{"gene":"ASXL1","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2012,"finding":"ASXL1 physically associates with the Polycomb Repressive Complex 2 (PRC2), and loss of ASXL1 results in global reduction of H3K27 tri-methylation; ASXL1 loss collaborates with NRASG12D to promote myeloid leukemogenesis in vivo.","method":"Co-immunoprecipitation (Co-IP), ChIP-Seq, microarray, in vivo mouse leukemia model","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP demonstrating PRC2 association, ChIP-Seq genome-wide H3K27me3 profiling, and in vivo functional validation across multiple orthogonal methods","pmids":["22897849"],"is_preprint":false},{"year":2009,"finding":"ASXL1 represses RAR-mediated transcription by interacting with heterochromatin protein HP1 (via an HP1-binding PXVXL box in its N-terminus) and histone demethylase LSD1; HP1α facilitates formation of a ternary ASXL1-HP1-LSD1 complex that removes H3K4 methylation (active mark) at retinoic acid-responsive promoters.","method":"Transfection transcription assays, in vitro pull-down, Co-IP, HP1α knockdown, chromatin immunoprecipitation (ChIP)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (in vitro pull-down, Co-IP, ChIP, KD rescue) in a single focused study establishing the HP1/LSD1 mechanism","pmids":["19880879"],"is_preprint":false},{"year":2015,"finding":"ASXL1 is the obligate regulatory subunit of the BAP1 deubiquitinase complex; cancer-associated C-terminal truncations of ASXL1 confer enhanced (gain-of-function) deubiquitinase activity on the ASXL1-BAP1 complex, leading to global erasure of H2AK119Ub and depletion of H3K27me3, with downstream effects requiring BAP1 catalytic activity.","method":"Stable expression of truncated ASXL1-BAP1 in hematopoietic cell lines, global histone modification analysis, BAP1 catalytic mutant rescue, in vivo bone marrow experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — enzymatic activity assays with catalytic mutants, global histone profiling, and in vivo validation; replicated by multiple subsequent studies","pmids":["26095772"],"is_preprint":false},{"year":2016,"finding":"The BAP1 C-terminal extension auto-recruits BAP1 to nucleosomes independently of the nucleosome acidic patch, forming an unproductive encounter complex; activation requires DEUBAD domains of ASXL1/2/3, which increase BAP1 affinity for ubiquitin on H2AK119 to drive deubiquitination. The PR-DUB complex is specific for Polycomb H2AK119Ub and cannot deubiquitinate DNA damage-associated H2A K13/15Ub.","method":"Biochemical reconstitution, nucleosome binding assays, deubiquitinase activity assays, domain deletion mutants","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with domain mutants establishing mechanistic steps of BAP1 activation by ASXL1 DEUBAD domain","pmids":["26739236"],"is_preprint":false},{"year":2023,"finding":"Cryo-EM structure of human BAP1 and the ASXL1 DEUBAD domain in complex with an H2AK119Ub nucleosome reveals molecular interactions of BAP1 and ASXL1 with histones and DNA that restructure the nucleosome to establish specificity for H2AK119Ub; >50 cancer-associated mutations in BAP1 and ASXL1 were mechanistically explained by this structure.","method":"Cryo-EM structure determination, biochemical and cellular validation of interface mutants","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with biochemical and cellular validation of >50 cancer mutations providing direct structural mechanism","pmids":["37556531"],"is_preprint":false},{"year":2013,"finding":"C-terminal truncating Asxl1 mutations (ASXL1-MT) inhibit PRC2-mediated H3K27 methylation, causing derepression of Hoxa9 and miR-125a; miR-125a in turn reduces expression of Clec5a, thereby blocking myeloid differentiation and inducing MDS-like disease in mice.","method":"Retroviral expression of ASXL1-MT in mouse hematopoietic progenitors, transplantation model, gene expression analysis, ChIP for H3K27me3","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse model with mechanistic pathway dissection (PRC2→H3K27me3→HOXA9/miR-125a→CLEC5A) using multiple orthogonal approaches","pmids":["24216483"],"is_preprint":false},{"year":2018,"finding":"Mutant ASXL1 (ASXL1-MT) increases monoubiquitination of the truncated protein, which in turn enhances BAP1 catalytic function; the resulting hyperactive ASXL1-MT/BAP1 complex removes H2AK119 ubiquitination at posterior HOXA genes and IRF8 loci, upregulating their expression and promoting myeloid leukaemogenesis. BAP1 depletion inhibits posterior HOXA gene expression and leukaemogenicity.","method":"Co-immunoprecipitation, deubiquitinase activity assays, ChIP-seq for H2AK119Ub, bone marrow transplantation in vivo model, BAP1 shRNA knockdown","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical demonstration of enhanced ubiquitination of mutant ASXL1 and BAP1 activation, ChIP-seq, and in vivo rescue with BAP1 depletion","pmids":["30013160"],"is_preprint":false},{"year":2017,"finding":"A truncated ASXL1 protein (aa1-587) acquires a gain-of-function interaction with BRD4, demonstrated by liquid chromatography-tandem mass spectrometry and co-immunoprecipitation; expression of this truncation results in more open chromatin at critical HSC genes and hypersensitivity of cells to BET bromodomain inhibitors.","method":"LC-MS/MS, co-immunoprecipitation, ATAC-seq, RNA-seq, epigenetic drug screening in transgenic mouse model","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Moderate — MS-based interactome plus Co-IP plus functional genomics, all in the same study; novel gain-of-function interaction established","pmids":["29113963"],"is_preprint":false},{"year":2018,"finding":"ASXL1 forms a protein complex with HCFC1 and OGT; OGT directly stabilizes ASXL1 by O-GlcNAcylation. Disruption of this ASXL1-OGT axis inhibits myeloid differentiation and reduces H3K4 methylation and H2B glycosylation, with MLL5 identified as the H3K4 methyltransferase responsible for gene activation within this axis.","method":"Co-immunoprecipitation, mass spectrometry, O-GlcNAcylation assay, ChIP for H3K4me3, knockdown/rescue experiments in vivo and in vitro","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, MS identification of complex, direct PTM (O-GlcNAcylation) validated, ChIP-seq and in vivo rescue supporting functional consequence","pmids":["29556021"],"is_preprint":false},{"year":2021,"finding":"ASXL1-MT cooperates with BAP1 to deubiquitinate and activate AKT; overactive Akt/mTOR signaling leads to aberrant HSC proliferation, DNA damage accumulation, and clonal expansion. Treatment with the mTOR inhibitor rapamycin ameliorated aberrant HSC expansion and dysregulated hematopoiesis in ASXL1-MT knockin mice.","method":"Co-immunoprecipitation, AKT deubiquitination assay, knockin mouse model, rapamycin treatment rescue, competitive transplantation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct biochemical demonstration of AKT deubiquitination by ASXL1-MT/BAP1, in vivo rescue with mTOR inhibitor, replicated across multiple experimental approaches","pmids":["33758188"],"is_preprint":false},{"year":2015,"finding":"ASXL1 and BAP1 co-occupy the INK4B locus; ASXL1-mediated H2AK119Ub deubiquitination is specifically required for activation of p15(INK4B) expression in response to oncogenic signaling and anti-proliferative signals. ASXL1 mutations are associated with lower p15(INK4B) expression and proliferative advantage of hematopoietic progenitors.","method":"ChIP-seq showing ASXL1 and BAP1 enrichment at INK4B locus, deubiquitylation assay, ASXL1 KD in multiple cell lines, primary bone marrow analysis","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct occupancy, DUB activity assay, functional KD with defined molecular readout across multiple cell types","pmids":["26470845"],"is_preprint":false},{"year":2018,"finding":"Mutant ASXL1 (ASXL1G643fs) loses the ability to interact with BMI1 (a PRC1 subunit); this abolishes BMI1-driven H2AK119Ub1 at the p16Ink4a promoter, derepressing p16Ink4a and inducing cellular senescence in HSCs, causing low-risk MDS-like phenotypes. Heterozygous deletion of p16Ink4a restored the HSC pool.","method":"Co-immunoprecipitation (mutant vs. WT ASXL1 with BMI1), H2AK119Ub1 ChIP at p16Ink4a promoter, knockin mouse model, genetic rescue with p16Ink4a deletion","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP showing loss of BMI1 interaction, ChIP demonstrating reduced H2AK119Ub1 at p16Ink4a, and genetic rescue confirming the pathway","pmids":["29967380"],"is_preprint":false},{"year":2018,"finding":"Physiological expression of C-terminally truncated Asxl1 mutant in knockin mice causes substantial reductions in H3K4me3 and H2AK119Ub without significant reductions in H3K27me3; ChIP-seq shows opposing effects of wild-type vs. mutant Asxl1 on H3K4me3 at target loci. These histone changes are distinct from the effects of Asxl1 loss.","method":"Conditional knockin mouse model, ChIP-seq for H3K4me3, H2AK119Ub, H3K27me3; competitive transplantation; viral insertional mutagenesis","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq in knockin model distinguishing mutant from loss-of-function effects with multiple histone marks","pmids":["29643185"],"is_preprint":false},{"year":2021,"finding":"ASXL1 forms phase-separated droplets and upregulates NEAT1 expression through its C-terminal intrinsically disordered region (IDR), increasing NONO-NEAT1 interactions and paraspeckle formation in hematopoietic cells. A pathogenic ASXL1 mutant lacking the IDR does not support paraspeckle assembly, and disrupted paraspeckles impair HSC repopulating potential.","method":"Phase separation assays, Co-IP of ASXL1 with NONO and NEAT1, knockin mouse model with live imaging, NONO knockdown and cytoplasmic NONO forced-expression rescue","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — phase separation biochemistry, Co-IP, knockin mouse model, and rescue experiments; multiple orthogonal methods in a single study","pmids":["34433054"],"is_preprint":false},{"year":2018,"finding":"ASXL1 interacts with the core subunits of RNA polymerase II (RNAPII) complex in bone marrow stromal cells (BMSCs); loss of Asxl1 in BMSCs deregulates RNAPII transcriptional function and alters expression of genes critical for HSC maintenance (e.g., Vcam1), leading to altered HSC/HPC pool and myeloid differentiation bias.","method":"Co-immunoprecipitation, ChIP-seq for ASXL1 and RNAPII, RNA-seq, conditional Asxl1 deletion in BMSCs","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with RNAPII, ChIP-seq and RNA-seq convergent analysis, and in vivo conditional KO","pmids":["29423272"],"is_preprint":false},{"year":2021,"finding":"Cancer-associated frameshift mutations in ASXL1 encode stable truncated gain-of-function proteins (not destabilizing loss-of-function). Truncated ASXL1 increases BAP1 protein stability, enhances BAP1 recruitment to chromatin, and promotes expression of a pro-leukemic transcriptional signature; BAP1 catalytic inhibitors impair truncated-ASXL1-driven leukemic gene expression and tumor progression in vivo.","method":"Biochemical protein stability assays, ChIP for BAP1 chromatin recruitment, RNA-seq transcriptome analysis, BAP1 inhibitor screen, in vivo xenograft tumor progression model","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (stability assays, ChIP, RNA-seq, in vivo inhibitor treatment) establishing gain-of-function mechanism of truncated ASXL1","pmids":["35122023"],"is_preprint":false},{"year":2020,"finding":"Wild-type ASXL1 interacts with FOXK1 and FOXK2 transcription factors to regulate a subset of their target genes. C-terminally truncated mutant ASXL1 is expressed at higher levels than wild-type but loses the ability to interact with FOXK1/K2; deletion of the mutant allele increased wild-type ASXL1 association with BAP1 and restored BAP1-ASXL1-FOXK1/K2 target gene expression (glucose metabolism, oxygen sensing, JAK-STAT3 signaling).","method":"Co-immunoprecipitation, CRISPR deletion of mutant allele, RNA-seq, allele-specific protein expression analysis","journal":"Protein & cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating FOXK1/K2 interaction, CRISPR allele deletion with functional rescue, RNA-seq; multiple orthogonal methods","pmids":["32683582"],"is_preprint":false},{"year":2020,"finding":"PR-DUB (BAP1-ASXL1 complex) requires ASXL proteins and FOXK1/2 for BAP1-dependent gene activation; by counteracting accumulation of H2AK119Ub1 across the genome, PR-DUB maintains chromatin in an optimal configuration for expression of genes important for cell metabolism and homeostasis. Minimal functional interaction with PRC2 was found in embryonic stem cells.","method":"ChIP-seq for BAP1, ASXL proteins, H2AK119Ub1; ASXL and FOXK1/2 depletion; comparative analysis with EZH2/PRC2 targets","journal":"Genome research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq with genetic depletion of complex components establishing mechanistic roles in gene activation","pmids":["32747411"],"is_preprint":false},{"year":2013,"finding":"Constitutive loss of Asxl1 results in global reduction of H3K27 trimethylation and dysregulated expression of known hematopoietic regulators. Concomitant deletion of Tet2 restores HSC self-renewal reduced by Asxl1 loss (genetic epistasis), and compound Asxl1/Tet2 deletion accelerates MDS with hastened death.","method":"Conditional/constitutive Asxl1 knockout mice, hematopoietic-specific deletion, RNA-seq, ChIP-seq, serial transplantation, Tet2 double KO epistasis","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq for H3K27me3, RNA-seq, genetic epistasis with Tet2, serial transplantation; replicated in multiple mouse models","pmids":["24218140"],"is_preprint":false},{"year":2017,"finding":"Asxl1 deficiency in mouse embryonic fibroblasts (MEFs) impairs AKT1 activation: ASXL1 (aa 371-655) interacts with the kinase domain of AKT1, and p27Kip1 forms a ternary complex with ASXL1 and AKT1. Loss of Asxl1 prevents IGF-1-induced AKT1 phosphorylation, leaving p27Kip1 unphosphorylated and nuclear, inhibiting E2F target genes and promoting senescence. Asxl1 also cooperates directly with Ezh2.","method":"Co-immunoprecipitation, domain mapping, MEF knockout model, IGF-1 stimulation assay, AKT inhibitor, microarray, SA-β-gal senescence staining","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, functional readouts (AKT phosphorylation, p27 localization, E2F targets), single lab","pmids":["28701722"],"is_preprint":false},{"year":2015,"finding":"Truncated ASXL1 proteins from C-terminal truncating mutations are detectable by mass spectrometry and Western blot in cell lines bearing homozygous ASXL1 mutations, demonstrating that the truncated protein is expressed and not subject to NMD; this establishes the foundation for dominant-negative or gain-of-function mechanisms.","method":"Mass spectrometry (LC-MS/MS), Western blot analysis in homozygous mutant cell lines","journal":"Experimental hematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — orthogonal methods (MS + WB) in homozygous mutant cells; single lab but direct protein detection","pmids":["26700326"],"is_preprint":false},{"year":2021,"finding":"Truncated ASXL1 leads to global redistribution (not simply loss) of the repressive chromatin mark H2AK119Ub, increases transposase-accessible chromatin, and activates both myeloid and stem cell gene-expression programs in primary human HSPCs; H2AK119Ub levels are tied to truncated ASXL1 expression levels, and PRC1 inhibition is identified as a potential ASXL1-mutant-specific therapeutic vulnerability.","method":"CRISPR-engineered primary human HSPC model, ATAC-seq, RNA-seq, ChIP/CUT&RUN for H2AK119Ub, xenotransplantation model","journal":"Blood cancer discovery","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genome-wide chromatin and transcriptome profiling with primary human cells and in vivo xenotransplantation; multiple orthogonal methods","pmids":["38359087"],"is_preprint":false},{"year":2013,"finding":"Loss of ASXL1 in human CD34+ progenitors impairs granulomonocytic differentiation (decreased CD11b+ and CD15+ cells, decreased CFU-GM and CFU-G, increased CFU-GEMM colonies); the most deregulated pathway is LXR/RXR activation and PRC2 target genes are over-represented among deregulated genes in ASXL1-deficient cells.","method":"Lentiviral shRNA knockdown of ASXL1 in human CD34+ cells, colony-forming assays, flow cytometry, gene expression profiling","journal":"British journal of haematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined differentiation phenotype and pathway analysis; single lab but multiple readouts","pmids":["23294243"],"is_preprint":false},{"year":2018,"finding":"Loss of ASXL1 in osteoclasts results in concordant loss of inhibitory H3K27me3 with gain of H3K4me3 at NFATc1 and itgb3 promoters, inducing a 40-fold increase in the H3K27 demethylase Jmjd3; increased NFATc1 then binds the Blimp1 promoter, enhancing expression of this pro-osteoclastogenic gene and driving excess bone resorption.","method":"Conditional Asxl1 deletion in myeloid cells, ChIP for H3K27me3/H3K4me3, Jmjd3 knockdown rescue, NFATc1 ChIP at Blimp1 promoter","journal":"Blood advances","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating histone mark changes at specific loci, Jmjd3 KD rescue, and NFATc1 ChIP; multiple orthogonal methods establishing mechanism","pmids":["30266822"],"is_preprint":false},{"year":2013,"finding":"Asxl1 loss in mice leads to decreased global H3K27me3 and H3K4me3, increased apoptosis and mitosis in Lin-cKit+ cells, and altered expression of apoptosis regulators (Bcl2, Bcl2l12, Bcl2l13), resulting in MDS-like disease.","method":"Constitutional Asxl1 knockout mice, flow cytometry, global histone modification analysis, gene expression profiling","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with quantified global histone modifications and defined molecular targets; single lab","pmids":["24255920"],"is_preprint":false},{"year":2024,"finding":"Mutant ASXL1 proteins interact with the EHMT1-EHMT2 complex (generating H3K9me1/me2); in aged ASXL1-mutant knockin mice, myeloid cells show genome-wide decreases of H3K9me2, H3K9me3, and H2AK119Ub, with increased expression of transposable elements and satellite repeats, and upregulation of nearby interferon-inducible genes.","method":"Co-immunoprecipitation of mutant ASXL1 with EHMT1/2, ChIP-seq for H3K9me2/3 and H2AK119Ub, knockin mouse model, transposable element expression profiling in CMML patient monocytes","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing new EHMT1/2 interaction, genome-wide ChIP-seq in knockin model, and validation in human patient samples; multiple orthogonal methods","pmids":["39752521"],"is_preprint":false},{"year":2021,"finding":"Oncogenic ASXL1 truncation mutations expose a motif near the truncation breakpoint that binds the BRD4 ET domain; the prevalent ASXL1Y591X truncation markedly increases BRD4-ASXL1 binding compared to full-length ASXL1 or truncations that delete this epitope. All three ASXL orthologs contain a functional BRD4 ET-domain binding epitope.","method":"In vitro binding studies (pull-down/affinity), peptide competition, isothermal calorimetry/NMR-type binding measurements for ET-domain interaction","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — direct in vitro binding assays with domain mutants and multiple ASXL1 truncation variants; single lab with quantitative binding data","pmids":["34536441"],"is_preprint":false},{"year":2018,"finding":"ASXL1 and SETBP1 mutations cooperate to repress TGFβ pathway genes through aberrantly reduced acetylation of histone H3 and H4 lysine residues at their promoters; HDAC inhibitor vorinostat reverses this histone hypoacetylation and transcriptionally derepresses TGFβ pathway genes, selectively inhibiting growth of ASXL1-mutant cells.","method":"ChIP for histone acetylation marks at TGFβ pathway gene promoters, constitutively active ALK5-TD rescue, vorinostat treatment, co-expression mouse bone marrow transplant model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating specific histone acetylation changes, pharmacological rescue and ALK5 genetic rescue; single lab","pmids":["30367089"],"is_preprint":false},{"year":2013,"finding":"ASXL1 represses LXRα-mediated transcriptional activity through direct interaction and ligand-dependent recruitment to ABCA1 promoters; ASXL1 knockdown increases lipid accumulation in hepatic cells and ASXL1 expression changes under fasting/insulin conditions, implicating it in lipid homeostasis.","method":"Co-immunoprecipitation, ChIP at ABCA1 promoter, luciferase transcription assays, ASXL1 knockdown with lipid accumulation assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, and functional KD; single lab with multiple complementary methods","pmids":["24321552"],"is_preprint":false},{"year":2020,"finding":"ASXL1 is specifically required for H2AK119 deubiquitylation at the Pten promoter, activating PTEN transcription and thereby suppressing PI3K/AKT signaling; Asxl1 depletion in murine 32D cells confers IL3-independent growth due to sustained AKT activation, and ASXL1 mutations associate with lower PTEN expression in human myeloid malignancies.","method":"ChIP for ASXL1 and H2AK119Ub at Pten promoter, Asxl1 depletion IL3-independence assay, correlation analysis in patient data, AKT inhibitor sensitivity assay","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishing direct occupancy and DUB activity at PTEN locus, functional KD phenotype, single lab","pmids":["32236560"],"is_preprint":false},{"year":2015,"finding":"ASXL1 interacts with Wilms tumor 1-interacting protein (WTIP) through its PHD domain; loss of Asxl1 in mice causes defects in kidney size and glomerular podocyte morphology, with up-regulation of Wt1/Wtip target genes, implicating ASXL1 in WT1 signaling during kidney development.","method":"Co-immunoprecipitation (Asxl1-Wtip), Asxl1-null mouse embryo kidney morphology analysis, gene expression analysis of Wt1/Wtip targets","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP establishing binding partner, KO mouse phenotype with gene expression changes; single lab","pmids":["26385183"],"is_preprint":false},{"year":2018,"finding":"ASXL1 represses Nmyc expression in lung epithelial cells by recruiting HCF-1 and E2F1 to the Nmyc promoter; the interaction is between the C-terminal region of Asxl1 and the N-terminal Kelch domain of HCF-1. This is associated with enrichment of H3K27me3 and H3K9me3 at the Nmyc promoter, and Asxl1 ablation causes lung hyperplasia.","method":"Asxl1-null mouse lung model, HCF-1 purification/Co-IP, ChIP for H3K27me3 and H3K9me3 at Nmyc promoter, domain mapping","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — protein interaction established by Co-IP with domain mapping, ChIP at specific locus, and KO phenotype; single lab","pmids":["30389914"],"is_preprint":false},{"year":2024,"finding":"Upregulation of KDM6B (a H3K27me3 demethylase) occurs in ASXL1-mutant leukemic cells and further reduces H3K27me3; heterozygous deletion of Kdm6b restored H3K27me3 levels, normalized dysregulated gene expression, decreased the HSPC pool, restored self-renewal, and abrogated myeloid malignancy progression in Asxl1Y588XTg mice. KDM6B inhibitor GSK-J4 restored H3K27me3 and reduced disease burden in xenograft models.","method":"Genetic Kdm6b deletion in Asxl1 transgenic mice, ChIP for H3K27me3, RNA-seq, NSG xenograft with KDM6B inhibitor treatment","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (Kdm6b deletion rescuing Asxl1 mutant phenotype), ChIP-seq, RNA-seq, and pharmacological validation in vivo; multiple orthogonal methods","pmids":["37917239"],"is_preprint":false},{"year":2006,"finding":"Murine Asxl1 contains an ASX homology domain (ASXH) with two nuclear receptor (NR) co-regulator binding motifs (LXXLL-like), a conserved C-terminal PHD domain, and three additional NR co-regulator binding motifs not present in Drosophila Asx; Asxl1 is expressed as multiple transcripts in adult tissues and in 10.5-11.0 dpc mouse embryos.","method":"Sequence analysis, Northern blot, whole-mount RNA in situ hybridization","journal":"Gene","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — characterization of domain structure and expression pattern by Northern/ISH; no direct functional experiments","pmids":["16412590"],"is_preprint":false}],"current_model":"ASXL1 is an epigenetic scaffold protein that functions as the obligate regulatory subunit of the BAP1 deubiquitinase complex (PR-DUB), activating BAP1 via its DEUBAD domain to deubiquitinate H2AK119Ub at Polycomb target loci; it also associates with PRC2 to maintain H3K27me3 at repressed loci including posterior HOXA genes, interacts with HP1α and LSD1 to repress RAR-target genes, binds FOXK1/K2 and RNA Pol II to activate target genes, and is stabilized by OGT-mediated O-GlcNAcylation within an ASXL1-HCFC1-OGT complex that promotes H3K4 methylation; cancer-associated C-terminal truncating mutations generate stable gain-of-function proteins that hyperactivate BAP1 (erasing H2AK119Ub and depleting H3K27me3), acquire novel interactions with BRD4 and EHMT1/2, activate AKT/mTOR signaling, and disrupt paraspeckle assembly, collectively driving myeloid malignancy through aberrant epigenomic reprogramming."},"narrative":{"mechanistic_narrative":"ASXL1 is a chromatin-associated scaffold that controls the deposition and erasure of Polycomb histone marks to govern hematopoietic stem cell self-renewal and myeloid differentiation [PMID:22897849, PMID:24218140]. Its central biochemical function is as the obligate regulatory subunit of the BAP1 deubiquitinase complex (PR-DUB): the ASXL1 DEUBAD domain increases BAP1 affinity for H2AK119-ubiquitinated nucleosomes, restructuring the nucleosome to confer specificity for Polycomb H2AK119Ub while excluding DNA-damage-associated H2A ubiquitylation [PMID:26739236, PMID:37556531]. Through this activity, together with FOXK1/FOXK2 transcription factors, PR-DUB counteracts genome-wide H2AK119Ub accumulation to maintain chromatin permissive for expression of metabolic and homeostatic genes including p15(INK4B) and PTEN [PMID:26470845, PMID:32683582, PMID:32747411, PMID:32236560]. ASXL1 additionally associates with PRC2, and its loss reduces global H3K27me3 and dysregulates hematopoietic regulators, a phenotype genetically epistatic with Tet2 [PMID:22897849, PMID:24218140]. It is stabilized by OGT-mediated O-GlcNAcylation within an ASXL1-HCFC1-OGT complex that supports H3K4 methylation via MLL5 [PMID:29556021]. Cancer-associated C-terminal truncating mutations produce stable gain-of-function proteins, not loss-of-function products, that escape nonsense-mediated decay [PMID:26700326, PMID:35122023]; the truncated protein becomes monoubiquitinated and hyperactivates BAP1, erasing H2AK119Ub at posterior HOXA and IRF8 loci and redistributing this mark genome-wide to activate stem and myeloid gene programs [PMID:30013160, PMID:38359087, PMID:35122023]. Truncated ASXL1 also acquires neomorphic interactions with the BRD4 ET domain and the EHMT1/EHMT2 complex, and drives AKT/mTOR activation through BAP1-dependent AKT deubiquitination, collectively reprogramming the epigenome to cause myelodysplasia and myeloid leukemia [PMID:29113963, PMID:34536441, PMID:39752521, PMID:33758188].","teleology":[{"year":2006,"claim":"Established the domain architecture of mammalian ASXL1, defining the modules later shown to mediate its chromatin and nuclear-receptor functions.","evidence":"Sequence analysis, Northern blot, and whole-mount in situ hybridization of murine Asxl1","pmids":["16412590"],"confidence":"Low","gaps":["No direct functional assay of any domain","Does not assign biochemical activity to the ASXH or PHD domains"]},{"year":2009,"claim":"First defined ASXL1 as a transcriptional repressor recruiting chromatin modifiers, showing it bridges HP1 and the demethylase LSD1 to strip active H3K4 marks at RAR-responsive promoters.","evidence":"In vitro pull-down, Co-IP, ChIP, and HP1α knockdown in transfected cells","pmids":["19880879"],"confidence":"High","gaps":["Restricted to RAR target loci","Genome-wide scope of the HP1/LSD1 complex not defined"]},{"year":2012,"claim":"Linked ASXL1 to Polycomb repression by showing it associates with PRC2 and is required for global H3K27me3, and that its loss cooperates with NRAS to drive leukemia.","evidence":"Reciprocal Co-IP, ChIP-seq for H3K27me3, and in vivo mouse leukemia model","pmids":["22897849"],"confidence":"High","gaps":["Did not resolve direct vs. indirect PRC2 association","Mechanism connecting H3K27me3 loss to leukemogenesis not yet defined"]},{"year":2013,"claim":"Connected ASXL1 mutation and loss to specific differentiation defects and disease pathways, including PRC2-target derepression, HOXA9/miR-125a/CLEC5A axis, apoptosis regulators, and Tet2 epistasis.","evidence":"Constitutive/conditional Asxl1 knockout mice, retroviral mutant expression, human CD34+ knockdown, ChIP, RNA-seq, and Tet2 double-KO epistasis","pmids":["24216483","24218140","24255920","23294243"],"confidence":"High","gaps":["Mutant gain-of-function vs. loss-of-function not yet biochemically distinguished","Direct enzymatic mechanism of mutant ASXL1 unresolved"]},{"year":2015,"claim":"Identified ASXL1 as the obligate regulatory subunit of the BAP1 deubiquitinase and showed truncating mutations confer gain-of-function H2AK119Ub-erasing activity; established truncated protein is expressed and escapes NMD.","evidence":"Stable truncated ASXL1-BAP1 expression, catalytic-mutant rescue, global histone profiling, ChIP at INK4B, mass spectrometry/Western detection in homozygous mutant lines","pmids":["26095772","26470845","26700326"],"confidence":"High","gaps":["Structural basis of activation not yet resolved","How truncation enhances catalysis biochemically unclear"]},{"year":2016,"claim":"Defined the mechanistic steps of BAP1 activation, showing the BAP1 C-terminal extension forms an unproductive nucleosome encounter complex that the ASXL DEUBAD domain converts into a ubiquitin-engaging, H2AK119Ub-specific deubiquitinase.","evidence":"Biochemical reconstitution, nucleosome binding and deubiquitinase assays with domain-deletion mutants","pmids":["26739236"],"confidence":"High","gaps":["Did not provide atomic structure of the nucleosome-bound complex","Did not explain individual cancer mutations"]},{"year":2017,"claim":"Revealed neomorphic functions of truncated ASXL1: a gain-of-function BRD4 interaction opening chromatin at HSC genes, and an AKT1-binding role for the central region linking ASXL1 to senescence control.","evidence":"LC-MS/MS, Co-IP, ATAC-seq, BET-inhibitor screening in transgenic mice; domain mapping and IGF-1 stimulation in Asxl1-null MEFs","pmids":["29113963","28701722"],"confidence":"High","gaps":["MEF AKT1 study Medium-confidence and single-lab","Direct BRD4 binding interface not yet mapped"]},{"year":2018,"claim":"Expanded the functional repertoire of ASXL1 across complexes and tissues: OGT/HCFC1 stabilization, RNAPII association, BMI1/PRC1 interaction at p16, HCF-1/E2F1 recruitment, SETBP1 cooperation, and mutant-specific enhanced ubiquitination driving BAP1 hyperactivity; knockin mice distinguished mutant from loss-of-function chromatin effects.","evidence":"Co-IP, mass spectrometry, O-GlcNAcylation assays, ChIP-seq for multiple histone marks, conditional KO and knockin mouse models","pmids":["30013160","29556021","29423272","29967380","29643185","30389914","30367089","30266822"],"confidence":"High","gaps":["Relative contributions of these partner complexes to leukemogenesis not ranked","Several interactions documented in single tissue contexts"]},{"year":2020,"claim":"Established PR-DUB as a gene-activating complex requiring ASXL and FOXK1/2 to counteract genome-wide H2AK119Ub, and showed truncated ASXL1 loses FOXK1/2 binding while sequestering BAP1; defined PTEN as a direct deubiquitylation target.","evidence":"ChIP-seq for BAP1/ASXL/H2AK119Ub with component depletion, Co-IP, CRISPR mutant-allele deletion, ChIP at Pten promoter, AKT-inhibitor sensitivity assays","pmids":["32747411","32683582","32236560"],"confidence":"High","gaps":["PTEN axis study Medium-confidence and single-lab","Balance between gene-activating and gene-repressing roles of PR-DUB context-dependent"]},{"year":2021,"claim":"Demonstrated truncated ASXL1 is a stabilizing gain-of-function protein driving leukemia through enhanced BAP1 chromatin recruitment, AKT/mTOR activation, H2AK119Ub redistribution, and paraspeckle assembly via its intrinsically disordered region.","evidence":"Protein stability assays, ChIP, RNA-seq, BAP1 inhibitor screen, AKT deubiquitination and knockin/rapamycin rescue, phase-separation assays with NONO/NEAT1, CRISPR primary human HSPC model","pmids":["35122023","33758188","34433054","38359087","34536441"],"confidence":"High","gaps":["Therapeutic vulnerabilities (BAP1, PRC1, mTOR inhibitors) tested largely in models","Whether paraspeckle and PR-DUB functions are mechanistically coupled unclear"]},{"year":2023,"claim":"Provided the atomic mechanism of substrate specificity by solving the cryo-EM structure of BAP1–ASXL1 DEUBAD on an H2AK119Ub nucleosome and rationalizing >50 cancer mutations.","evidence":"Cryo-EM structure determination with biochemical and cellular validation of interface mutants","pmids":["37556531"],"confidence":"High","gaps":["Structure of the truncated gain-of-function complex not determined","Does not capture full-length ASXL1 or neomorphic partner-bound states"]},{"year":2024,"claim":"Identified mutant-specific epigenetic vulnerabilities, showing truncated ASXL1 recruits EHMT1/2 with genome-wide loss of repressive marks and repeat derepression, and that KDM6B upregulation drives H3K27me3 loss that genetic or pharmacologic KDM6B inhibition reverses.","evidence":"Co-IP, ChIP-seq for H3K9/H2AK119Ub marks, knockin mouse models, Kdm6b genetic epistasis, and GSK-J4 treatment in xenografts; CMML patient sample validation","pmids":["39752521","37917239"],"confidence":"High","gaps":["Clinical translatability of KDM6B/EHMT-targeting not established","Interplay between EHMT-mediated H3K9 loss and BAP1-mediated H2AK119Ub loss not integrated"]},{"year":null,"claim":"How the diverse ASXL1 partner complexes (PR-DUB, PRC2, OGT/HCFC1, RNAPII, FOXK1/2, neomorphic BRD4/EHMT1-2) are coordinated in space and time within normal versus mutant hematopoiesis remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No integrated model of partner-complex switching","Structural basis of mutant gain-of-function interactions undetermined","Determinants directing PR-DUB to activate vs. repress specific loci unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,3,4,6,9,10,29]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,16,17,28,31]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,8,14,16]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,3,4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,14,33]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,2,6,18]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[13]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,2,3,6,18,21]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[14,16,17,28,31]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,5,6,15,25,32]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,29]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[22,23,30,31]}],"complexes":["PR-DUB (BAP1-ASXL1 deubiquitinase complex)","PRC2","ASXL1-HCFC1-OGT complex","ASXL1-HP1-LSD1 complex"],"partners":["BAP1","FOXK1","FOXK2","OGT","HCFC1","BMI1","BRD4","EHMT2"],"other_free_text":[]}},"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 mutations promote myeloid transformation through loss of PRC2-mediated gene repression.","date":"2012","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/22897849","citation_count":505,"is_preprint":false},{"pmid":"19388938","id":"PMC_19388938","title":"Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia.","date":"2009","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/19388938","citation_count":480,"is_preprint":false},{"pmid":"20428194","id":"PMC_20428194","title":"Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1.","date":"2010","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/20428194","citation_count":419,"is_preprint":false},{"pmid":"24218140","id":"PMC_24218140","title":"Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo.","date":"2013","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24218140","citation_count":285,"is_preprint":false},{"pmid":"26095772","id":"PMC_26095772","title":"Cancer-associated ASXL1 mutations may act as gain-of-function mutations of the ASXL1-BAP1 complex.","date":"2015","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/26095772","citation_count":173,"is_preprint":false},{"pmid":"26739236","id":"PMC_26739236","title":"BAP1/ASXL1 recruitment and activation for H2A deubiquitination.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/26739236","citation_count":169,"is_preprint":false},{"pmid":"24255920","id":"PMC_24255920","title":"Loss of Asxl1 leads to myelodysplastic syndrome-like disease in mice.","date":"2013","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/24255920","citation_count":156,"is_preprint":false},{"pmid":"23628959","id":"PMC_23628959","title":"SETBP1 mutations occur in 9% of MDS/MPN and in 4% of MPN cases and are strongly associated with atypical CML, monosomy 7, isochromosome i(17)(q10), ASXL1 and CBL mutations.","date":"2013","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/23628959","citation_count":150,"is_preprint":false},{"pmid":"32518416","id":"PMC_32518416","title":"Clonal myelopoiesis in the UK Biobank cohort: ASXL1 mutations are strongly associated with smoking.","date":"2020","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/32518416","citation_count":149,"is_preprint":false},{"pmid":"24216483","id":"PMC_24216483","title":"Myelodysplastic syndromes are induced by histone methylation–altering ASXL1 mutations.","date":"2013","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/24216483","citation_count":148,"is_preprint":false},{"pmid":"29113963","id":"PMC_29113963","title":"Gain of function of ASXL1 truncating protein in the pathogenesis of myeloid malignancies.","date":"2017","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/29113963","citation_count":143,"is_preprint":false},{"pmid":"20678218","id":"PMC_20678218","title":"Combined mutations of ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 and WT1 genes in myelodysplastic syndromes and acute myeloid leukemias.","date":"2010","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20678218","citation_count":134,"is_preprint":false},{"pmid":"29643185","id":"PMC_29643185","title":"Expression of mutant Asxl1 perturbs hematopoiesis and promotes susceptibility to leukemic transformation.","date":"2018","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29643185","citation_count":130,"is_preprint":false},{"pmid":"21346257","id":"PMC_21346257","title":"CBL, CBLB, TET2, ASXL1, and IDH1/2 mutations and additional chromosomal aberrations constitute molecular events in chronic myelogenous leukemia.","date":"2011","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/21346257","citation_count":128,"is_preprint":false},{"pmid":"22489043","id":"PMC_22489043","title":"Mutation analysis of ASXL1, CBL, DNMT3A, IDH1, IDH2, JAK2, MPL, NF1, SF3B1, SUZ12, and TET2 in myeloproliferative neoplasms.","date":"2012","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/22489043","citation_count":125,"is_preprint":false},{"pmid":"30013160","id":"PMC_30013160","title":"Mutant ASXL1 cooperates with BAP1 to promote myeloid leukaemogenesis.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30013160","citation_count":111,"is_preprint":false},{"pmid":"30927018","id":"PMC_30927018","title":"The role of ASXL1 in hematopoiesis and myeloid malignancies.","date":"2019","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/30927018","citation_count":105,"is_preprint":false},{"pmid":"22905207","id":"PMC_22905207","title":"Single nucleotide polymorphism array lesions, TET2, DNMT3A, ASXL1 and CBL mutations are present in systemic mastocytosis.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22905207","citation_count":98,"is_preprint":false},{"pmid":"33758188","id":"PMC_33758188","title":"Mutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33758188","citation_count":87,"is_preprint":false},{"pmid":"24442206","id":"PMC_24442206","title":"Dynamics of ASXL1 mutation and other associated genetic alterations during disease progression in patients with primary myelodysplastic syndrome.","date":"2014","source":"Blood cancer journal","url":"https://pubmed.ncbi.nlm.nih.gov/24442206","citation_count":83,"is_preprint":false},{"pmid":"25306901","id":"PMC_25306901","title":"SETBP1 mutations drive leukemic transformation in ASXL1-mutated MDS.","date":"2014","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/25306901","citation_count":79,"is_preprint":false},{"pmid":"16412590","id":"PMC_16412590","title":"Characterization of Asxl1, a murine homolog of Additional sex combs, and analysis of the Asx-like gene family.","date":"2006","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/16412590","citation_count":79,"is_preprint":false},{"pmid":"19880879","id":"PMC_19880879","title":"ASXL1 represses retinoic acid receptor-mediated transcription through associating with HP1 and LSD1.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19880879","citation_count":77,"is_preprint":false},{"pmid":"20410925","id":"PMC_20410925","title":"High-density single nucleotide polymorphism array analysis and ASXL1 gene mutation screening in chronic myeloid leukemia during disease progression.","date":"2010","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/20410925","citation_count":71,"is_preprint":false},{"pmid":"35122023","id":"PMC_35122023","title":"Epigenetic targeted therapy of stabilized BAP1 in ASXL1 gain-of-function mutated leukemia.","date":"2021","source":"Nature cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35122023","citation_count":70,"is_preprint":false},{"pmid":"23365461","id":"PMC_23365461","title":"Cooperating gene mutations in childhood acute myeloid leukemia with special reference on mutations of ASXL1, TET2, IDH1, IDH2, and DNMT3A.","date":"2013","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/23365461","citation_count":69,"is_preprint":false},{"pmid":"21712540","id":"PMC_21712540","title":"Disruption of the ASXL1 gene is frequent in primary, post-essential thrombocytosis and post-polycythemia vera myelofibrosis, but not essential thrombocytosis or polycythemia vera: analysis of molecular genetics and clinical phenotypes.","date":"2011","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/21712540","citation_count":69,"is_preprint":false},{"pmid":"31372051","id":"PMC_31372051","title":"Circ-ITGA7 sponges miR-3187-3p to upregulate ASXL1, suppressing colorectal cancer proliferation.","date":"2019","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/31372051","citation_count":63,"is_preprint":false},{"pmid":"26700326","id":"PMC_26700326","title":"Truncation mutants of ASXL1 observed in myeloid malignancies are expressed at detectable protein levels.","date":"2015","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/26700326","citation_count":61,"is_preprint":false},{"pmid":"29556021","id":"PMC_29556021","title":"A novel ASXL1-OGT axis plays roles in H3K4 methylation and tumor suppression in myeloid malignancies.","date":"2018","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/29556021","citation_count":60,"is_preprint":false},{"pmid":"34548471","id":"PMC_34548471","title":"ASXL1 mutations are associated with distinct epigenomic alterations that lead to sensitivity to venetoclax and azacytidine.","date":"2021","source":"Blood cancer journal","url":"https://pubmed.ncbi.nlm.nih.gov/34548471","citation_count":58,"is_preprint":false},{"pmid":"25921057","id":"PMC_25921057","title":"Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.","date":"2015","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/25921057","citation_count":57,"is_preprint":false},{"pmid":"26623729","id":"PMC_26623729","title":"ASXL1 mutation correction by CRISPR/Cas9 restores gene function in leukemia cells and increases survival in mouse xenografts.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26623729","citation_count":55,"is_preprint":false},{"pmid":"32747411","id":"PMC_32747411","title":"PR-DUB maintains the expression of critical genes through FOXK1/2- and ASXL1/2/3-dependent recruitment to chromatin and H2AK119ub1 deubiquitination.","date":"2020","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/32747411","citation_count":54,"is_preprint":false},{"pmid":"31945396","id":"PMC_31945396","title":"ASXL1 mutation in clonal hematopoiesis.","date":"2020","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/31945396","citation_count":53,"is_preprint":false},{"pmid":"25835095","id":"PMC_25835095","title":"Functional proteomics of the epigenetic regulators ASXL1, ASXL2 and ASXL3: a convergence of proteomics and epigenetics for translational medicine.","date":"2015","source":"Expert review of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/25835095","citation_count":52,"is_preprint":false},{"pmid":"35902731","id":"PMC_35902731","title":"ASXL1 mutations predict inferior molecular response to nilotinib treatment in chronic myeloid leukemia.","date":"2022","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/35902731","citation_count":49,"is_preprint":false},{"pmid":"34699595","id":"PMC_34699595","title":"Asxl1 loss cooperates with oncogenic Nras in mice to reprogram the immune microenvironment and drive leukemic transformation.","date":"2022","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/34699595","citation_count":48,"is_preprint":false},{"pmid":"26508027","id":"PMC_26508027","title":"Genetic landscape of recurrent ASXL1, U2AF1, SF3B1, SRSF2, and EZH2 mutations in 304 Chinese patients with myelodysplastic syndromes.","date":"2015","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26508027","citation_count":46,"is_preprint":false},{"pmid":"28697759","id":"PMC_28697759","title":"The distinct biological implications of Asxl1 mutation and its roles in leukemogenesis revealed by a knock-in mouse model.","date":"2017","source":"Journal of hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28697759","citation_count":45,"is_preprint":false},{"pmid":"34529785","id":"PMC_34529785","title":"ASXL1 and STAG2 are common mutations in GATA2 deficiency patients with bone marrow disease and myelodysplastic syndrome.","date":"2022","source":"Blood advances","url":"https://pubmed.ncbi.nlm.nih.gov/34529785","citation_count":44,"is_preprint":false},{"pmid":"36068610","id":"PMC_36068610","title":"ASXL1/2 mutations and myeloid malignancies.","date":"2022","source":"Journal of hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36068610","citation_count":42,"is_preprint":false},{"pmid":"29967380","id":"PMC_29967380","title":"Modeling ASXL1 mutation revealed impaired hematopoiesis caused by derepression of p16Ink4a through aberrant PRC1-mediated histone modification.","date":"2018","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/29967380","citation_count":42,"is_preprint":false},{"pmid":"37556531","id":"PMC_37556531","title":"Structural basis of histone H2A lysine 119 deubiquitination by Polycomb repressive deubiquitinase BAP1/ASXL1.","date":"2023","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/37556531","citation_count":41,"is_preprint":false},{"pmid":"21904853","id":"PMC_21904853","title":"TET2, ASXL1, IDH1, IDH2, and c-CBL genes in JAK2- and MPL-negative myeloproliferative neoplasms.","date":"2011","source":"Annals of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/21904853","citation_count":41,"is_preprint":false},{"pmid":"27352931","id":"PMC_27352931","title":"ASXL1 plays an important role in erythropoiesis.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27352931","citation_count":41,"is_preprint":false},{"pmid":"26470845","id":"PMC_26470845","title":"Tumor suppressor ASXL1 is essential for the activation of INK4B expression in response to oncogene activity and anti-proliferative signals.","date":"2015","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/26470845","citation_count":41,"is_preprint":false},{"pmid":"38598228","id":"PMC_38598228","title":"Atrial Fibrillation and Clonal Hematopoiesis in TET2 and ASXL1.","date":"2024","source":"JAMA cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/38598228","citation_count":39,"is_preprint":false},{"pmid":"23099237","id":"PMC_23099237","title":"TET2, ASXL1 and EZH2 mutations in Chinese with myelodysplastic syndromes.","date":"2012","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/23099237","citation_count":38,"is_preprint":false},{"pmid":"35133065","id":"PMC_35133065","title":"CHIP-associated mutant ASXL1 in blood cells promotes solid tumor progression.","date":"2022","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/35133065","citation_count":34,"is_preprint":false},{"pmid":"31640815","id":"PMC_31640815","title":"RUNX1 mutations promote leukemogenesis of myeloid malignancies in ASXL1-mutated leukemia.","date":"2019","source":"Journal of hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31640815","citation_count":34,"is_preprint":false},{"pmid":"26019984","id":"PMC_26019984","title":"Impact of TET2, SRSF2, ASXL1 and SETBP1 mutations on survival of patients with chronic myelomonocytic leukemia.","date":"2015","source":"Experimental hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/26019984","citation_count":33,"is_preprint":false},{"pmid":"28667884","id":"PMC_28667884","title":"Exome sequencing reveals DNMT3A and ASXL1 variants associate with progression of chronic myeloid leukemia after tyrosine kinase inhibitor therapy.","date":"2017","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/28667884","citation_count":32,"is_preprint":false},{"pmid":"30367089","id":"PMC_30367089","title":"ASXL1 and SETBP1 mutations promote leukaemogenesis by repressing TGFβ pathway genes through histone deacetylation.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30367089","citation_count":30,"is_preprint":false},{"pmid":"32683582","id":"PMC_32683582","title":"Tumor-derived neomorphic mutations in ASXL1 impairs the BAP1-ASXL1-FOXK1/K2 transcription network.","date":"2020","source":"Protein & cell","url":"https://pubmed.ncbi.nlm.nih.gov/32683582","citation_count":29,"is_preprint":false},{"pmid":"34433054","id":"PMC_34433054","title":"A histone modifier, ASXL1, interacts with NONO and is involved in paraspeckle formation in hematopoietic cells.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/34433054","citation_count":29,"is_preprint":false},{"pmid":"29423272","id":"PMC_29423272","title":"Loss of ASXL1 in the bone marrow niche dysregulates hematopoietic stem and progenitor cell fates.","date":"2018","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/29423272","citation_count":29,"is_preprint":false},{"pmid":"23009937","id":"PMC_23009937","title":"Role of TET2 and ASXL1 mutations in the pathogenesis of myeloproliferative neoplasms.","date":"2012","source":"Hematology/oncology clinics of North America","url":"https://pubmed.ncbi.nlm.nih.gov/23009937","citation_count":28,"is_preprint":false},{"pmid":"30266822","id":"PMC_30266822","title":"ASXL1 impairs osteoclast formation by epigenetic regulation of NFATc1.","date":"2018","source":"Blood advances","url":"https://pubmed.ncbi.nlm.nih.gov/30266822","citation_count":26,"is_preprint":false},{"pmid":"30226831","id":"PMC_30226831","title":"Chromatin regulator Asxl1 loss and Nf1 haploinsufficiency cooperate to accelerate myeloid malignancy.","date":"2018","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/30226831","citation_count":26,"is_preprint":false},{"pmid":"29411666","id":"PMC_29411666","title":"ASXL1 mutations in AML are associated with specific clinical and cytogenetic characteristics.","date":"2018","source":"Leukemia & lymphoma","url":"https://pubmed.ncbi.nlm.nih.gov/29411666","citation_count":24,"is_preprint":false},{"pmid":"28027687","id":"PMC_28027687","title":"ASXL1 mutations in myeloid neoplasms: pathogenetic considerations, impact on clinical outcomes and survival.","date":"2017","source":"Current medical research and opinion","url":"https://pubmed.ncbi.nlm.nih.gov/28027687","citation_count":24,"is_preprint":false},{"pmid":"33483612","id":"PMC_33483612","title":"Asxl1 C-terminal mutation perturbs neutrophil differentiation in zebrafish.","date":"2021","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/33483612","citation_count":23,"is_preprint":false},{"pmid":"30222780","id":"PMC_30222780","title":"Clinical molecular testing for ASXL1 c.1934dupG p.Gly646fs mutation in hematologic neoplasms in the NGS era.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30222780","citation_count":23,"is_preprint":false},{"pmid":"36183966","id":"PMC_36183966","title":"Role of ASXL1 in hematopoiesis and myeloid diseases.","date":"2022","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/36183966","citation_count":22,"is_preprint":false},{"pmid":"36005555","id":"PMC_36005555","title":"ASXL1 mutations accelerate bone marrow fibrosis via EGR1-TNFA axis-mediated neoplastic fibrocyte generation in myeloproliferative neoplasms.","date":"2023","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/36005555","citation_count":22,"is_preprint":false},{"pmid":"28701722","id":"PMC_28701722","title":"Asxl1 deficiency in embryonic fibroblasts leads to cellular senescence via impairment of the AKT-E2F pathway and Ezh2 inactivation.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28701722","citation_count":21,"is_preprint":false},{"pmid":"38359087","id":"PMC_38359087","title":"Human ASXL1-Mutant Hematopoiesis Is Driven by a Truncated Protein Associated with Aberrant Deubiquitination of H2AK119.","date":"2024","source":"Blood cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/38359087","citation_count":20,"is_preprint":false},{"pmid":"31312376","id":"PMC_31312376","title":"Co-occurrence of RUNX1 and ASXL1 mutations underlie poor response and outcome for MDS patients treated with HMAs.","date":"2019","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/31312376","citation_count":20,"is_preprint":false},{"pmid":"23294243","id":"PMC_23294243","title":"Silencing of ASXL1 impairs the granulomonocytic lineage potential of human CD34⁺ progenitor cells.","date":"2013","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/23294243","citation_count":20,"is_preprint":false},{"pmid":"29681100","id":"PMC_29681100","title":"Bohring-Opitz syndrome caused by an ASXL1 mutation inherited from a germline mosaic mother.","date":"2018","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/29681100","citation_count":20,"is_preprint":false},{"pmid":"29907810","id":"PMC_29907810","title":"ASXL1/EZH2 mutations promote clonal expansion of neoplastic HSC and impair erythropoiesis in PMF.","date":"2018","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/29907810","citation_count":19,"is_preprint":false},{"pmid":"30515738","id":"PMC_30515738","title":"Aberrant histone modifications induced by mutant ASXL1 in myeloid neoplasms.","date":"2018","source":"International journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/30515738","citation_count":18,"is_preprint":false},{"pmid":"37062051","id":"PMC_37062051","title":"Epigenetic regulation by ASXL1 in myeloid malignancies.","date":"2023","source":"International journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/37062051","citation_count":17,"is_preprint":false},{"pmid":"32492700","id":"PMC_32492700","title":"HHEX promotes myeloid transformation in cooperation with mutant ASXL1.","date":"2020","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/32492700","citation_count":17,"is_preprint":false},{"pmid":"32216059","id":"PMC_32216059","title":"ASXL1 mutation as a surrogate marker in acute myeloid leukemia with myelodysplasia-related changes and normal karyotype.","date":"2020","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32216059","citation_count":17,"is_preprint":false},{"pmid":"27237378","id":"PMC_27237378","title":"Loss of Asxl1 Alters Self-Renewal and Cell Fate of Bone Marrow Stromal Cell, Leading to Bohring-Opitz-like Syndrome in Mice.","date":"2016","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27237378","citation_count":17,"is_preprint":false},{"pmid":"31006630","id":"PMC_31006630","title":"Pathological ASXL1 Mutations and Protein Variants Impair Neural Crest Development.","date":"2019","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/31006630","citation_count":16,"is_preprint":false},{"pmid":"31064769","id":"PMC_31064769","title":"Disruption of asxl1 results in myeloproliferative neoplasms in zebrafish.","date":"2019","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/31064769","citation_count":16,"is_preprint":false},{"pmid":"32381577","id":"PMC_32381577","title":"The ASXL1-G643W variant accelerates the development of CEBPA mutant acute myeloid leukemia.","date":"2021","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/32381577","citation_count":15,"is_preprint":false},{"pmid":"27736885","id":"PMC_27736885","title":"Dynamic ASXL1 Exon Skipping and Alternative Circular Splicing in Single Human Cells.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27736885","citation_count":15,"is_preprint":false},{"pmid":"24321552","id":"PMC_24321552","title":"Reciprocal regulation of LXRα activity by ASXL1 and ASXL2 in lipogenesis.","date":"2013","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/24321552","citation_count":15,"is_preprint":false},{"pmid":"32236560","id":"PMC_32236560","title":"Deregulation of tumor suppressive ASXL1-PTEN/AKT axis in myeloid malignancies.","date":"2020","source":"Journal of molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/32236560","citation_count":14,"is_preprint":false},{"pmid":"26286068","id":"PMC_26286068","title":"Familial hematological malignancies: ASXL1 gene investigation.","date":"2015","source":"Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico","url":"https://pubmed.ncbi.nlm.nih.gov/26286068","citation_count":13,"is_preprint":false},{"pmid":"25000259","id":"PMC_25000259","title":"ASXL1 and DNMT3A mutation in a cytogenetically normal B3 thymoma.","date":"2014","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/25000259","citation_count":13,"is_preprint":false},{"pmid":"37053013","id":"PMC_37053013","title":"Multiomics of Bohring-Opitz syndrome truncating ASXL1 mutations identify canonical and noncanonical Wnt signaling dysregulation.","date":"2023","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/37053013","citation_count":12,"is_preprint":false},{"pmid":"32066200","id":"PMC_32066200","title":"ASXL1 mutations, previous vascular complications and age at diagnosis predict survival in 85 WHO-defined polycythaemia vera patients.","date":"2020","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/32066200","citation_count":12,"is_preprint":false},{"pmid":"27616637","id":"PMC_27616637","title":"Loss of ASXL1 triggers an apoptotic response in human hematopoietic stem and progenitor cells.","date":"2016","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/27616637","citation_count":12,"is_preprint":false},{"pmid":"26768331","id":"PMC_26768331","title":"Screening of CD96 and ASXL1 in 11 patients with Opitz C or Bohring-Opitz syndromes.","date":"2015","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/26768331","citation_count":11,"is_preprint":false},{"pmid":"26385183","id":"PMC_26385183","title":"Role of Asxl1 in kidney podocyte development via its interaction with Wtip.","date":"2015","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/26385183","citation_count":11,"is_preprint":false},{"pmid":"35586041","id":"PMC_35586041","title":"LINC00586 Represses ASXL1 Expression Thus Inducing Epithelial-To-Mesenchymal Transition of Colorectal Cancer Cells Through LSD1-Mediated H3K4me2 Demethylation.","date":"2022","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35586041","citation_count":11,"is_preprint":false},{"pmid":"30389914","id":"PMC_30389914","title":"Asxl1 exerts an antiproliferative effect on mouse lung maturation via epigenetic repression of the E2f1-Nmyc axis.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/30389914","citation_count":11,"is_preprint":false},{"pmid":"32317519","id":"PMC_32317519","title":"Loss of ASXL1 expression is associated with lymph node metastasis in colorectal cancer.","date":"2020","source":"Indian journal of pathology & microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/32317519","citation_count":11,"is_preprint":false},{"pmid":"38190984","id":"PMC_38190984","title":"DNMT3A/TET2/ASXL1 Mutations are an Age-independent Thrombotic Risk Factor in Polycythemia Vera Patients: An Observational Study.","date":"2024","source":"Thrombosis and haemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/38190984","citation_count":11,"is_preprint":false},{"pmid":"34536441","id":"PMC_34536441","title":"Oncogenic Truncations of ASXL1 Enhance a Motif for BRD4 ET-Domain Binding.","date":"2021","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/34536441","citation_count":10,"is_preprint":false},{"pmid":"29456859","id":"PMC_29456859","title":"Acute myeloid leukemia in a father and son with a germline mutation of ASXL1.","date":"2018","source":"Biomarker research","url":"https://pubmed.ncbi.nlm.nih.gov/29456859","citation_count":10,"is_preprint":false},{"pmid":"37917239","id":"PMC_37917239","title":"Targeting lysine demethylase 6B ameliorates ASXL1 truncation-mediated myeloid malignancies in preclinical models.","date":"2024","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/37917239","citation_count":9,"is_preprint":false},{"pmid":"39752521","id":"PMC_39752521","title":"A mutant ASXL1-BAP1-EHMT complex contributes to heterochromatin dysfunction in clonal hematopoiesis and chronic monomyelocytic leukemia.","date":"2025","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/39752521","citation_count":9,"is_preprint":false},{"pmid":"32522152","id":"PMC_32522152","title":"Hcfc1a regulates neural precursor proliferation and asxl1 expression in the developing brain.","date":"2020","source":"BMC neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/32522152","citation_count":9,"is_preprint":false},{"pmid":"34186160","id":"PMC_34186160","title":"Reducing hyperactivated BAP1 attenuates mutant ASXL1-driven myeloid malignancies in human haematopoietic cells.","date":"2021","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/34186160","citation_count":9,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53264,"output_tokens":9395,"usd":0.150359,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19214,"output_tokens":4989,"usd":0.110397,"stage2_stop_reason":"end_turn"},"total_usd":0.260756,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"ASXL1 physically associates with the Polycomb Repressive Complex 2 (PRC2), and loss of ASXL1 results in global reduction of H3K27 tri-methylation; ASXL1 loss collaborates with NRASG12D to promote myeloid leukemogenesis in vivo.\",\n      \"method\": \"Co-immunoprecipitation (Co-IP), ChIP-Seq, microarray, in vivo mouse leukemia model\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP demonstrating PRC2 association, ChIP-Seq genome-wide H3K27me3 profiling, and in vivo functional validation across multiple orthogonal methods\",\n      \"pmids\": [\"22897849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ASXL1 represses RAR-mediated transcription by interacting with heterochromatin protein HP1 (via an HP1-binding PXVXL box in its N-terminus) and histone demethylase LSD1; HP1α facilitates formation of a ternary ASXL1-HP1-LSD1 complex that removes H3K4 methylation (active mark) at retinoic acid-responsive promoters.\",\n      \"method\": \"Transfection transcription assays, in vitro pull-down, Co-IP, HP1α knockdown, chromatin immunoprecipitation (ChIP)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (in vitro pull-down, Co-IP, ChIP, KD rescue) in a single focused study establishing the HP1/LSD1 mechanism\",\n      \"pmids\": [\"19880879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ASXL1 is the obligate regulatory subunit of the BAP1 deubiquitinase complex; cancer-associated C-terminal truncations of ASXL1 confer enhanced (gain-of-function) deubiquitinase activity on the ASXL1-BAP1 complex, leading to global erasure of H2AK119Ub and depletion of H3K27me3, with downstream effects requiring BAP1 catalytic activity.\",\n      \"method\": \"Stable expression of truncated ASXL1-BAP1 in hematopoietic cell lines, global histone modification analysis, BAP1 catalytic mutant rescue, in vivo bone marrow experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — enzymatic activity assays with catalytic mutants, global histone profiling, and in vivo validation; replicated by multiple subsequent studies\",\n      \"pmids\": [\"26095772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The BAP1 C-terminal extension auto-recruits BAP1 to nucleosomes independently of the nucleosome acidic patch, forming an unproductive encounter complex; activation requires DEUBAD domains of ASXL1/2/3, which increase BAP1 affinity for ubiquitin on H2AK119 to drive deubiquitination. The PR-DUB complex is specific for Polycomb H2AK119Ub and cannot deubiquitinate DNA damage-associated H2A K13/15Ub.\",\n      \"method\": \"Biochemical reconstitution, nucleosome binding assays, deubiquitinase activity assays, domain deletion mutants\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with domain mutants establishing mechanistic steps of BAP1 activation by ASXL1 DEUBAD domain\",\n      \"pmids\": [\"26739236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM structure of human BAP1 and the ASXL1 DEUBAD domain in complex with an H2AK119Ub nucleosome reveals molecular interactions of BAP1 and ASXL1 with histones and DNA that restructure the nucleosome to establish specificity for H2AK119Ub; >50 cancer-associated mutations in BAP1 and ASXL1 were mechanistically explained by this structure.\",\n      \"method\": \"Cryo-EM structure determination, biochemical and cellular validation of interface mutants\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with biochemical and cellular validation of >50 cancer mutations providing direct structural mechanism\",\n      \"pmids\": [\"37556531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"C-terminal truncating Asxl1 mutations (ASXL1-MT) inhibit PRC2-mediated H3K27 methylation, causing derepression of Hoxa9 and miR-125a; miR-125a in turn reduces expression of Clec5a, thereby blocking myeloid differentiation and inducing MDS-like disease in mice.\",\n      \"method\": \"Retroviral expression of ASXL1-MT in mouse hematopoietic progenitors, transplantation model, gene expression analysis, ChIP for H3K27me3\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse model with mechanistic pathway dissection (PRC2→H3K27me3→HOXA9/miR-125a→CLEC5A) using multiple orthogonal approaches\",\n      \"pmids\": [\"24216483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Mutant ASXL1 (ASXL1-MT) increases monoubiquitination of the truncated protein, which in turn enhances BAP1 catalytic function; the resulting hyperactive ASXL1-MT/BAP1 complex removes H2AK119 ubiquitination at posterior HOXA genes and IRF8 loci, upregulating their expression and promoting myeloid leukaemogenesis. BAP1 depletion inhibits posterior HOXA gene expression and leukaemogenicity.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitinase activity assays, ChIP-seq for H2AK119Ub, bone marrow transplantation in vivo model, BAP1 shRNA knockdown\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical demonstration of enhanced ubiquitination of mutant ASXL1 and BAP1 activation, ChIP-seq, and in vivo rescue with BAP1 depletion\",\n      \"pmids\": [\"30013160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A truncated ASXL1 protein (aa1-587) acquires a gain-of-function interaction with BRD4, demonstrated by liquid chromatography-tandem mass spectrometry and co-immunoprecipitation; expression of this truncation results in more open chromatin at critical HSC genes and hypersensitivity of cells to BET bromodomain inhibitors.\",\n      \"method\": \"LC-MS/MS, co-immunoprecipitation, ATAC-seq, RNA-seq, epigenetic drug screening in transgenic mouse model\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based interactome plus Co-IP plus functional genomics, all in the same study; novel gain-of-function interaction established\",\n      \"pmids\": [\"29113963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ASXL1 forms a protein complex with HCFC1 and OGT; OGT directly stabilizes ASXL1 by O-GlcNAcylation. Disruption of this ASXL1-OGT axis inhibits myeloid differentiation and reduces H3K4 methylation and H2B glycosylation, with MLL5 identified as the H3K4 methyltransferase responsible for gene activation within this axis.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, O-GlcNAcylation assay, ChIP for H3K4me3, knockdown/rescue experiments in vivo and in vitro\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, MS identification of complex, direct PTM (O-GlcNAcylation) validated, ChIP-seq and in vivo rescue supporting functional consequence\",\n      \"pmids\": [\"29556021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ASXL1-MT cooperates with BAP1 to deubiquitinate and activate AKT; overactive Akt/mTOR signaling leads to aberrant HSC proliferation, DNA damage accumulation, and clonal expansion. Treatment with the mTOR inhibitor rapamycin ameliorated aberrant HSC expansion and dysregulated hematopoiesis in ASXL1-MT knockin mice.\",\n      \"method\": \"Co-immunoprecipitation, AKT deubiquitination assay, knockin mouse model, rapamycin treatment rescue, competitive transplantation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct biochemical demonstration of AKT deubiquitination by ASXL1-MT/BAP1, in vivo rescue with mTOR inhibitor, replicated across multiple experimental approaches\",\n      \"pmids\": [\"33758188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ASXL1 and BAP1 co-occupy the INK4B locus; ASXL1-mediated H2AK119Ub deubiquitination is specifically required for activation of p15(INK4B) expression in response to oncogenic signaling and anti-proliferative signals. ASXL1 mutations are associated with lower p15(INK4B) expression and proliferative advantage of hematopoietic progenitors.\",\n      \"method\": \"ChIP-seq showing ASXL1 and BAP1 enrichment at INK4B locus, deubiquitylation assay, ASXL1 KD in multiple cell lines, primary bone marrow analysis\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct occupancy, DUB activity assay, functional KD with defined molecular readout across multiple cell types\",\n      \"pmids\": [\"26470845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Mutant ASXL1 (ASXL1G643fs) loses the ability to interact with BMI1 (a PRC1 subunit); this abolishes BMI1-driven H2AK119Ub1 at the p16Ink4a promoter, derepressing p16Ink4a and inducing cellular senescence in HSCs, causing low-risk MDS-like phenotypes. Heterozygous deletion of p16Ink4a restored the HSC pool.\",\n      \"method\": \"Co-immunoprecipitation (mutant vs. WT ASXL1 with BMI1), H2AK119Ub1 ChIP at p16Ink4a promoter, knockin mouse model, genetic rescue with p16Ink4a deletion\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP showing loss of BMI1 interaction, ChIP demonstrating reduced H2AK119Ub1 at p16Ink4a, and genetic rescue confirming the pathway\",\n      \"pmids\": [\"29967380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Physiological expression of C-terminally truncated Asxl1 mutant in knockin mice causes substantial reductions in H3K4me3 and H2AK119Ub without significant reductions in H3K27me3; ChIP-seq shows opposing effects of wild-type vs. mutant Asxl1 on H3K4me3 at target loci. These histone changes are distinct from the effects of Asxl1 loss.\",\n      \"method\": \"Conditional knockin mouse model, ChIP-seq for H3K4me3, H2AK119Ub, H3K27me3; competitive transplantation; viral insertional mutagenesis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq in knockin model distinguishing mutant from loss-of-function effects with multiple histone marks\",\n      \"pmids\": [\"29643185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ASXL1 forms phase-separated droplets and upregulates NEAT1 expression through its C-terminal intrinsically disordered region (IDR), increasing NONO-NEAT1 interactions and paraspeckle formation in hematopoietic cells. A pathogenic ASXL1 mutant lacking the IDR does not support paraspeckle assembly, and disrupted paraspeckles impair HSC repopulating potential.\",\n      \"method\": \"Phase separation assays, Co-IP of ASXL1 with NONO and NEAT1, knockin mouse model with live imaging, NONO knockdown and cytoplasmic NONO forced-expression rescue\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phase separation biochemistry, Co-IP, knockin mouse model, and rescue experiments; multiple orthogonal methods in a single study\",\n      \"pmids\": [\"34433054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ASXL1 interacts with the core subunits of RNA polymerase II (RNAPII) complex in bone marrow stromal cells (BMSCs); loss of Asxl1 in BMSCs deregulates RNAPII transcriptional function and alters expression of genes critical for HSC maintenance (e.g., Vcam1), leading to altered HSC/HPC pool and myeloid differentiation bias.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq for ASXL1 and RNAPII, RNA-seq, conditional Asxl1 deletion in BMSCs\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with RNAPII, ChIP-seq and RNA-seq convergent analysis, and in vivo conditional KO\",\n      \"pmids\": [\"29423272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cancer-associated frameshift mutations in ASXL1 encode stable truncated gain-of-function proteins (not destabilizing loss-of-function). Truncated ASXL1 increases BAP1 protein stability, enhances BAP1 recruitment to chromatin, and promotes expression of a pro-leukemic transcriptional signature; BAP1 catalytic inhibitors impair truncated-ASXL1-driven leukemic gene expression and tumor progression in vivo.\",\n      \"method\": \"Biochemical protein stability assays, ChIP for BAP1 chromatin recruitment, RNA-seq transcriptome analysis, BAP1 inhibitor screen, in vivo xenograft tumor progression model\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (stability assays, ChIP, RNA-seq, in vivo inhibitor treatment) establishing gain-of-function mechanism of truncated ASXL1\",\n      \"pmids\": [\"35122023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Wild-type ASXL1 interacts with FOXK1 and FOXK2 transcription factors to regulate a subset of their target genes. C-terminally truncated mutant ASXL1 is expressed at higher levels than wild-type but loses the ability to interact with FOXK1/K2; deletion of the mutant allele increased wild-type ASXL1 association with BAP1 and restored BAP1-ASXL1-FOXK1/K2 target gene expression (glucose metabolism, oxygen sensing, JAK-STAT3 signaling).\",\n      \"method\": \"Co-immunoprecipitation, CRISPR deletion of mutant allele, RNA-seq, allele-specific protein expression analysis\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating FOXK1/K2 interaction, CRISPR allele deletion with functional rescue, RNA-seq; multiple orthogonal methods\",\n      \"pmids\": [\"32683582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PR-DUB (BAP1-ASXL1 complex) requires ASXL proteins and FOXK1/2 for BAP1-dependent gene activation; by counteracting accumulation of H2AK119Ub1 across the genome, PR-DUB maintains chromatin in an optimal configuration for expression of genes important for cell metabolism and homeostasis. Minimal functional interaction with PRC2 was found in embryonic stem cells.\",\n      \"method\": \"ChIP-seq for BAP1, ASXL proteins, H2AK119Ub1; ASXL and FOXK1/2 depletion; comparative analysis with EZH2/PRC2 targets\",\n      \"journal\": \"Genome research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq with genetic depletion of complex components establishing mechanistic roles in gene activation\",\n      \"pmids\": [\"32747411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Constitutive loss of Asxl1 results in global reduction of H3K27 trimethylation and dysregulated expression of known hematopoietic regulators. Concomitant deletion of Tet2 restores HSC self-renewal reduced by Asxl1 loss (genetic epistasis), and compound Asxl1/Tet2 deletion accelerates MDS with hastened death.\",\n      \"method\": \"Conditional/constitutive Asxl1 knockout mice, hematopoietic-specific deletion, RNA-seq, ChIP-seq, serial transplantation, Tet2 double KO epistasis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq for H3K27me3, RNA-seq, genetic epistasis with Tet2, serial transplantation; replicated in multiple mouse models\",\n      \"pmids\": [\"24218140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Asxl1 deficiency in mouse embryonic fibroblasts (MEFs) impairs AKT1 activation: ASXL1 (aa 371-655) interacts with the kinase domain of AKT1, and p27Kip1 forms a ternary complex with ASXL1 and AKT1. Loss of Asxl1 prevents IGF-1-induced AKT1 phosphorylation, leaving p27Kip1 unphosphorylated and nuclear, inhibiting E2F target genes and promoting senescence. Asxl1 also cooperates directly with Ezh2.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, MEF knockout model, IGF-1 stimulation assay, AKT inhibitor, microarray, SA-β-gal senescence staining\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, functional readouts (AKT phosphorylation, p27 localization, E2F targets), single lab\",\n      \"pmids\": [\"28701722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Truncated ASXL1 proteins from C-terminal truncating mutations are detectable by mass spectrometry and Western blot in cell lines bearing homozygous ASXL1 mutations, demonstrating that the truncated protein is expressed and not subject to NMD; this establishes the foundation for dominant-negative or gain-of-function mechanisms.\",\n      \"method\": \"Mass spectrometry (LC-MS/MS), Western blot analysis in homozygous mutant cell lines\",\n      \"journal\": \"Experimental hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — orthogonal methods (MS + WB) in homozygous mutant cells; single lab but direct protein detection\",\n      \"pmids\": [\"26700326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Truncated ASXL1 leads to global redistribution (not simply loss) of the repressive chromatin mark H2AK119Ub, increases transposase-accessible chromatin, and activates both myeloid and stem cell gene-expression programs in primary human HSPCs; H2AK119Ub levels are tied to truncated ASXL1 expression levels, and PRC1 inhibition is identified as a potential ASXL1-mutant-specific therapeutic vulnerability.\",\n      \"method\": \"CRISPR-engineered primary human HSPC model, ATAC-seq, RNA-seq, ChIP/CUT&RUN for H2AK119Ub, xenotransplantation model\",\n      \"journal\": \"Blood cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide chromatin and transcriptome profiling with primary human cells and in vivo xenotransplantation; multiple orthogonal methods\",\n      \"pmids\": [\"38359087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Loss of ASXL1 in human CD34+ progenitors impairs granulomonocytic differentiation (decreased CD11b+ and CD15+ cells, decreased CFU-GM and CFU-G, increased CFU-GEMM colonies); the most deregulated pathway is LXR/RXR activation and PRC2 target genes are over-represented among deregulated genes in ASXL1-deficient cells.\",\n      \"method\": \"Lentiviral shRNA knockdown of ASXL1 in human CD34+ cells, colony-forming assays, flow cytometry, gene expression profiling\",\n      \"journal\": \"British journal of haematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined differentiation phenotype and pathway analysis; single lab but multiple readouts\",\n      \"pmids\": [\"23294243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss of ASXL1 in osteoclasts results in concordant loss of inhibitory H3K27me3 with gain of H3K4me3 at NFATc1 and itgb3 promoters, inducing a 40-fold increase in the H3K27 demethylase Jmjd3; increased NFATc1 then binds the Blimp1 promoter, enhancing expression of this pro-osteoclastogenic gene and driving excess bone resorption.\",\n      \"method\": \"Conditional Asxl1 deletion in myeloid cells, ChIP for H3K27me3/H3K4me3, Jmjd3 knockdown rescue, NFATc1 ChIP at Blimp1 promoter\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating histone mark changes at specific loci, Jmjd3 KD rescue, and NFATc1 ChIP; multiple orthogonal methods establishing mechanism\",\n      \"pmids\": [\"30266822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Asxl1 loss in mice leads to decreased global H3K27me3 and H3K4me3, increased apoptosis and mitosis in Lin-cKit+ cells, and altered expression of apoptosis regulators (Bcl2, Bcl2l12, Bcl2l13), resulting in MDS-like disease.\",\n      \"method\": \"Constitutional Asxl1 knockout mice, flow cytometry, global histone modification analysis, gene expression profiling\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with quantified global histone modifications and defined molecular targets; single lab\",\n      \"pmids\": [\"24255920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Mutant ASXL1 proteins interact with the EHMT1-EHMT2 complex (generating H3K9me1/me2); in aged ASXL1-mutant knockin mice, myeloid cells show genome-wide decreases of H3K9me2, H3K9me3, and H2AK119Ub, with increased expression of transposable elements and satellite repeats, and upregulation of nearby interferon-inducible genes.\",\n      \"method\": \"Co-immunoprecipitation of mutant ASXL1 with EHMT1/2, ChIP-seq for H3K9me2/3 and H2AK119Ub, knockin mouse model, transposable element expression profiling in CMML patient monocytes\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing new EHMT1/2 interaction, genome-wide ChIP-seq in knockin model, and validation in human patient samples; multiple orthogonal methods\",\n      \"pmids\": [\"39752521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Oncogenic ASXL1 truncation mutations expose a motif near the truncation breakpoint that binds the BRD4 ET domain; the prevalent ASXL1Y591X truncation markedly increases BRD4-ASXL1 binding compared to full-length ASXL1 or truncations that delete this epitope. All three ASXL orthologs contain a functional BRD4 ET-domain binding epitope.\",\n      \"method\": \"In vitro binding studies (pull-down/affinity), peptide competition, isothermal calorimetry/NMR-type binding measurements for ET-domain interaction\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct in vitro binding assays with domain mutants and multiple ASXL1 truncation variants; single lab with quantitative binding data\",\n      \"pmids\": [\"34536441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ASXL1 and SETBP1 mutations cooperate to repress TGFβ pathway genes through aberrantly reduced acetylation of histone H3 and H4 lysine residues at their promoters; HDAC inhibitor vorinostat reverses this histone hypoacetylation and transcriptionally derepresses TGFβ pathway genes, selectively inhibiting growth of ASXL1-mutant cells.\",\n      \"method\": \"ChIP for histone acetylation marks at TGFβ pathway gene promoters, constitutively active ALK5-TD rescue, vorinostat treatment, co-expression mouse bone marrow transplant model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating specific histone acetylation changes, pharmacological rescue and ALK5 genetic rescue; single lab\",\n      \"pmids\": [\"30367089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ASXL1 represses LXRα-mediated transcriptional activity through direct interaction and ligand-dependent recruitment to ABCA1 promoters; ASXL1 knockdown increases lipid accumulation in hepatic cells and ASXL1 expression changes under fasting/insulin conditions, implicating it in lipid homeostasis.\",\n      \"method\": \"Co-immunoprecipitation, ChIP at ABCA1 promoter, luciferase transcription assays, ASXL1 knockdown with lipid accumulation assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, and functional KD; single lab with multiple complementary methods\",\n      \"pmids\": [\"24321552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ASXL1 is specifically required for H2AK119 deubiquitylation at the Pten promoter, activating PTEN transcription and thereby suppressing PI3K/AKT signaling; Asxl1 depletion in murine 32D cells confers IL3-independent growth due to sustained AKT activation, and ASXL1 mutations associate with lower PTEN expression in human myeloid malignancies.\",\n      \"method\": \"ChIP for ASXL1 and H2AK119Ub at Pten promoter, Asxl1 depletion IL3-independence assay, correlation analysis in patient data, AKT inhibitor sensitivity assay\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishing direct occupancy and DUB activity at PTEN locus, functional KD phenotype, single lab\",\n      \"pmids\": [\"32236560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ASXL1 interacts with Wilms tumor 1-interacting protein (WTIP) through its PHD domain; loss of Asxl1 in mice causes defects in kidney size and glomerular podocyte morphology, with up-regulation of Wt1/Wtip target genes, implicating ASXL1 in WT1 signaling during kidney development.\",\n      \"method\": \"Co-immunoprecipitation (Asxl1-Wtip), Asxl1-null mouse embryo kidney morphology analysis, gene expression analysis of Wt1/Wtip targets\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP establishing binding partner, KO mouse phenotype with gene expression changes; single lab\",\n      \"pmids\": [\"26385183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ASXL1 represses Nmyc expression in lung epithelial cells by recruiting HCF-1 and E2F1 to the Nmyc promoter; the interaction is between the C-terminal region of Asxl1 and the N-terminal Kelch domain of HCF-1. This is associated with enrichment of H3K27me3 and H3K9me3 at the Nmyc promoter, and Asxl1 ablation causes lung hyperplasia.\",\n      \"method\": \"Asxl1-null mouse lung model, HCF-1 purification/Co-IP, ChIP for H3K27me3 and H3K9me3 at Nmyc promoter, domain mapping\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — protein interaction established by Co-IP with domain mapping, ChIP at specific locus, and KO phenotype; single lab\",\n      \"pmids\": [\"30389914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Upregulation of KDM6B (a H3K27me3 demethylase) occurs in ASXL1-mutant leukemic cells and further reduces H3K27me3; heterozygous deletion of Kdm6b restored H3K27me3 levels, normalized dysregulated gene expression, decreased the HSPC pool, restored self-renewal, and abrogated myeloid malignancy progression in Asxl1Y588XTg mice. KDM6B inhibitor GSK-J4 restored H3K27me3 and reduced disease burden in xenograft models.\",\n      \"method\": \"Genetic Kdm6b deletion in Asxl1 transgenic mice, ChIP for H3K27me3, RNA-seq, NSG xenograft with KDM6B inhibitor treatment\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (Kdm6b deletion rescuing Asxl1 mutant phenotype), ChIP-seq, RNA-seq, and pharmacological validation in vivo; multiple orthogonal methods\",\n      \"pmids\": [\"37917239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Murine Asxl1 contains an ASX homology domain (ASXH) with two nuclear receptor (NR) co-regulator binding motifs (LXXLL-like), a conserved C-terminal PHD domain, and three additional NR co-regulator binding motifs not present in Drosophila Asx; Asxl1 is expressed as multiple transcripts in adult tissues and in 10.5-11.0 dpc mouse embryos.\",\n      \"method\": \"Sequence analysis, Northern blot, whole-mount RNA in situ hybridization\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — characterization of domain structure and expression pattern by Northern/ISH; no direct functional experiments\",\n      \"pmids\": [\"16412590\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ASXL1 is an epigenetic scaffold protein that functions as the obligate regulatory subunit of the BAP1 deubiquitinase complex (PR-DUB), activating BAP1 via its DEUBAD domain to deubiquitinate H2AK119Ub at Polycomb target loci; it also associates with PRC2 to maintain H3K27me3 at repressed loci including posterior HOXA genes, interacts with HP1α and LSD1 to repress RAR-target genes, binds FOXK1/K2 and RNA Pol II to activate target genes, and is stabilized by OGT-mediated O-GlcNAcylation within an ASXL1-HCFC1-OGT complex that promotes H3K4 methylation; cancer-associated C-terminal truncating mutations generate stable gain-of-function proteins that hyperactivate BAP1 (erasing H2AK119Ub and depleting H3K27me3), acquire novel interactions with BRD4 and EHMT1/2, activate AKT/mTOR signaling, and disrupt paraspeckle assembly, collectively driving myeloid malignancy through aberrant epigenomic reprogramming.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ASXL1 is a chromatin-associated scaffold that controls the deposition and erasure of Polycomb histone marks to govern hematopoietic stem cell self-renewal and myeloid differentiation [#0, #18]. Its central biochemical function is as the obligate regulatory subunit of the BAP1 deubiquitinase complex (PR-DUB): the ASXL1 DEUBAD domain increases BAP1 affinity for H2AK119-ubiquitinated nucleosomes, restructuring the nucleosome to confer specificity for Polycomb H2AK119Ub while excluding DNA-damage-associated H2A ubiquitylation [#3, #4]. Through this activity, together with FOXK1/FOXK2 transcription factors, PR-DUB counteracts genome-wide H2AK119Ub accumulation to maintain chromatin permissive for expression of metabolic and homeostatic genes including p15(INK4B) and PTEN [#10, #16, #17, #29]. ASXL1 additionally associates with PRC2, and its loss reduces global H3K27me3 and dysregulates hematopoietic regulators, a phenotype genetically epistatic with Tet2 [#0, #18]. It is stabilized by OGT-mediated O-GlcNAcylation within an ASXL1-HCFC1-OGT complex that supports H3K4 methylation via MLL5 [#8]. Cancer-associated C-terminal truncating mutations produce stable gain-of-function proteins, not loss-of-function products, that escape nonsense-mediated decay [#20, #15]; the truncated protein becomes monoubiquitinated and hyperactivates BAP1, erasing H2AK119Ub at posterior HOXA and IRF8 loci and redistributing this mark genome-wide to activate stem and myeloid gene programs [#6, #21, #15]. Truncated ASXL1 also acquires neomorphic interactions with the BRD4 ET domain and the EHMT1/EHMT2 complex, and drives AKT/mTOR activation through BAP1-dependent AKT deubiquitination, collectively reprogramming the epigenome to cause myelodysplasia and myeloid leukemia [#7, #26, #25, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established the domain architecture of mammalian ASXL1, defining the modules later shown to mediate its chromatin and nuclear-receptor functions.\",\n      \"evidence\": \"Sequence analysis, Northern blot, and whole-mount in situ hybridization of murine Asxl1\",\n      \"pmids\": [\"16412590\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct functional assay of any domain\", \"Does not assign biochemical activity to the ASXH or PHD domains\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"First defined ASXL1 as a transcriptional repressor recruiting chromatin modifiers, showing it bridges HP1 and the demethylase LSD1 to strip active H3K4 marks at RAR-responsive promoters.\",\n      \"evidence\": \"In vitro pull-down, Co-IP, ChIP, and HP1\\u03b1 knockdown in transfected cells\",\n      \"pmids\": [\"19880879\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Restricted to RAR target loci\", \"Genome-wide scope of the HP1/LSD1 complex not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked ASXL1 to Polycomb repression by showing it associates with PRC2 and is required for global H3K27me3, and that its loss cooperates with NRAS to drive leukemia.\",\n      \"evidence\": \"Reciprocal Co-IP, ChIP-seq for H3K27me3, and in vivo mouse leukemia model\",\n      \"pmids\": [\"22897849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve direct vs. indirect PRC2 association\", \"Mechanism connecting H3K27me3 loss to leukemogenesis not yet defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected ASXL1 mutation and loss to specific differentiation defects and disease pathways, including PRC2-target derepression, HOXA9/miR-125a/CLEC5A axis, apoptosis regulators, and Tet2 epistasis.\",\n      \"evidence\": \"Constitutive/conditional Asxl1 knockout mice, retroviral mutant expression, human CD34+ knockdown, ChIP, RNA-seq, and Tet2 double-KO epistasis\",\n      \"pmids\": [\"24216483\", \"24218140\", \"24255920\", \"23294243\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mutant gain-of-function vs. loss-of-function not yet biochemically distinguished\", \"Direct enzymatic mechanism of mutant ASXL1 unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified ASXL1 as the obligate regulatory subunit of the BAP1 deubiquitinase and showed truncating mutations confer gain-of-function H2AK119Ub-erasing activity; established truncated protein is expressed and escapes NMD.\",\n      \"evidence\": \"Stable truncated ASXL1-BAP1 expression, catalytic-mutant rescue, global histone profiling, ChIP at INK4B, mass spectrometry/Western detection in homozygous mutant lines\",\n      \"pmids\": [\"26095772\", \"26470845\", \"26700326\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of activation not yet resolved\", \"How truncation enhances catalysis biochemically unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the mechanistic steps of BAP1 activation, showing the BAP1 C-terminal extension forms an unproductive nucleosome encounter complex that the ASXL DEUBAD domain converts into a ubiquitin-engaging, H2AK119Ub-specific deubiquitinase.\",\n      \"evidence\": \"Biochemical reconstitution, nucleosome binding and deubiquitinase assays with domain-deletion mutants\",\n      \"pmids\": [\"26739236\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not provide atomic structure of the nucleosome-bound complex\", \"Did not explain individual cancer mutations\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed neomorphic functions of truncated ASXL1: a gain-of-function BRD4 interaction opening chromatin at HSC genes, and an AKT1-binding role for the central region linking ASXL1 to senescence control.\",\n      \"evidence\": \"LC-MS/MS, Co-IP, ATAC-seq, BET-inhibitor screening in transgenic mice; domain mapping and IGF-1 stimulation in Asxl1-null MEFs\",\n      \"pmids\": [\"29113963\", \"28701722\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"MEF AKT1 study Medium-confidence and single-lab\", \"Direct BRD4 binding interface not yet mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Expanded the functional repertoire of ASXL1 across complexes and tissues: OGT/HCFC1 stabilization, RNAPII association, BMI1/PRC1 interaction at p16, HCF-1/E2F1 recruitment, SETBP1 cooperation, and mutant-specific enhanced ubiquitination driving BAP1 hyperactivity; knockin mice distinguished mutant from loss-of-function chromatin effects.\",\n      \"evidence\": \"Co-IP, mass spectrometry, O-GlcNAcylation assays, ChIP-seq for multiple histone marks, conditional KO and knockin mouse models\",\n      \"pmids\": [\"30013160\", \"29556021\", \"29423272\", \"29967380\", \"29643185\", \"30389914\", \"30367089\", \"30266822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of these partner complexes to leukemogenesis not ranked\", \"Several interactions documented in single tissue contexts\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established PR-DUB as a gene-activating complex requiring ASXL and FOXK1/2 to counteract genome-wide H2AK119Ub, and showed truncated ASXL1 loses FOXK1/2 binding while sequestering BAP1; defined PTEN as a direct deubiquitylation target.\",\n      \"evidence\": \"ChIP-seq for BAP1/ASXL/H2AK119Ub with component depletion, Co-IP, CRISPR mutant-allele deletion, ChIP at Pten promoter, AKT-inhibitor sensitivity assays\",\n      \"pmids\": [\"32747411\", \"32683582\", \"32236560\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PTEN axis study Medium-confidence and single-lab\", \"Balance between gene-activating and gene-repressing roles of PR-DUB context-dependent\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated truncated ASXL1 is a stabilizing gain-of-function protein driving leukemia through enhanced BAP1 chromatin recruitment, AKT/mTOR activation, H2AK119Ub redistribution, and paraspeckle assembly via its intrinsically disordered region.\",\n      \"evidence\": \"Protein stability assays, ChIP, RNA-seq, BAP1 inhibitor screen, AKT deubiquitination and knockin/rapamycin rescue, phase-separation assays with NONO/NEAT1, CRISPR primary human HSPC model\",\n      \"pmids\": [\"35122023\", \"33758188\", \"34433054\", \"38359087\", \"34536441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Therapeutic vulnerabilities (BAP1, PRC1, mTOR inhibitors) tested largely in models\", \"Whether paraspeckle and PR-DUB functions are mechanistically coupled unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided the atomic mechanism of substrate specificity by solving the cryo-EM structure of BAP1\\u2013ASXL1 DEUBAD on an H2AK119Ub nucleosome and rationalizing >50 cancer mutations.\",\n      \"evidence\": \"Cryo-EM structure determination with biochemical and cellular validation of interface mutants\",\n      \"pmids\": [\"37556531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the truncated gain-of-function complex not determined\", \"Does not capture full-length ASXL1 or neomorphic partner-bound states\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified mutant-specific epigenetic vulnerabilities, showing truncated ASXL1 recruits EHMT1/2 with genome-wide loss of repressive marks and repeat derepression, and that KDM6B upregulation drives H3K27me3 loss that genetic or pharmacologic KDM6B inhibition reverses.\",\n      \"evidence\": \"Co-IP, ChIP-seq for H3K9/H2AK119Ub marks, knockin mouse models, Kdm6b genetic epistasis, and GSK-J4 treatment in xenografts; CMML patient sample validation\",\n      \"pmids\": [\"39752521\", \"37917239\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Clinical translatability of KDM6B/EHMT-targeting not established\", \"Interplay between EHMT-mediated H3K9 loss and BAP1-mediated H2AK119Ub loss not integrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse ASXL1 partner complexes (PR-DUB, PRC2, OGT/HCFC1, RNAPII, FOXK1/2, neomorphic BRD4/EHMT1-2) are coordinated in space and time within normal versus mutant hematopoiesis remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No integrated model of partner-complex switching\", \"Structural basis of mutant gain-of-function interactions undetermined\", \"Determinants directing PR-DUB to activate vs. repress specific loci unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 3, 4, 6, 9, 10, 29]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 16, 17, 28, 31]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 8, 14, 16]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 14, 33]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 2, 6, 18]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 2, 3, 6, 18, 21]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [14, 16, 17, 28, 31]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 5, 6, 15, 25, 32]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 29]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [22, 23, 30, 31]}\n    ],\n    \"complexes\": [\"PR-DUB (BAP1-ASXL1 deubiquitinase complex)\", \"PRC2\", \"ASXL1-HCFC1-OGT complex\", \"ASXL1-HP1-LSD1 complex\"],\n    \"partners\": [\"BAP1\", \"FOXK1\", \"FOXK2\", \"OGT\", \"HCFC1\", \"BMI1\", \"BRD4\", \"EHMT2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}