Affinage

ASXL1

Polycomb group protein ASXL1 · UniProt Q8IXJ9

Length
1541 aa
Mass
165.4 kDa
Annotated
2026-06-09
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2006 Low

    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

    PMID:16412590

    Open questions at the time
    • No direct functional assay of any domain
    • Does not assign biochemical activity to the ASXH or PHD domains
  2. 2009 High

    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

    PMID:19880879

    Open questions at the time
    • Restricted to RAR target loci
    • Genome-wide scope of the HP1/LSD1 complex not defined
  3. 2012 High

    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

    PMID:22897849

    Open questions at the time
    • Did not resolve direct vs. indirect PRC2 association
    • Mechanism connecting H3K27me3 loss to leukemogenesis not yet defined
  4. 2013 High

    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

    PMID:23294243 PMID:24216483 PMID:24218140 PMID:24255920

    Open questions at the time
    • Mutant gain-of-function vs. loss-of-function not yet biochemically distinguished
    • Direct enzymatic mechanism of mutant ASXL1 unresolved
  5. 2015 High

    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

    PMID:26095772 PMID:26470845 PMID:26700326

    Open questions at the time
    • Structural basis of activation not yet resolved
    • How truncation enhances catalysis biochemically unclear
  6. 2016 High

    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

    PMID:26739236

    Open questions at the time
    • Did not provide atomic structure of the nucleosome-bound complex
    • Did not explain individual cancer mutations
  7. 2017 High

    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

    PMID:28701722 PMID:29113963

    Open questions at the time
    • MEF AKT1 study Medium-confidence and single-lab
    • Direct BRD4 binding interface not yet mapped
  8. 2018 High

    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

    PMID:29423272 PMID:29556021 PMID:29643185 PMID:29967380 PMID:30013160 PMID:30266822 PMID:30367089 PMID:30389914

    Open questions at the time
    • Relative contributions of these partner complexes to leukemogenesis not ranked
    • Several interactions documented in single tissue contexts
  9. 2020 High

    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

    PMID:32236560 PMID:32683582 PMID:32747411

    Open questions at the time
    • PTEN axis study Medium-confidence and single-lab
    • Balance between gene-activating and gene-repressing roles of PR-DUB context-dependent
  10. 2021 High

    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

    PMID:33758188 PMID:34433054 PMID:34536441 PMID:35122023 PMID:38359087

    Open questions at the time
    • Therapeutic vulnerabilities (BAP1, PRC1, mTOR inhibitors) tested largely in models
    • Whether paraspeckle and PR-DUB functions are mechanistically coupled unclear
  11. 2023 High

    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

    PMID:37556531

    Open questions at the time
    • Structure of the truncated gain-of-function complex not determined
    • Does not capture full-length ASXL1 or neomorphic partner-bound states
  12. 2024 High

    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

    PMID:37917239 PMID:39752521

    Open questions at the time
    • Clinical translatability of KDM6B/EHMT-targeting not established
    • Interplay between EHMT-mediated H3K9 loss and BAP1-mediated H2AK119Ub loss not integrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0140110 transcription regulator activity 5 GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0000228 nuclear chromosome 4 GO:0005634 nucleus 4 GO:0005654 nucleoplasm 1
Pathway
R-HSA-1643685 Disease 6 R-HSA-4839726 Chromatin organization 6 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 2
Partners
BAP1BMI1BRD4EHMT2FOXK1FOXK2HCFC1OGT
Complex memberships
ASXL1-HCFC1-OGT complexASXL1-HP1-LSD1 complexPR-DUB (BAP1-ASXL1 deubiquitinase complex)PRC2

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 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. Co-immunoprecipitation (Co-IP), ChIP-Seq, microarray, in vivo mouse leukemia model Cancer cell High 22897849
2009 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. Transfection transcription assays, in vitro pull-down, Co-IP, HP1α knockdown, chromatin immunoprecipitation (ChIP) The Journal of biological chemistry High 19880879
2015 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. Stable expression of truncated ASXL1-BAP1 in hematopoietic cell lines, global histone modification analysis, BAP1 catalytic mutant rescue, in vivo bone marrow experiments Nature communications High 26095772
2016 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. Biochemical reconstitution, nucleosome binding assays, deubiquitinase activity assays, domain deletion mutants Nature communications High 26739236
2023 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. Cryo-EM structure determination, biochemical and cellular validation of interface mutants Science advances High 37556531
2013 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. Retroviral expression of ASXL1-MT in mouse hematopoietic progenitors, transplantation model, gene expression analysis, ChIP for H3K27me3 The Journal of clinical investigation High 24216483
2018 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. Co-immunoprecipitation, deubiquitinase activity assays, ChIP-seq for H2AK119Ub, bone marrow transplantation in vivo model, BAP1 shRNA knockdown Nature communications High 30013160
2017 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. LC-MS/MS, co-immunoprecipitation, ATAC-seq, RNA-seq, epigenetic drug screening in transgenic mouse model Blood High 29113963
2018 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. Co-immunoprecipitation, mass spectrometry, O-GlcNAcylation assay, ChIP for H3K4me3, knockdown/rescue experiments in vivo and in vitro Leukemia High 29556021
2021 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. Co-immunoprecipitation, AKT deubiquitination assay, knockin mouse model, rapamycin treatment rescue, competitive transplantation Nature communications High 33758188
2015 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. ChIP-seq showing ASXL1 and BAP1 enrichment at INK4B locus, deubiquitylation assay, ASXL1 KD in multiple cell lines, primary bone marrow analysis Cell research High 26470845
2018 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. Co-immunoprecipitation (mutant vs. WT ASXL1 with BMI1), H2AK119Ub1 ChIP at p16Ink4a promoter, knockin mouse model, genetic rescue with p16Ink4a deletion Leukemia High 29967380
2018 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. Conditional knockin mouse model, ChIP-seq for H3K4me3, H2AK119Ub, H3K27me3; competitive transplantation; viral insertional mutagenesis The Journal of experimental medicine High 29643185
2021 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. 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 Cell reports High 34433054
2018 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. Co-immunoprecipitation, ChIP-seq for ASXL1 and RNAPII, RNA-seq, conditional Asxl1 deletion in BMSCs Cell discovery High 29423272
2021 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. Biochemical protein stability assays, ChIP for BAP1 chromatin recruitment, RNA-seq transcriptome analysis, BAP1 inhibitor screen, in vivo xenograft tumor progression model Nature cancer High 35122023
2020 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). Co-immunoprecipitation, CRISPR deletion of mutant allele, RNA-seq, allele-specific protein expression analysis Protein & cell High 32683582
2020 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. ChIP-seq for BAP1, ASXL proteins, H2AK119Ub1; ASXL and FOXK1/2 depletion; comparative analysis with EZH2/PRC2 targets Genome research High 32747411
2013 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. Conditional/constitutive Asxl1 knockout mice, hematopoietic-specific deletion, RNA-seq, ChIP-seq, serial transplantation, Tet2 double KO epistasis The Journal of experimental medicine High 24218140
2017 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. Co-immunoprecipitation, domain mapping, MEF knockout model, IGF-1 stimulation assay, AKT inhibitor, microarray, SA-β-gal senescence staining Scientific reports Medium 28701722
2015 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. Mass spectrometry (LC-MS/MS), Western blot analysis in homozygous mutant cell lines Experimental hematology Medium 26700326
2021 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. CRISPR-engineered primary human HSPC model, ATAC-seq, RNA-seq, ChIP/CUT&RUN for H2AK119Ub, xenotransplantation model Blood cancer discovery High 38359087
2013 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. Lentiviral shRNA knockdown of ASXL1 in human CD34+ cells, colony-forming assays, flow cytometry, gene expression profiling British journal of haematology Medium 23294243
2018 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. Conditional Asxl1 deletion in myeloid cells, ChIP for H3K27me3/H3K4me3, Jmjd3 knockdown rescue, NFATc1 ChIP at Blimp1 promoter Blood advances High 30266822
2013 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. Constitutional Asxl1 knockout mice, flow cytometry, global histone modification analysis, gene expression profiling Blood Medium 24255920
2024 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. 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 Proceedings of the National Academy of Sciences of the United States of America High 39752521
2021 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. In vitro binding studies (pull-down/affinity), peptide competition, isothermal calorimetry/NMR-type binding measurements for ET-domain interaction Journal of molecular biology Medium 34536441
2018 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. ChIP for histone acetylation marks at TGFβ pathway gene promoters, constitutively active ALK5-TD rescue, vorinostat treatment, co-expression mouse bone marrow transplant model Scientific reports Medium 30367089
2013 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. Co-immunoprecipitation, ChIP at ABCA1 promoter, luciferase transcription assays, ASXL1 knockdown with lipid accumulation assay Biochemical and biophysical research communications Medium 24321552
2020 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. ChIP for ASXL1 and H2AK119Ub at Pten promoter, Asxl1 depletion IL3-independence assay, correlation analysis in patient data, AKT inhibitor sensitivity assay Journal of molecular cell biology Medium 32236560
2015 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. Co-immunoprecipitation (Asxl1-Wtip), Asxl1-null mouse embryo kidney morphology analysis, gene expression analysis of Wt1/Wtip targets Biochemical and biophysical research communications Medium 26385183
2018 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. Asxl1-null mouse lung model, HCF-1 purification/Co-IP, ChIP for H3K27me3 and H3K9me3 at Nmyc promoter, domain mapping Cell death & disease Medium 30389914
2024 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. Genetic Kdm6b deletion in Asxl1 transgenic mice, ChIP for H3K27me3, RNA-seq, NSG xenograft with KDM6B inhibitor treatment The Journal of clinical investigation High 37917239
2006 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. Sequence analysis, Northern blot, whole-mount RNA in situ hybridization Gene Low 16412590

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression. Cancer cell 505 22897849
2009 Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. British journal of haematology 480 19388938
2010 Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia 419 20428194
2013 Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo. The Journal of experimental medicine 285 24218140
2015 Cancer-associated ASXL1 mutations may act as gain-of-function mutations of the ASXL1-BAP1 complex. Nature communications 173 26095772
2016 BAP1/ASXL1 recruitment and activation for H2A deubiquitination. Nature communications 169 26739236
2013 Loss of Asxl1 leads to myelodysplastic syndrome-like disease in mice. Blood 156 24255920
2013 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. Leukemia 150 23628959
2020 Clonal myelopoiesis in the UK Biobank cohort: ASXL1 mutations are strongly associated with smoking. Leukemia 149 32518416
2013 Myelodysplastic syndromes are induced by histone methylation–altering ASXL1 mutations. The Journal of clinical investigation 148 24216483
2017 Gain of function of ASXL1 truncating protein in the pathogenesis of myeloid malignancies. Blood 143 29113963
2010 Combined mutations of ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 and WT1 genes in myelodysplastic syndromes and acute myeloid leukemias. BMC cancer 134 20678218
2018 Expression of mutant Asxl1 perturbs hematopoiesis and promotes susceptibility to leukemic transformation. The Journal of experimental medicine 130 29643185
2011 CBL, CBLB, TET2, ASXL1, and IDH1/2 mutations and additional chromosomal aberrations constitute molecular events in chronic myelogenous leukemia. Blood 128 21346257
2012 Mutation analysis of ASXL1, CBL, DNMT3A, IDH1, IDH2, JAK2, MPL, NF1, SF3B1, SUZ12, and TET2 in myeloproliferative neoplasms. Genes, chromosomes & cancer 125 22489043
2018 Mutant ASXL1 cooperates with BAP1 to promote myeloid leukaemogenesis. Nature communications 111 30013160
2019 The role of ASXL1 in hematopoiesis and myeloid malignancies. Cellular and molecular life sciences : CMLS 105 30927018
2012 Single nucleotide polymorphism array lesions, TET2, DNMT3A, ASXL1 and CBL mutations are present in systemic mastocytosis. PloS one 98 22905207
2021 Mutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway. Nature communications 87 33758188
2014 Dynamics of ASXL1 mutation and other associated genetic alterations during disease progression in patients with primary myelodysplastic syndrome. Blood cancer journal 83 24442206
2014 SETBP1 mutations drive leukemic transformation in ASXL1-mutated MDS. Leukemia 79 25306901
2006 Characterization of Asxl1, a murine homolog of Additional sex combs, and analysis of the Asx-like gene family. Gene 79 16412590
2009 ASXL1 represses retinoic acid receptor-mediated transcription through associating with HP1 and LSD1. The Journal of biological chemistry 77 19880879
2010 High-density single nucleotide polymorphism array analysis and ASXL1 gene mutation screening in chronic myeloid leukemia during disease progression. Leukemia 71 20410925
2021 Epigenetic targeted therapy of stabilized BAP1 in ASXL1 gain-of-function mutated leukemia. Nature cancer 70 35122023
2013 Cooperating gene mutations in childhood acute myeloid leukemia with special reference on mutations of ASXL1, TET2, IDH1, IDH2, and DNMT3A. Blood 69 23365461
2011 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. Haematologica 69 21712540
2019 Circ-ITGA7 sponges miR-3187-3p to upregulate ASXL1, suppressing colorectal cancer proliferation. Cancer management and research 63 31372051
2015 Truncation mutants of ASXL1 observed in myeloid malignancies are expressed at detectable protein levels. Experimental hematology 61 26700326
2018 A novel ASXL1-OGT axis plays roles in H3K4 methylation and tumor suppression in myeloid malignancies. Leukemia 60 29556021
2021 ASXL1 mutations are associated with distinct epigenomic alterations that lead to sensitivity to venetoclax and azacytidine. Blood cancer journal 58 34548471
2015 Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance. American journal of medical genetics. Part A 57 25921057
2015 ASXL1 mutation correction by CRISPR/Cas9 restores gene function in leukemia cells and increases survival in mouse xenografts. Oncotarget 55 26623729
2020 PR-DUB maintains the expression of critical genes through FOXK1/2- and ASXL1/2/3-dependent recruitment to chromatin and H2AK119ub1 deubiquitination. Genome research 54 32747411
2020 ASXL1 mutation in clonal hematopoiesis. Experimental hematology 53 31945396
2015 Functional proteomics of the epigenetic regulators ASXL1, ASXL2 and ASXL3: a convergence of proteomics and epigenetics for translational medicine. Expert review of proteomics 52 25835095
2022 ASXL1 mutations predict inferior molecular response to nilotinib treatment in chronic myeloid leukemia. Leukemia 49 35902731
2022 Asxl1 loss cooperates with oncogenic Nras in mice to reprogram the immune microenvironment and drive leukemic transformation. Blood 48 34699595
2015 Genetic landscape of recurrent ASXL1, U2AF1, SF3B1, SRSF2, and EZH2 mutations in 304 Chinese patients with myelodysplastic syndromes. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 46 26508027
2017 The distinct biological implications of Asxl1 mutation and its roles in leukemogenesis revealed by a knock-in mouse model. Journal of hematology & oncology 45 28697759
2022 ASXL1 and STAG2 are common mutations in GATA2 deficiency patients with bone marrow disease and myelodysplastic syndrome. Blood advances 44 34529785
2022 ASXL1/2 mutations and myeloid malignancies. Journal of hematology & oncology 42 36068610
2018 Modeling ASXL1 mutation revealed impaired hematopoiesis caused by derepression of p16Ink4a through aberrant PRC1-mediated histone modification. Leukemia 42 29967380
2023 Structural basis of histone H2A lysine 119 deubiquitination by Polycomb repressive deubiquitinase BAP1/ASXL1. Science advances 41 37556531
2016 ASXL1 plays an important role in erythropoiesis. Scientific reports 41 27352931
2015 Tumor suppressor ASXL1 is essential for the activation of INK4B expression in response to oncogene activity and anti-proliferative signals. Cell research 41 26470845
2011 TET2, ASXL1, IDH1, IDH2, and c-CBL genes in JAK2- and MPL-negative myeloproliferative neoplasms. Annals of hematology 41 21904853
2024 Atrial Fibrillation and Clonal Hematopoiesis in TET2 and ASXL1. JAMA cardiology 39 38598228
2012 TET2, ASXL1 and EZH2 mutations in Chinese with myelodysplastic syndromes. Leukemia research 38 23099237
2022 CHIP-associated mutant ASXL1 in blood cells promotes solid tumor progression. Cancer science 34 35133065
2019 RUNX1 mutations promote leukemogenesis of myeloid malignancies in ASXL1-mutated leukemia. Journal of hematology & oncology 34 31640815
2015 Impact of TET2, SRSF2, ASXL1 and SETBP1 mutations on survival of patients with chronic myelomonocytic leukemia. Experimental hematology & oncology 33 26019984
2017 Exome sequencing reveals DNMT3A and ASXL1 variants associate with progression of chronic myeloid leukemia after tyrosine kinase inhibitor therapy. Leukemia research 32 28667884
2018 ASXL1 and SETBP1 mutations promote leukaemogenesis by repressing TGFβ pathway genes through histone deacetylation. Scientific reports 30 30367089
2021 A histone modifier, ASXL1, interacts with NONO and is involved in paraspeckle formation in hematopoietic cells. Cell reports 29 34433054
2020 Tumor-derived neomorphic mutations in ASXL1 impairs the BAP1-ASXL1-FOXK1/K2 transcription network. Protein & cell 29 32683582
2018 Loss of ASXL1 in the bone marrow niche dysregulates hematopoietic stem and progenitor cell fates. Cell discovery 29 29423272
2012 Role of TET2 and ASXL1 mutations in the pathogenesis of myeloproliferative neoplasms. Hematology/oncology clinics of North America 28 23009937
2018 Chromatin regulator Asxl1 loss and Nf1 haploinsufficiency cooperate to accelerate myeloid malignancy. The Journal of clinical investigation 26 30226831
2018 ASXL1 impairs osteoclast formation by epigenetic regulation of NFATc1. Blood advances 26 30266822
2018 ASXL1 mutations in AML are associated with specific clinical and cytogenetic characteristics. Leukemia & lymphoma 24 29411666
2017 ASXL1 mutations in myeloid neoplasms: pathogenetic considerations, impact on clinical outcomes and survival. Current medical research and opinion 24 28027687
2021 Asxl1 C-terminal mutation perturbs neutrophil differentiation in zebrafish. Leukemia 23 33483612
2018 Clinical molecular testing for ASXL1 c.1934dupG p.Gly646fs mutation in hematologic neoplasms in the NGS era. PloS one 23 30222780
2023 ASXL1 mutations accelerate bone marrow fibrosis via EGR1-TNFA axis-mediated neoplastic fibrocyte generation in myeloproliferative neoplasms. Haematologica 22 36005555
2022 Role of ASXL1 in hematopoiesis and myeloid diseases. Experimental hematology 22 36183966
2017 Asxl1 deficiency in embryonic fibroblasts leads to cellular senescence via impairment of the AKT-E2F pathway and Ezh2 inactivation. Scientific reports 21 28701722
2024 Human ASXL1-Mutant Hematopoiesis Is Driven by a Truncated Protein Associated with Aberrant Deubiquitination of H2AK119. Blood cancer discovery 20 38359087
2019 Co-occurrence of RUNX1 and ASXL1 mutations underlie poor response and outcome for MDS patients treated with HMAs. American journal of translational research 20 31312376
2018 Bohring-Opitz syndrome caused by an ASXL1 mutation inherited from a germline mosaic mother. American journal of medical genetics. Part A 20 29681100
2013 Silencing of ASXL1 impairs the granulomonocytic lineage potential of human CD34⁺ progenitor cells. British journal of haematology 20 23294243
2018 ASXL1/EZH2 mutations promote clonal expansion of neoplastic HSC and impair erythropoiesis in PMF. Leukemia 19 29907810
2018 Aberrant histone modifications induced by mutant ASXL1 in myeloid neoplasms. International journal of hematology 18 30515738
2023 Epigenetic regulation by ASXL1 in myeloid malignancies. International journal of hematology 17 37062051
2020 ASXL1 mutation as a surrogate marker in acute myeloid leukemia with myelodysplasia-related changes and normal karyotype. Cancer medicine 17 32216059
2020 HHEX promotes myeloid transformation in cooperation with mutant ASXL1. Blood 17 32492700
2016 Loss of Asxl1 Alters Self-Renewal and Cell Fate of Bone Marrow Stromal Cell, Leading to Bohring-Opitz-like Syndrome in Mice. Stem cell reports 17 27237378
2019 Pathological ASXL1 Mutations and Protein Variants Impair Neural Crest Development. Stem cell reports 16 31006630
2019 Disruption of asxl1 results in myeloproliferative neoplasms in zebrafish. Disease models & mechanisms 16 31064769
2021 The ASXL1-G643W variant accelerates the development of CEBPA mutant acute myeloid leukemia. Haematologica 15 32381577
2016 Dynamic ASXL1 Exon Skipping and Alternative Circular Splicing in Single Human Cells. PloS one 15 27736885
2013 Reciprocal regulation of LXRα activity by ASXL1 and ASXL2 in lipogenesis. Biochemical and biophysical research communications 15 24321552
2020 Deregulation of tumor suppressive ASXL1-PTEN/AKT axis in myeloid malignancies. Journal of molecular cell biology 14 32236560
2015 Familial hematological malignancies: ASXL1 gene investigation. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 13 26286068
2014 ASXL1 and DNMT3A mutation in a cytogenetically normal B3 thymoma. Oncogenesis 13 25000259
2023 Multiomics of Bohring-Opitz syndrome truncating ASXL1 mutations identify canonical and noncanonical Wnt signaling dysregulation. JCI insight 12 37053013
2020 ASXL1 mutations, previous vascular complications and age at diagnosis predict survival in 85 WHO-defined polycythaemia vera patients. British journal of haematology 12 32066200
2016 Loss of ASXL1 triggers an apoptotic response in human hematopoietic stem and progenitor cells. Experimental hematology 12 27616637
2024 DNMT3A/TET2/ASXL1 Mutations are an Age-independent Thrombotic Risk Factor in Polycythemia Vera Patients: An Observational Study. Thrombosis and haemostasis 11 38190984
2022 LINC00586 Represses ASXL1 Expression Thus Inducing Epithelial-To-Mesenchymal Transition of Colorectal Cancer Cells Through LSD1-Mediated H3K4me2 Demethylation. Frontiers in pharmacology 11 35586041
2020 Loss of ASXL1 expression is associated with lymph node metastasis in colorectal cancer. Indian journal of pathology & microbiology 11 32317519
2018 Asxl1 exerts an antiproliferative effect on mouse lung maturation via epigenetic repression of the E2f1-Nmyc axis. Cell death & disease 11 30389914
2015 Role of Asxl1 in kidney podocyte development via its interaction with Wtip. Biochemical and biophysical research communications 11 26385183
2015 Screening of CD96 and ASXL1 in 11 patients with Opitz C or Bohring-Opitz syndromes. American journal of medical genetics. Part A 11 26768331
2021 Oncogenic Truncations of ASXL1 Enhance a Motif for BRD4 ET-Domain Binding. Journal of molecular biology 10 34536441
2018 Acute myeloid leukemia in a father and son with a germline mutation of ASXL1. Biomarker research 10 29456859
2025 A mutant ASXL1-BAP1-EHMT complex contributes to heterochromatin dysfunction in clonal hematopoiesis and chronic monomyelocytic leukemia. Proceedings of the National Academy of Sciences of the United States of America 9 39752521
2024 Targeting lysine demethylase 6B ameliorates ASXL1 truncation-mediated myeloid malignancies in preclinical models. The Journal of clinical investigation 9 37917239
2021 Reducing hyperactivated BAP1 attenuates mutant ASXL1-driven myeloid malignancies in human haematopoietic cells. Cancer letters 9 34186160
2020 Hcfc1a regulates neural precursor proliferation and asxl1 expression in the developing brain. BMC neuroscience 9 32522152

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