Affinage

IKZF3

Zinc finger protein Aiolos · UniProt Q9UKT9

Length
509 aa
Mass
58.0 kDa
Annotated
2026-06-10
100 papers in source corpus 38 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IKZF3 (Aiolos) is a lymphoid zinc finger transcription factor that acts predominantly as a sequence-specific transcriptional repressor governing lymphocyte development, differentiation, and activation (PMID:39179932, PMID:22751139). It heterodimerizes with Ikaros, and homo- versus heteromeric complexes carry distinct transcriptional activities, with dominant-negative Ikaros isoforms interfering with Aiolos function (PMID:9155026). Repression is executed through two repression domains that recruit mSin3 and the NuRD nucleosome-remodeling/deacetylase machinery to drive promoter histone deacetylation, and is relieved by HDAC inhibitors (PMID:10357820, PMID:30228232). Aiolos directly binds and silences a defined target set including the surrogate light chain genes Igll1/Vpreb1, c-Myc, Il2, and interferon-stimulated genes such as CD38, thereby enforcing cell-cycle withdrawal and developmental checkpoints (PMID:39179932, PMID:20566697, PMID:22751139, PMID:30228232). DNA binding requires intact zinc-finger residues (N160) and directs the protein to pericentromeric heterochromatin (PMID:31251838, PMID:34155405). Across lineages it shapes B cell development and high-affinity plasma cell generation, NK cell maturation, TH17, TFH, CD4/CD8 cytotoxic and virtual-memory programming, and tissue lymphocyte restraint, often by co-opting or antagonizing STAT5/STAT1 activity at target loci (PMID:14718515, PMID:25319415, PMID:38182668, PMID:36964178, PMID:38049581). Aiolos protein abundance is controlled by the CRBN-CRL4 E3 ubiquitin ligase, which mediates IMiD/CELMoD drug-induced ubiquitination and proteasomal degradation (PMID:24292625, PMID:24328678, PMID:28425720), and its chromatin association is dynamically regulated by phosphorylation, including PBK/TOPK-mediated eviction during mitosis (PMID:40987773). Heterozygous missense variants in the DNA-binding zinc fingers cause disease through dominant-negative heterodimeric interference with IKAROS, altering DNA-binding specificity to drive immunodeficiency and CLL-like malignancy, whereas variants affecting dimerization or the stability domain cause haploinsufficiency (PMID:34155405, PMID:33689703, PMID:34694366, PMID:38015619).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1997 High

    Established Aiolos as an Ikaros-family partner whose transcriptional output depends on the composition of its dimeric complexes, defining the combinatorial logic of the family.

    Evidence Molecular cloning with heterodimerization and transcriptional activity assays

    PMID:9155026

    Open questions at the time
    • Did not define DNA target sequences
    • Did not identify co-repressor machinery
  2. 1999 High

    Defined the molecular mechanism of repression by linking Aiolos/Ikaros repression domains to mSin3-HDAC recruitment and promoter histone deacetylation.

    Evidence In vivo/in vitro Co-IP, HDAC inhibitor treatment, and histone acetylation assays

    PMID:10357820

    Open questions at the time
    • Did not map endogenous target genes
    • Did not address NuRD versus mSin3 selectivity
  3. 1998 High

    Demonstrated through genetic ablation that Aiolos negatively regulates BCR signaling and is required for specific peripheral B cell populations, anchoring its physiological role in B lymphocytes.

    Evidence Aiolos-null mouse with BCR stimulation, flow cytometry, and immunization

    PMID:9806640

    Open questions at the time
    • Did not identify direct target genes underlying the phenotype
    • Cell-intrinsic versus extrinsic contribution not resolved here
  4. 2008 High

    Identified direct developmental targets, showing Aiolos enforces the pre-B checkpoint by silencing and repositioning surrogate light chain genes, later confirmed by acute degradation/ChIP-seq.

    Evidence Aiolos/OBF-1 double-KO mice, FISH repositioning, and auxin-inducible degron with ChIP-seq

    PMID:17971486 PMID:18974788 PMID:39179932

    Open questions at the time
    • Mechanism of locus repositioning incompletely defined
    • Relative contribution of OBF-1 antagonism versus direct repression
  5. 2010 High

    Connected Aiolos repressor activity to proliferative control by showing direct binding and suppression of the c-Myc promoter precedes cell-cycle exit.

    Evidence ChIP and gain/loss-of-function in pre-B cells

    PMID:20566697

    Open questions at the time
    • Co-repressor complex at the c-Myc promoter not specified
    • Direct versus indirect p27/cyclin D3 effects
  6. 2012 High

    Extended the repressor model to T helper differentiation by identifying upstream inducers (STAT3/AhR) and a direct Il2 silencing event driving TH17 fate.

    Evidence Aiolos-deficient mice with TH17 differentiation and Il2 chromatin analysis

    PMID:22751139

    Open questions at the time
    • Genome-wide TH17 target set not fully defined
    • Co-repressor recruitment in T cells not addressed
  7. 2013 High

    Revealed that IMiD drugs act by hijacking the CRBN-CRL4 ligase to ubiquitinate and degrade Aiolos, explaining their anti-tumor and immunomodulatory effects.

    Evidence Quantitative proteomics, ubiquitination assays, and mutagenesis-based rescue

    PMID:24292625 PMID:24328678

    Open questions at the time
    • Degron structural basis not yet defined in these studies
    • Downstream transcriptional consequences of degradation not fully mapped
  8. 2017 High

    Provided the structural and kinetic basis for differential drug-induced degradation, with crystallography of cereblon-compound complexes and rate-of-degradation correlations to efficacy.

    Evidence X-ray crystallography of cereblon-DDB1-CC-220 plus kinetic degradation assays

    PMID:26430725 PMID:28425720

    Open questions at the time
    • Full Aiolos degron contacts not resolved in the structure
    • In vivo kinetics in patients not addressed
  9. 2018 High

    Showed Aiolos loss alone recapitulates IMiD effects in myeloma and that Aiolos/Ikaros repress interferon-stimulated genes (including CD38) via NuRD, linking degradation to an interferon-like death program.

    Evidence CRISPR knockout, RNA-seq, NuRD Co-IP, and CD38/ADCC assays

    PMID:30228232

    Open questions at the time
    • Direct versus indirect ISG regulation not fully separated
    • NuRD subunit selectivity not defined
  10. 2021 High

    Defined the disease mechanism of zinc-finger missense variants as dominant-negative heterodimeric interference that redirects DNA binding, causing immunodeficiency and CLL-like malignancy.

    Evidence Knockin and conditional knockin mouse models with ChIP-seq, DNA binding, and dimerization-deficient rescue

    PMID:33689703 PMID:34155405 PMID:34694366

    Open questions at the time
    • Why specific neomorphic genomic sites are bound is unresolved
    • Penetrance determinants of malignancy unknown
  11. 2024 Medium

    Defined post-translational and domain-level control of Aiolos: PBK/TOPK phosphorylation evicts it from mitotic chromosomes, and ZF5-6/stability-domain variants cause haploinsufficiency, distinguishing dominant-negative from loss-of-expression mechanisms.

    Evidence Pbk-/- mice with chromatin proteomics/ATAC-seq, and patient variant biochemistry/stability assays

    PMID:38015619 PMID:40987773

    Open questions at the time
    • Functional consequence of mitotic eviction for gene expression not fully traced
    • OTUB1-mediated stabilization (#36) rests on a single low-confidence Co-IP
  12. 2024 High

    Broadened the lineage role of Aiolos by showing it binds AP-1 factors and balances STAT5/STAT1-driven programs across NK, CD4-CTL, virtual-memory, and tissue lymphocytes, acting as a node that tunes cytokine responsiveness.

    Evidence Conditional double KO with ChIP, plus multiple Ikzf3-/- models with ChIP for STAT occupancy

    PMID:36964178 PMID:38049581 PMID:38182668 PMID:38363226 PMID:39560988 PMID:41392082

    Open questions at the time
    • Whether STAT antagonism is via direct competition or chromatin closure varies by locus
    • Co-repressor requirement in these contexts not uniformly tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the choice between canonical repression complexes (mSin3 vs NuRD), neomorphic DNA targeting by mutants, and lineage-specific STAT partnering is mechanistically selected remains unresolved.
  • No structural model of Aiolos-DNA or Aiolos-co-repressor complexes
  • Rules governing context-specific target selection unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 4 GO:0003677 DNA binding 3 GO:0042393 histone binding 2
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 2
Pathway
R-HSA-168256 Immune System 4 R-HSA-4839726 Chromatin organization 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
CRBNIKZF1OTUB1PBKPOU2AF1PRDM1STAT1STAT5
Complex memberships
CRL4(CRBN) E3 ubiquitin ligase (substrate)NuRD complexmSin3-HDAC co-repressor complex

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 Lenalidomide causes selective ubiquitination and degradation of IKZF3 (Aiolos) by the CRBN-CRL4 E3 ubiquitin ligase complex; a single amino acid substitution in IKZF3 conferred resistance to lenalidomide-induced degradation and rescued lenalidomide-induced inhibition of cell growth. IKZF3 degradation also mediates lenalidomide-induced IL-2 production in T cells. Quantitative proteomics, ubiquitination assays, mutagenesis (single amino acid substitution), cell growth rescue experiments Science (New York, N.Y.) High 24292625
2013 Lenalidomide and pomalidomide induce interaction of IKZF3 (Aiolos) with CRL4(CRBN), promoting IKZF3 binding to the complex, enhanced ubiquitination, and cereblon-dependent proteasomal degradation in T lymphocytes. IKZF3 and IKZF1 function as transcriptional repressors of IL-2 expression. Co-immunoprecipitation, ubiquitination assays, Western blot, flow cytometry, reporter gene assays British journal of haematology High 24328678
1997 IKZF3 (Aiolos) heterodimerizes with Ikaros proteins; mutant dominant-negative Ikaros isoforms interfere with Aiolos activity, demonstrating functional interdependence. Aiolos homo- and heteromeric complexes with Ikaros have distinct relative transcriptional activities. Molecular cloning, protein interaction studies (heterodimerization assays), transcriptional activity assays, expression analysis The EMBO journal High 9155026
1998 Aiolos-null B cells exhibit augmented BCR-mediated proliferative responses and an activated surface phenotype, establishing Aiolos as a negative regulator of BCR signaling and B cell activation. Peritoneal, marginal zone, and recirculating bone marrow B cell populations are greatly reduced in Aiolos-deficient mice. Aiolos-null mouse model, in vitro BCR stimulation proliferation assays, flow cytometry, in vivo immunization Immunity High 9806640
1999 Ikaros and Aiolos function as transcriptional repressors through two repression domains; repression correlates with histone deacetylation at promoters and is relieved by HDAC inhibitors. Ikaros/Aiolos repression domains interact in vivo and in vitro with mSin3 co-repressors that bind HDACs. Transcriptional repression assays, HDAC inhibitor treatment, histone acetylation assays (chromatin), co-immunoprecipitation (in vivo and in vitro) The EMBO journal High 10357820
1999 Aiolos interacts with Ras in T cells; IL-2 controls subcellular distribution of Aiolos and induces its tyrosine phosphorylation, required for dissociation from Ras. Aiolos binds functional sites in the Bcl-2 promoter and activates Bcl-2 transcription, preventing apoptosis in IL-2-deprived cells. Co-immunoprecipitation (in vitro and in vivo), indirect immunofluorescence, promoter reporter (luciferase) assays, site-directed mutagenesis of Bcl-2 promoter, co-transfection experiments The EMBO journal Medium 10369681
2001 Aiolos associates with Bcl-xL in IL-4-stimulated T cells; IL-4 deprivation increases the Bcl-xL/Aiolos interaction. IL-4 induces tyrosine phosphorylation of Aiolos, required for dissociation from Bcl-xL. Cells overexpressing both Bcl-xL and Aiolos cannot block apoptosis, establishing Aiolos as a regulator of Bcl-xL anti-apoptotic function. Yeast two-hybrid, co-immunoprecipitation, indirect immunofluorescence, co-transfection overexpression experiments Journal of immunology (Baltimore, Md. : 1950) Medium 11714801
2001 BCR signaling and MZ B cell development are regulated by Aiolos in epistasis with Btk and CD21; loss of Aiolos enhances follicular B cell maturation signals through a pathway requiring Btk, placing Btk downstream of (epistatic to) Aiolos. Genetic epistasis analysis using Aiolos-null, Btk-null, and CD21-null mouse models Immunity Medium 11371362
2004 Aiolos is specifically required (in a B cell-intrinsic manner demonstrated by chimera reconstitution) for the generation of high-affinity bone marrow plasma cells responsible for long-term immunity, without affecting somatic hypermutation, memory B cells, or short-lived splenic plasma cells. Aiolos-null mouse model, bone marrow chimera reconstitution, serum antibody titer measurement, immunization with hapten concentrations The Journal of experimental medicine High 14718515
2010 Aiolos and Ikaros directly bind the c-Myc promoter in pre-B cells in vivo and suppress c-Myc expression. Downregulation of c-Myc is required for the growth-inhibitory effect of Aiolos/Ikaros and precedes p27 induction and cyclin D3 downregulation, establishing c-Myc as a direct downstream target. ChIP (chromatin immunoprecipitation), gene expression analysis, gain/loss-of-function in pre-B cells Molecular and cellular biology High 20566697
2007 IRF4 and IRF8 induce Aiolos expression in pre-B cells; reconstitution of Aiolos (or Ikaros) expression is sufficient to suppress surrogate light chain expression and down-regulate pre-BCR in cells lacking IRF4/8. Aiolos is required downstream of IRF4/8 for cell-cycle withdrawal. Gain- and loss-of-function experiments in pre-B cells, gene expression analysis, cell cycle analysis Blood Medium 17971486
2012 Under TH17-polarizing conditions, STAT3 and AhR upregulate Aiolos expression. Aiolos directly silences the Il2 locus, promoting TH17 differentiation in vitro and in vivo, demonstrated using Aiolos-deficient mice. Aiolos-deficient mouse model, in vitro and in vivo TH17 differentiation assays, chromatin analysis of Il2 locus Nature immunology High 22751139
2014 Aiolos is required for peripheral NK cell maturation; Aiolos expression is initiated at NK lineage commitment. Loss of Aiolos causes a block in CD11b(high)CD27(-) NK cell maturation intrinsic to the NK lineage, and genetic analysis revealed Aiolos acts independently of T-bet and Blimp1. Aiolos-null mouse model, flow cytometry of NK maturation stages, cell surface marker analysis, genetic epistasis with T-bet and Blimp1 null mice, NK cell tumor and viral infection models The EMBO journal High 25319415
2014 Aiolos reconfigures chromatin structure within the SHC1 gene, causing isoform-specific silencing of p66Shc (an anchorage reporter), blocking anoikis. Aiolos also decreases expression of adhesion-related genes, disrupting cell-cell and cell-matrix interactions in cancer cells. Chromatin analysis (epigenetic assays), gene expression profiling, anoikis assays in vitro and in vivo (xenograft) Cancer cell Medium 24823637
2015 The rate (half-maximal rate) of CRL4(CRBN)-dependent Aiolos and Ikaros degradation—not the final extent—correlates with the relative anti-proliferative efficacy of lenalidomide vs. pomalidomide. Sequential downregulation of Aiolos/Ikaros → c-Myc → IRF4 is required for growth inhibition and apoptosis in MM cells. Kinetic degradation analysis, Western blot time course, cell growth inhibition and apoptosis assays Blood cancer journal Medium 26430725
2016 Aiolos interacts with Blimp-1 in multiple myeloma cells (identified by mass spectrometry). Aiolos and Blimp-1 co-bind a large number of genomic targets including apoptosis-related genes. Aiolos promotes Blimp-1 binding to target genes and enhances Blimp-1-dependent transcriptional repression. Mass spectrometry (Aiolos-Blimp-1 interaction), ChIP-chip (genome-wide co-binding), transcriptome analysis, functional repression assays Cell death and differentiation Medium 26823144
2017 CC-220 (iberdomide) binds cereblon with higher affinity than lenalidomide or pomalidomide, resulting in more potent and extensive cellular degradation of Ikaros and Aiolos. Crystal structure of cereblon-DDB1-CC-220 complex reveals additional contacts between CC-220 and cereblon outside the modeled IKZF1/IKZF3 binding site that account for increased potency. Crystal structure (X-ray crystallography) of cereblon-DDB1-compound complex, binding affinity measurements, cellular degradation assays Journal of medicinal chemistry High 28425720
2018 CRISPR-Cas9 deletion of IKZF3 (Aiolos) alone in MM cell lines recapitulates IMiD-induced cell cycle arrest and apoptosis. Aiolos/Ikaros repress interferon-stimulated genes (ISGs) including CD38 through interaction with the NuRD (nucleosome remodeling and deacetylase) complex, and their loss activates an interferon-like response that contributes to MM cell death and increases CD38 surface expression. CRISPR-Cas9 knockout, RNA-seq transcriptomics, co-immunoprecipitation (NuRD complex association), flow cytometry (CD38 surface expression), NK cell ADCC assays Blood High 30228232
2021 A heterozygous IKZF3 missense variant (G→R in DNA-binding domain) causes mutant AIOLOS homodimers and AIOLOS-IKAROS heterodimers to fail binding the canonical DNA sequence. Instead, these dimers bind genomic regions lacking canonical motifs. Removal of the dimerization capacity from mutant AIOLOS restored B cell development, establishing that the dominance is due to heterodimeric interference with IKAROS function. Mouse knockin model (corresponding variant), DNA binding assays, ChIP-seq (altered genomic targeting), B cell development analysis, dimerization-deficient variant rescue experiments Nature immunology High 34155405
2021 The IKZF3-L162R hotspot mutation alters DNA binding specificity and target gene selection, causing hyperactivation of BCR signaling and overexpression of NF-κB target genes, driving CLL-like disease in a conditional knockin mouse model (~40% penetrance). B cell-restricted conditional knockin mouse model, ChIP-seq (altered DNA binding), RNA-seq, BCR signaling assays (ibrutinib sensitivity) Cancer cell High 33689703
2021 AIOLOS p.N160S heterozygous variant causes dominant-negative impairment of B and T cell development; mutant protein fails DNA binding and pericentromeric targeting. The mutant has a dominant-negative effect over WT AIOLOS but not WT IKAROS. Patient analysis, in vitro DNA binding assays, pericentromeric targeting assays, murine model recapitulation The Journal of experimental medicine Medium 34694366
2007 Full-length Aiolos isoforms localize to heterochromatin; different Aiolos isoforms arising from alternative splicing have distinct abilities to heterodimerize with Ikaros, associate with HDAC-containing complexes, and produce histone modifications. The cellular activities of Aiolos are dependent on combinations of functional domains determined by differential splicing. Cellular localization studies (immunofluorescence), co-immunoprecipitation (Ikaros heterodimerization, HDAC complex), histone modification assays, DNA-binding assays of isoforms Journal of cell science Medium 17646674
2008 Aiolos and OBF-1 cooperate to silence lambda5 surrogate light chain gene expression and mediate its developmentally regulated nuclear repositioning at the pre-B cell stage; without both factors, lambda5 and VpreB fail to be efficiently silenced, and nuclear repositioning of lambda5 is impaired. Aiolos/OBF-1 double-knockout mouse model, gene expression analysis, nuclear repositioning assays (FISH), light chain rearrangement analysis PloS one Medium 18974788
2003 OBF-1 is required for the SLE-like phenotypes in Aiolos-null mice; loss of OBF-1 reverses B cell hyperproliferation, activation marker overexpression, and spontaneous germinal center formation in Aiolos-null mice. The double-mutant mice show a block in pre-B to immature B cell transition, establishing that Aiolos suppresses OBF-1-dependent B cell activation. Aiolos/OBF-1 double-knockout mouse model, flow cytometry, B cell proliferation assays, antibody measurements Journal of immunology (Baltimore, Md. : 1950) Medium 12574333
2019 N160 is a key amino acid for IKZF3 DNA-binding activity; mutation of N160A results in loss of peripheral heterochromatin localization, dissociation from target genes, and inability to change target gene expression. Site-directed mutagenesis (N160A), immunofluorescence (heterochromatin localization), ChIP (target gene association), gene expression analysis Anatomical record (Hoboken, N.J. : 2007) Medium 31251838
2023 Aiolos deficiency results in reduced expression of key TFH transcription factors and reduced TFH differentiation during influenza infection, while CD4-CTL programming is elevated with enhanced Eomes and cytolytic molecule expression. Aiolos deficiency allows enhanced IL-2 sensitivity and increased STAT5 association with CD4-CTL gene targets including Eomes, effector molecules, and IL2Ra. Aiolos-deficient mouse model (influenza infection), flow cytometry, ChIP (STAT5 occupancy at CD4-CTL gene targets), gene expression analysis Nature communications Medium 36964178
2024 IKZF1 (Ikaros) and IKZF3 (Aiolos) directly bind AP-1 family transcription factors; deletion of both Ikzf1 and Ikzf3 in NK cells results in further reduction of Jun/Fos expression and complete loss of peripheral NK cells. IKZF3 upregulation is observed in Ikzf1-null NK cells, indicating compensatory regulation. Conditional genetic inactivation in NK cells (Ikzf1 and Ikzf3 single and double conditional KO), ChIP (direct AP-1 binding), transcriptional analysis, flow cytometry Nature immunology High 38182668
2024 AIOLOS zinc finger 5-6 domain is required for dimerization; a Q402* truncation mutant lacking ZF5-6 can still homodimerize with WT AIOLOS and negatively regulates DNA binding through ZF1 (a previously unrecognized function for this domain). An E82K variant leads to haploinsufficiency by affecting a protein stability domain. Patient variant analysis, in vitro DNA binding assays, pericentromeric targeting assays, transcriptome analysis, protein stability assays, homodimerization assays The Journal of clinical investigation Medium 38015619
2024 Aiolos represses Eomes expression and the IL-15R subunit CD122 (CD8+ T cell virtual memory regulators); Aiolos-deficient mice show enhanced virtual memory CD8+ T cell frequency and function, establishing Aiolos as a molecular repressor of virtual memory T cell programming. Ikzf3-/- mouse model, flow cytometry, cytokine stimulation assays, gene expression analysis, influenza infection model Nature communications Medium 41392082
2024 PBK/TOPK mitotic kinase phosphorylates Aiolos (IKZF3) to promote its dissociation from chromosomes during mitosis; Aiolos is retained on mitotic chromosomes in Pbk-/- cells, and PBK inhibitor OTS514 rapidly reverses Aiolos eviction from chromosomes. Pbk-/- mouse model, mitotic chromosome fractionation proteomics, immunofluorescence, PBK inhibitor (OTS514) treatment, ATAC-seq (chromatin accessibility) Nature communications Medium 40987773
2024 Aiolos promotes CXCR3 expression on Th1 cells by sustaining expression of JAK2 and STAT1; Aiolos deficiency reduces STAT1 tyrosine phosphorylation and STAT1 enrichment at the Cxcr3 promoter. Aiolos and STAT1 form a positive feedback loop via reciprocal regulation downstream of IFN-γ signaling. Aiolos-deficient mouse model (influenza infection), ChIP (STAT1 at Cxcr3 promoter), flow cytometry (phospho-STAT1), gene expression analysis JCI insight Medium 39560988
2024 Aiolos is a downstream effector of Kidins220 during thymic iNKT cell development. Aiolos expression is downregulated in Kidins220-deficient iNKT cells, and Aiolos KO phenocopies enhanced apoptosis at iNKT stages 2 and 3, placing Aiolos downstream of Kidins220 in this pathway. T cell-specific Kidins220 KO mouse model, Aiolos KO mouse model, scRNA-seq, flow cytometry, apoptosis assays Science advances Medium 38489359
2021 Aiolos facilitates eosinophil tissue homing by supporting IL-5 production and ST2+ ILC2 proliferation through inhibiting PD-1. Aiolos deficiency reduces eosinophil CCR3 surface expression, intracellular ERK1/2 signaling, and CCL11-induced actin polymerization, impairing chemotaxis. Aiolos-deficient mouse model, chimeric mouse model (intrinsic requirement), flow cytometry, ERK1/2 signaling assays, actin polymerization assay, in vivo inflammatory models Mucosal immunology Medium 34341502
2024 In vitro acute protein degradation in mice revealed that Aiolos (together with Ikaros) acts as a dedicated transcriptional repressor to cooperatively control early B cell development; both directly repress surrogate light chain genes Igll1 and Vpreb1 in small pre-B cells. Acute protein degradation (auxin-inducible degron) in mice, ChIP-seq, RNA-seq, chromatin accessibility assays Nature immunology High 39179932
2023 Aiolos restrains intestinal intraepithelial lymphocyte (IEL) activation; Ikzf3-/- CD8αα+ IELs show elevated NK receptors, cytotoxic enzymes, cytokines, and chemokines. Aiolos binding sites are proximal to STAT5 and RUNX binding sites, and Ikzf3 deficiency increases chromatin accessibility and histone acetylation in these regions. Ikzf3 deficiency enhances IL-15 responsiveness of IELs. Ikzf3-/- mouse model, scRNA-seq, ATAC-seq (chromatin accessibility), histone acetylation assays, IL-15 signaling assays, colitis model Nature immunology High 38049581
2024 Aiolos (IKZF3) represses Eos (IKZF4) expression by antagonizing STAT5-dependent activation of the Ikzf4 promoter; this establishes opposing roles of Aiolos and Eos in regulating CD4-CTL cytotoxic programming. Aiolos-deficient and Eos-deficient mouse models (influenza infection), ChIP (STAT5 occupancy at Ikzf4 promoter), flow cytometry, gene expression analysis Journal of immunology (Baltimore, Md. : 1950) Medium 38363226
2024 OTUB1, a deubiquitinating enzyme, specifically binds Aiolos and reduces its ubiquitination, potentially influencing Aiolos stability and its biological functions in lung cancer cell migration and invasion. Co-immunoprecipitation (OTUB1-Aiolos interaction), ubiquitination assays, functional cell migration and invasion assays Heliyon Low 39315162
2021 Intestinal-specific transcription factor AhR binds the Ikzf3 locus, increases chromatin accessibility at an intestinal ILC2-specific open chromatin region, and promotes Ikzf3 transcription by enhancing H3K27ac, establishing AhR as an upstream regulator of Aiolos expression in intestinal ILC2s. ChIP (AhR binding at Ikzf3 locus), ATAC-seq (chromatin accessibility), H3K27ac ChIP-seq, gene expression analysis Mucosal immunology Medium 34349237

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science (New York, N.Y.) 1492 24292625
2013 Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN.). British journal of haematology 524 24328678
1997 Aiolos, a lymphoid restricted transcription factor that interacts with Ikaros to regulate lymphocyte differentiation. The EMBO journal 317 9155026
1998 Aiolos regulates B cell activation and maturation to effector state. Immunity 262 9806640
1999 Repression by Ikaros and Aiolos is mediated through histone deacetylase complexes. The EMBO journal 259 10357820
2001 The follicular versus marginal zone B lymphocyte cell fate decision is regulated by Aiolos, Btk, and CD21. Immunity 258 11371362
2017 A Cereblon Modulator (CC-220) with Improved Degradation of Ikaros and Aiolos. Journal of medicinal chemistry 217 28425720
2012 Aiolos promotes TH17 differentiation by directly silencing Il2 expression. Nature immunology 215 22751139
2015 Rate of CRL4(CRBN) substrate Ikaros and Aiolos degradation underlies differential activity of lenalidomide and pomalidomide in multiple myeloma cells by regulation of c-Myc and IRF4. Blood cancer journal 189 26430725
2012 Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as susceptibility loci for systemic lupus erythematosus in a large-scale multiracial replication study. American journal of human genetics 156 22464253
2004 Aiolos is required for the generation of high affinity bone marrow plasma cells responsible for long-term immunity. The Journal of experimental medicine 118 14718515
2003 Ikaros, Aiolos and Helios: transcription regulators and lymphoid malignancies. Immunology and cell biology 114 12752680
2010 Ikaros and Aiolos inhibit pre-B-cell proliferation by directly suppressing c-Myc expression. Molecular and cellular biology 106 20566697
2007 Interferon regulatory factors 4 and 8 induce the expression of Ikaros and Aiolos to down-regulate pre-B-cell receptor and promote cell-cycle withdrawal in pre-B-cell development. Blood 91 17971486
2018 IMiDs prime myeloma cells for daratumumab-mediated cytotoxicity through loss of Ikaros and Aiolos. Blood 79 30228232
1999 Aiolos transcription factor controls cell death in T cells by regulating Bcl-2 expression and its cellular localization. The EMBO journal 78 10369681
2019 Suppression of Aiolos and Ikaros expression by lenalidomide reduces human ILC3-ILC1/NK cell transdifferentiation. European journal of immunology 76 31151137
2014 Aiolos promotes anchorage independence by silencing p66Shc transcription in cancer cells. Cancer cell 72 24823637
2014 Peripheral natural killer cell maturation depends on the transcription factor Aiolos. The EMBO journal 72 25319415
2002 Aiolos and Ikaros: regulators of lymphocyte development, homeostasis and lymphoproliferation. Apoptosis : an international journal on programmed cell death 68 11997672
2014 Lenalidomide induces degradation of IKZF1 and IKZF3. Oncoimmunology 66 25610725
2018 Cereblon modulator iberdomide induces degradation of the transcription factors Ikaros and Aiolos: immunomodulation in healthy volunteers and relevance to systemic lupus erythematosus. Annals of the rheumatic diseases 63 29945920
2023 Single-cell epigenetic, transcriptional, and protein profiling of latent and active HIV-1 reservoir revealed that IKZF3 promotes HIV-1 persistence. Immunity 61 37922905
2017 Protein Degradation via CRL4CRBN Ubiquitin Ligase: Discovery and Structure-Activity Relationships of Novel Glutarimide Analogs That Promote Degradation of Aiolos and/or GSPT1. Journal of medicinal chemistry 57 28358507
2013 Human memory Helios- FOXP3+ regulatory T cells (Tregs) encompass induced Tregs that express Aiolos and respond to IL-1β by downregulating their suppressor functions. Journal of immunology (Baltimore, Md. : 1950) 55 24068664
2021 A variant in human AIOLOS impairs adaptive immunity by interfering with IKAROS. Nature immunology 54 34155405
2003 Lack of the transcriptional coactivator OBF-1 prevents the development of systemic lupus erythematosus-like phenotypes in Aiolos mutant mice. Journal of immunology (Baltimore, Md. : 1950) 51 12574333
2021 A hotspot mutation in transcription factor IKZF3 drives B cell neoplasia via transcriptional dysregulation. Cancer cell 50 33689703
2022 Discovery of a First-in-Class Degrader for Nuclear Receptor Binding SET Domain Protein 2 (NSD2) and Ikaros/Aiolos. Journal of medicinal chemistry 46 35895319
2017 Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity. Journal of immunology (Baltimore, Md. : 1950) 43 28848067
2021 IKZF3 deficiency potentiates chimeric antigen receptor T cells targeting solid tumors. Cancer letters 40 34687790
2021 T and B cell abnormalities, pneumocystis pneumonia, and chronic lymphocytic leukemia associated with an AIOLOS defect in patients. The Journal of experimental medicine 40 34694366
2007 Combinatorial effects of splice variants modulate function of Aiolos. Journal of cell science 39 17646674
2021 Role of Aiolos and Ikaros in the Antitumor and Immunomodulatory Activity of IMiDs in Multiple Myeloma: Better to Lose Than to Find Them. International journal of molecular sciences 37 33499314
2010 Deregulation of Aiolos expression in chronic lymphocytic leukemia is associated with epigenetic modifications. Blood 37 21139082
2017 Role of DNA methylation in expression control of the IKZF3-GSDMA region in human epithelial cells. PloS one 36 28241063
2021 Tissue signals imprint Aiolos expression in ILC2s to modulate type 2 immunity. Mucosal immunology 29 34349237
2015 Differential expression of the immunosuppressive enzyme IL4I1 in human induced Aiolos+, but not natural Helios+, FOXP3+ Treg cells. European journal of immunology 28 25446972
2008 The Aiolos transcription factor is up-regulated in chronic lymphocytic leukemia. Blood 28 18184862
2018 Expression of CRBN, IKZF1, and IKZF3 does not predict lenalidomide sensitivity and mutations in the cereblon pathway are infrequent in multiple myeloma. Leukemia & lymphoma 26 29718735
2024 IKAROS and AIOLOS directly regulate AP-1 transcriptional complexes and are essential for NK cell development. Nature immunology 25 38182668
2016 Aiolos collaborates with Blimp-1 to regulate the survival of multiple myeloma cells. Cell death and differentiation 24 26823144
2007 Aiolos controls gene conversion and cell death in DT40 B cells. Scandinavian journal of immunology 23 17523942
2001 The association of Aiolos transcription factor and Bcl-xL is involved in the control of apoptosis. Journal of immunology (Baltimore, Md. : 1950) 23 11714801
2024 Transcriptional function of E2A, Ebf1, Pax5, Ikaros and Aiolos analyzed by in vivo acute protein degradation in early B cell development. Nature immunology 21 39179932
2023 Aiolos represses CD4+ T cell cytotoxic programming via reciprocal regulation of TFH transcription factors and IL-2 sensitivity. Nature communications 21 36964178
2020 IKZF3/Aiolos Is Associated with but Not Sufficient for the Expression of IL-10 by CD4+ T Cells. Journal of immunology (Baltimore, Md. : 1950) 21 32321757
2018 Polymorphisms of IKZF3 Gene and Autoimmune Thyroid Diseases: Associated with Graves' Disease but Not with Hashimoto's Thyroiditis. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 21 29510406
1999 Human aiolos, an ikaros-related zinc finger DNA binding protein: cDNA cloning, tissue expression pattern, and chromosomal mapping. Genomics 21 10552935
2023 The transcription factor Aiolos restrains the activation of intestinal intraepithelial lymphocytes. Nature immunology 18 38049581
2021 Effects of targeting the transcription factors Ikaros and Aiolos on B cell activation and differentiation in systemic lupus erythematosus. Lupus science & medicine 18 33727237
2014 Association between polymorphisms of the IKZF3 gene and systemic lupus erythematosus in a Chinese Han population. PloS one 18 25271777
2009 Differential aiolos expression in human hematopoietic subpopulations. Leukemia research 18 19540588
2021 Inborn errors of IKAROS and AIOLOS. Current opinion in immunology 17 34265590
2019 Overexpression of Aiolos promotes epithelial-mesenchymal transition and cancer stem cell-like properties in lung cancer cells. Scientific reports 17 30816208
2018 Lenalidomide combined with low-dose cyclophosphamide and prednisone modulates Ikaros and Aiolos in lymphocytes, resulting in immunostimulatory effects in lenalidomide-refractory multiple myeloma patients. Oncotarget 17 30338042
2008 Silencing and nuclear repositioning of the lambda5 gene locus at the pre-B cell stage requires Aiolos and OBF-1. PloS one 17 18974788
1999 The evolutionarily conserved avian Aiolos gene encodes alternative isoforms. European journal of immunology 15 10508239
2016 Allelic imbalance of multiple sclerosis susceptibility genes IKZF3 and IQGAP1 in human peripheral blood. BMC genetics 14 27080863
2009 Lacking of Aiolos accelerates pre-mature B cell apoptosis mediated by BCR signaling through elevation in cytochrome c release. Biochimica et biophysica acta 14 19427336
2001 Both normal and leukemic B lymphocytes express multiple isoforms of the human Aiolos gene. European journal of immunology 14 11745366
2024 Disease-associated AIOLOS variants lead to immune deficiency/dysregulation by haploinsufficiency and redefine AIOLOS functional domains. The Journal of clinical investigation 13 38015619
2018 Baicalein Inhibits Proliferation of Myeloma U266 Cells by Downregulating IKZF1 and IKZF3. Medical science monitor : international medical journal of experimental and clinical research 13 29729093
2022 AIOLOS Variants Causing Immunodeficiency in Human and Mice. Frontiers in immunology 12 35444653
2015 Overexpression of Aiolos in Peripheral Blood Mononuclear Cell Subsets from Patients with Systemic Lupus Erythematosus and Rheumatoid Arthritis. Biochemical genetics 12 26546109
2024 Targeting Ikaros and Aiolos: reviewing novel protein degraders for the treatment of multiple myeloma, with a focus on iberdomide and mezigdomide. Expert review of hematology 11 39054911
2021 Aiolos regulates eosinophil migration into tissues. Mucosal immunology 11 34341502
2014 Aiolos and Lymphocyte Mimicry in Lung Cancer. Molecular & cellular oncology 11 27308319
2013 Overexpression of AIOLOS inhibits cell proliferation and suppresses apoptosis in Nalm-6 cells. Oncology reports 11 24399134
2007 Aiolos: an ungrateful member of the Ikaros family. Immunity 11 17376390
2024 AIOLOS-Associated Inborn Errors of Immunity. Journal of clinical immunology 10 38773004
2022 IKZF3 modulates cerebral ischemia/reperfusion injury by inhibiting neuroinflammation. International immunopharmacology 10 36525791
2016 Ikaros, Helios, and Aiolos protein levels increase in human thymocytes after β selection. Immunologic research 10 26645971
2015 Adult Low-Hypodiploid Acute B-Lymphoblastic Leukemia With IKZF3 Deletion and TP53 Mutation: Comparison With Pediatric Patients. American journal of clinical pathology 10 26185311
2020 Urinary Cell Transcriptome Profiling and Identification of ITM2A, SLAMF6, and IKZF3 as Biomarkers of Acute Rejection in Human Kidney Allografts. Transplantation direct 9 32766436
2024 Synergy between BRD9- and IKZF3-Targeting as a Therapeutic Strategy for Multiple Myeloma. Cancers 8 38610997
2022 IKZF3 amplification frequently occurs in HER2-positive breast cancer and is a potential therapeutic target. Medical oncology (Northwood, London, England) 8 36180600
2002 Quantification of human Aiolos splice variants by real-time PCR. Journal of immunological methods 8 12445735
2022 Novel IKZF3 transcriptomic signature correlates with positive outcomes of skin cutaneous melanoma: A pan-cancer analysis. Frontiers in genetics 7 36353107
2019 N160 of Aiolos Determines its DNA-Binding Activity. Anatomical record (Hoboken, N.J. : 2007) 7 31251838
2024 Aiolos promotes CXCR3 expression on Th1 cells via positive regulation of IFN-γ/STAT1 signaling. JCI insight 6 39560988
2023 Impaired tissue homing by the Ikzf3N159S variant is mediated by interfering with Ikaros function. Frontiers in immunology 6 37662955
2008 Differential epigenetic regulation of Aiolos expression in human tumoral cell lines and primary cells. FEBS letters 6 18206652
2014 Upregulation of AIOLOS induces apoptosis and enhances etoposide chemosensitivity in Jurkat leukemia cells. Oncology reports 5 25524659
2024 Cytotoxic Programming of CD4+ T Cells Is Regulated by Opposing Actions of the Related Transcription Factors Eos and Aiolos. Journal of immunology (Baltimore, Md. : 1950) 4 38363226
2023 IKZF3 polymorphisms contribute to the increased risk of acute lymphoblastic leukemia in children. Cancer 4 38018448
2025 Targeting degradation of IKZF1 and IKZF3 through modulation of the E3 ligase substrates in the context of cellular therapies for multiple myeloma. Biomarker research 3 40817326
2021 [Relationship between IKZF3 Gene Single Nucleotide Polymorphisms and Childhood Acute Lymphoblastic Leukemia]. Zhongguo shi yan xue ye xue za zhi 3 34105458
2020 Development of Label-Free Impedimetric Immunosensors for IKZF1 and IKZF3 Femtomolar Detection for Monitoring Multiple Myeloma Patients Treated with Lenalidomide. Scientific reports 3 32591583
2024 Identification and Functional Analysis of a de novo IKZF3 Mutation in a Pediatric Patient with Combined Immunodeficiency. Journal of clinical immunology 2 38758229
2020 Author Correction: Overexpression of Aiolos promotes epithelial-mesenchymal transition and cancer stem cell-like properties in lung cancer cells. Scientific reports 2 31974483
2016 [Association between IKZF3 gene polymorphisms and systemic lupus erythematosus in Han ethnic group in southern China: a case-control study]. Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi 2 27453112
2007 A search for a mutation of the Aiolos phosphorylation domain in lymphocytes from patients with leukemia. Haematologica 2 17296582
2001 Genetic mapping and allelic loss analysis in mouse thymic lymphomas of Helios and Aiolos belonging to the Ikaros gene family. Japanese journal of cancer research : Gann 2 11173542
2025 Targeting Ikaros and Aiolos with pomalidomide fails to reactivate or induce apoptosis of the latent HIV reservoir. Journal of virology 1 39902962
2025 PBK/TOPK mediates Ikaros, Aiolos and CTCF displacement from mitotic chromosomes and alters chromatin accessibility at selected C2H2-zinc finger protein binding sites. Nature communications 1 40987773
2025 Aiolos restricts the generation of antigen-inexperienced, virtual memory CD8+ T cells in mice. Nature communications 1 41392082
2024 Kidins220 and Aiolos promote thymic iNKT cell development by reducing TCR signals. Science advances 1 38489359
2024 Exploring the oncogenic potential of Aiolos in lung cancer through OTUB1-mediated ubiquitination. Heliyon 1 39315162
2015 Overexpression of Aiolos in Nalm-6 acute lymphoblastic leukaemia cells reduces apoptosis by suppressing phosphatase and tensin homologue deleted on chromosome 10 and activating the phosphatidylinositol-3-kinase/Akt signalling pathway. Molecular medicine reports 1 25608224

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