and H2AK119Ub loss cooperate at individual loci\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Physiological knock-in of Asxl1 truncation revealed that mutant protein reduces H3K4me3 and H2AK119Ub without significantly reducing H3K27me3 — distinguishing gain-of-function truncation from loss-of-function and demonstrating opposing epigenomic effects of wild-type versus mutant at specific loci.\",\n      \"evidence\": \"Conditional knock-in mice, genome-wide ChIP-Seq, competitive transplantation\",\n      \"pmids\": [\"29643185\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Locus-specific rules governing which marks are affected remain incompletely defined\", \"Whether the epigenomic signature changes during disease progression\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Genome-wide PR-DUB mapping showed that ASXL proteins and FOXK1/2 are both required for BAP1 chromatin recruitment and H2AK119Ub removal, while truncated ASXL1 loses FOXK1/2 interaction, clarifying how the full complex is assembled and how truncation rewires its targeting.\",\n      \"evidence\": \"ChIP-seq, genetic knockouts in ESCs, proteomics, allele-specific CRISPR deletion in leukemia cells\",\n      \"pmids\": [\"32747411\", \"32683582\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PR-DUB target selection differs between ASXL1, ASXL2, and ASXL3\", \"Whether FOXK1/2 loss fully explains aberrant PR-DUB targeting in mutant cells\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Truncated ASXL1 cooperates with BAP1 to deubiquitinate and activate AKT, establishing a non-histone substrate for the hyperactive PR-DUB complex and connecting mutant ASXL1 to mTOR signaling; rapamycin rescue validated therapeutic targeting of this axis.\",\n      \"evidence\": \"Biochemical AKT deubiquitination assay, conditional knock-in mice, rapamycin treatment\",\n      \"pmids\": [\"33758188\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full repertoire of non-histone PR-DUB substrates is unknown\", \"Whether AKT deubiquitination contributes to leukemogenesis independently of chromatin effects\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery that ASXL1's C-terminal IDR drives phase separation supporting paraspeckle formation via NONO–NEAT1 interactions revealed a non-chromatin function lost in truncation mutants, broadening the functional consequences of pathogenic mutations beyond epigenetics.\",\n      \"evidence\": \"Phase separation assay, co-IP, knock-in mouse model, live imaging\",\n      \"pmids\": [\"34433054\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How paraspeckle disruption contributes quantitatively to mutant ASXL1-driven disease\", \"Whether phase separation also modulates ASXL1's chromatin functions\", \"Confirmation in independent systems needed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The cryo-EM structure of BAP1–ASXL1 DEUBAD bound to an H2AK119Ub nucleosome provided atomic-level explanation for substrate specificity and mapped >50 cancer-associated mutations onto the structure, unifying biochemical and genetic observations.\",\n      \"evidence\": \"Cryo-EM at near-atomic resolution, mutagenesis, deubiquitinase assays, cellular complementation\",\n      \"pmids\": [\"37556531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of full-length ASXL1 or truncated mutant in complex with BAP1 on nucleosomes not yet resolved\", \"Dynamic conformational changes during catalysis remain uncharacterized\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Genome-wide H2AK119Ub mapping in CRISPR-edited human HSPCs showed that truncated ASXL1 redistributes rather than simply depletes H2AK119Ub, activating myeloid/stem cell programs and establishing PRC1 inhibition as a mutation-specific therapeutic vulnerability.\",\n      \"evidence\": \"CUT&RUN, ATAC-seq, RNA-seq in primary human HSPCs, PRC1 inhibitor treatment\",\n      \"pmids\": [\"38359087\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether H2AK119Ub redistribution pattern predicts clinical progression\", \"Which PRC1 subcomplexes are responsible for the redistributed ubiquitination\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The full-length structure of ASXL1, the mechanistic basis for switching between its activating (PRC2, OGT) and repressive (HP1-LSD1) functions at specific loci, and the relative pathogenic contributions of its multiple neomorphic interactions (enhanced BAP1, BRD4, AKT deubiquitination, paraspeckle loss) remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length ASXL1 structure\", \"No quantitative model integrating chromatin and non-chromatin functions in disease\", \"Therapeutic window for BAP1/PRC1 inhibition in ASXL1-mutant patients undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 6, 8, 17]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [3, 8, 23]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 15, 25]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 6, 13, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2, 3, 7, 15]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [7, 8, 17, 23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [3, 4, 6, 7, 8, 12, 17, 23, 27]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 15, 25]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [11, 19, 26]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 6, 10, 21, 27]}\n    ],\n    \"complexes\": [\n      \"PR-DUB (BAP1-ASXL1)\",\n      \"ASXL1-HCFC1-OGT\",\n      \"ASXL1-HP1-LSD1\"\n    ],\n    \"partners\": [\n      \"BAP1\",\n      \"HCFC1\",\n      \"OGT\",\n      \"BRD4\",\n      \"FOXK1\",\n      \"FOXK2\",\n      \"BMI1\",\n      \"LSD1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}