Affinage

IKZF1

DNA-binding protein Ikaros · UniProt Q13422

Length
519 aa
Mass
57.5 kDa
Annotated
2026-06-10
100 papers in source corpus 32 papers cited in narrative 32 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

IKZF1/IKAROS is a lymphocyte-restricted zinc finger transcription factor that programs hematopoietic gene expression by binding GGAA-containing DNA motifs and orchestrating both activation and repression of lineage-specific genes (PMID:1922043, PMID:7935426). First identified as the DNA-binding protein LyF-1 that engages the TdT, mu enhancer, lambda5, VpreB, and lck promoters, its sequence specificity and dimerization properties are partitioned across distinct zinc finger domains and tuned by extensive alternative splicing into isoforms with differing DNA-binding affinity and pericentromeric heterochromatin localization (PMID:1922043, PMID:7935426, PMID:17135265). IKAROS executes transcriptional control through partner recruitment: its N-terminal zinc fingers engage Cdk9/P-TEFb to drive RNA Pol II elongation while its C-terminal fingers bind GATA1/2/3, and it additionally recruits HDAC1/Mi-2 (NuRD), PRC2, and assembles long-range, lineage-specific chromatin architecture that overrides CTCF boundaries (PMID:21245044, PMID:23732910, PMID:19114560, PMID:26549758, PMID:37995656). It directly represses growth and identity genes including c-Myc, T-bet, PP2A, Cish, and the megakaryocytic program, and antagonizes STAT5 by competing for overlapping GGAA sites, thereby setting proliferation thresholds and enforcing lineage choice across B, T, NK, and myeloid cells (PMID:20566697, PMID:19923223, PMID:24692537, PMID:38182668, PMID:33180866, PMID:23335373). Consistent with this role, IKAROS is a tumor suppressor whose loss or DNA-binding-domain mutation drives T cell hyperproliferation and leukemia (PMID:7585946, PMID:15713624). IKAROS activity is set by post-translational regulation: CK2 phosphorylation impairs DNA binding and promotes degradation, PP1-mediated dephosphorylation stabilizes the protein and enables heterochromatin localization, and SUMOylation blocks its repressive function (PMID:21750978, PMID:19282287, PMID:15767674). Lenalidomide and related IMiDs redirect the CRBN-CRL4 E3 ubiquitin ligase to ubiquitinate and degrade IKZF1, the basis of their anti-myeloma activity and of their immunomodulatory effects, with a Q146H substitution conferring degradation resistance (PMID:24292623, PMID:24292625, PMID:29496670). Germline IKZF1 variants disrupting either dimerization or DNA binding alter NuRD recruitment, stability, and downstream signaling, underlying immune dysregulation phenotypes (PMID:32845957, PMID:38885295).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1991 High

    Established the molecular identity of IKAROS as a sequence-specific transcriptional activator, answering what protein controls lymphocyte-specific promoters.

    Evidence Protein purification and EMSA on the TdT, mu enhancer, lambda5, VpreB, and lck promoters

    PMID:1922043

    Open questions at the time
    • Gene/cDNA identity not yet established at this stage
    • No in vivo loss-of-function
  2. 1994 High

    Linked LyF-1 DNA-binding activity to the Ikaros gene and showed alternative splicing generates isoforms with distinct DNA-binding specificities, explaining functional diversity from a single locus.

    Evidence Recombinant protein expression, antibody blocking, RT-PCR isoform analysis, gel-shift

    PMID:7935426

    Open questions at the time
    • Functional consequence of each isoform in vivo unresolved
    • Partner proteins not yet identified
  3. 1995 High

    Defined IKAROS as a tumor suppressor that sets T cell proliferation thresholds, answering whether IKAROS dysfunction is oncogenic.

    Evidence Mouse heterozygous knock-in of a DNA-binding domain mutation with clonal analysis

    PMID:7585946

    Open questions at the time
    • Direct target genes mediating tumor suppression not defined here
    • Mechanism of wild-type allele loss unclear
  4. 1999 Medium

    Connected IKAROS to higher-order chromatin and chromosome propagation, addressing where in the nucleus IKAROS acts upon T cell activation.

    Evidence Immunofluorescence localization to pericentromeric heterochromatin and chromosome analysis in proliferating T cells

    PMID:10204489

    Open questions at the time
    • Molecular basis of heterochromatin targeting not defined
    • Causal link between localization and chromosome stability correlative
  5. 2005 High

    Identified SUMOylation as a switch controlling IKAROS repression, answering how repressive activity is post-translationally toggled.

    Evidence In vivo SUMOylation assays, site mutagenesis, HDAC and localization readouts

    PMID:15767674

    Open questions at the time
    • SUMO ligase/protease responsible not identified
    • Single-lab finding
  6. 2006 Medium

    Showed IKAROS controls BCR signaling and that isoforms differ in DNA-binding and subcellular targeting, refining how IKAROS output is diversified.

    Evidence DT40 gene disruption with rescue plus signaling assays; isoform mutational and localization analysis

    PMID:16482514 PMID:17135265

    Open questions at the time
    • Direct transcriptional targets in BCR pathway not mapped
    • Isoform stoichiometry in primary cells unknown
  7. 2008 High

    Defined IKAROS as a recruiter of HDAC1/Mi-2 and a GATA-1 partner that reshapes locus architecture, answering how it silences specific genes.

    Evidence ChIP, Co-IP, reporter assays, and 3C at the human beta-globin locus

    PMID:19114560

    Open questions at the time
    • Generality beyond globin locus not addressed here
    • Order of complex assembly unresolved
  8. 2010 High

    Showed IKAROS directly represses c-Myc to inhibit pre-B cell growth, providing a target-level mechanism for its anti-proliferative role.

    Evidence ChIP, siRNA/overexpression, proliferation and time-course expression assays

    PMID:20566697

    Open questions at the time
    • Cofactor requirement at c-Myc promoter not defined
    • Cell-type generality untested here
  9. 2011 High

    Established the kinase/phosphatase logic and the P-TEFb/GATA recruitment mechanism, answering how IKAROS activity and activating output are controlled.

    Evidence CK2 phosphomimetic/phosphoresistant mutants and Cdk9/GATA domain-mapping with ChIP and elongation assays

    PMID:19282287 PMID:21245044 PMID:21750978

    Open questions at the time
    • In vivo phosphorylation dynamics during development unclear
    • Single-lab mechanistic studies
  10. 2013 High

    Revealed the IMiD/CRBN degradation mechanism and resolved domain-specific partner contacts, transforming IKAROS into a druggable target and mapping its activation interface.

    Evidence Quantitative proteomics, ubiquitination assays, mutagenesis rescue in myeloma; domain mutagenesis with ChIP for GATA/Cdk9 contacts

    PMID:23732910 PMID:24292623 PMID:24292625

    Open questions at the time
    • Full set of neosubstrate-determining residues incomplete
    • Long-range chromatin consequences of degradation not addressed here
  11. 2015 High

    Demonstrated IKAROS recruits PRC2 to deposit H3K27me3 at developmental loci, adding a Polycomb repression axis distinct from NuRD.

    Evidence Conditional KO, ChIP-seq, Co-IP, and H3K27me3 profiling in thymocytes

    PMID:26549758

    Open questions at the time
    • Recruitment determinants for PRC2 vs NuRD selectivity unknown
    • Direct vs indirect PRC2 contact not fully resolved
  12. 2020 Medium

    Showed IKAROS antagonizes STAT5 by motif competition rather than protein interaction, clarifying a mechanism of signaling cross-regulation.

    Evidence ChIP-seq with inducible IKAROS, Western blot, and negative Co-IP in pre-B cells

    PMID:33180866

    Open questions at the time
    • Functional consequences for B cell development not quantified here
    • Single-lab finding
  13. 2023 High

    Established IKAROS as a direct architect of lineage-specific 3D genome organization, answering how it imposes regulatory units genome-wide.

    Evidence Conditional KO, ectopic gain-of-function in epithelial cells, Hi-C and ChIP-seq

    PMID:37995656

    Open questions at the time
    • Mechanism of CTCF-boundary override not molecularly defined
    • Cohesin/loop-extrusion interplay unresolved
  14. 2024 Medium

    Extended IKAROS function to NK cell survival, T cell exhaustion, and AP-1 partnership, broadening its lineage roles and therapeutic relevance.

    Evidence Conditional/double-KO genetics with ChIP-seq (NK); ATAC-seq and TF occupancy with IKAROS degrader (T cell exhaustion); patient variant FYN promoter study

    PMID:38182668 PMID:38885295 PMID:39486420

    Open questions at the time
    • Direct vs cofactor-mediated AP-1 binding not fully resolved
    • Generalizability of exhaustion findings beyond model systems untested
  15. 2025 Medium

    Linked IKAROS dosage to B-cell identity antigen expression, explaining a mechanism of resistance to CD19/CD22-directed therapies.

    Evidence Single-cell analysis of patient samples plus dose-dependent manipulation with ATAC-seq

    PMID:40268897

    Open questions at the time
    • Direct vs indirect regulation of CD19/CD22 loci not separated
    • Reversibility kinetics in vivo unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How IKAROS selects between its repressive (NuRD, PRC2, HDAC) and activating (P-TEFb, GATA) partner programs at a given locus, and how this is coordinated with its 3D architecture function, remains unresolved.
  • No structural model of partner selection
  • Recruitment hierarchy at individual loci undefined
  • Integration of post-translational state with partner choice unmapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0003677 DNA binding 4
Localization
GO:0005634 nucleus 4 GO:0000228 nuclear chromosome 3 GO:0005654 nucleoplasm 2
Pathway
R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1266738 Developmental Biology 3 R-HSA-4839726 Chromatin organization 3
Partners
CDK9CRBNGATA1GATA2GATA3HDAC1IKZF3PPP1CA
Complex memberships
NuRDPRC2

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 Lenalidomide causes selective ubiquitination and proteasomal degradation of IKZF1 (and IKZF3) via the CRBN-CRL4 E3 ubiquitin ligase complex. A single amino acid substitution in IKZF3 conferred resistance to lenalidomide-induced degradation, confirming the mechanism. Lenalidomide-induced IL-2 production in T cells was also attributed to depletion of IKZF1/IKZF3. Quantitative proteomics, ubiquitination assays, rescue with amino acid substitution mutant, genetic knockdown Science High 24292623 24292625
2013 Lenalidomide-bound cereblon E3 ubiquitin ligase acquires the ability to target IKZF1 and IKZF3 for proteasomal degradation. Loss of IKZF1 and IKZF3 is both necessary and sufficient for lenalidomide's therapeutic effect in myeloma cell lines. Biochemical binding assays, genetic loss-of-function in myeloma cell lines, proteasomal degradation assays Science High 24292623
1994 LyF-1 (the lymphocyte-specific DNA-binding protein that activates TdT, lambda5, VpreB, and lck promoters) is encoded by specific alternatively spliced mRNAs from the Ikaros gene. Only isoforms containing the N-terminal zinc finger domain are necessary and sufficient for TdT promoter binding; at least six distinct mRNA isoforms arise from alternative splicing with differing DNA-binding specificities. Protein purification, partial amino acid sequencing, recombinant protein expression in E. coli, antibody blocking of DNA-binding activity, RT-PCR isoform analysis, gel-shift assays Molecular and cellular biology High 7935426
1991 LyF-1 (IKZF1) is a ~50 kDa sequence-specific DNA-binding protein that interacts with the consensus sequence PyPyTGGGAGPu in the TdT promoter (required for lymphocyte transcription), the immunoglobulin mu enhancer microB element, and promoters of lambda5, VpreB, and lck, identifying it as a general transcriptional activator for lymphocyte-specific genes. Protein purification, gel-shift (EMSA), transient transfection, promoter mutational analysis Molecular and cellular biology High 1922043
1995 Ikaros acts as a tumor suppressor and regulator of T cell proliferation thresholds; heterozygous mutation in the DNA-binding domain causes T cell hyperproliferation, autoproliferative peripheral T cells, and rapid T cell leukemia/lymphoma with 100% penetrance via clonal expansion and loss of the wild-type allele. Mouse genetics (heterozygous knock-in of DNA-binding domain mutation), flow cytometry, clonal analysis Cell High 7585946
2005 IKZF1 is SUMOylated in vivo at two identified sites; simultaneous modification of both SUMOylation sites abolishes Ikaros repression function by disrupting both HDAC-dependent and HDAC-independent repression, without affecting nuclear localization to pericentromeric heterochromatin. In vivo SUMOylation assays, site-directed mutagenesis of SUMOylation sites, HDAC activity assays, nuclear localization imaging Molecular and cellular biology High 15767674
2009 Ikaros interacts with protein phosphatase 1 (PP1) via a conserved RVXF motif in its C-terminus. PP1 dephosphorylates CK2-phosphorylated sites on Ikaros, stabilizing the protein and enabling pericentromeric heterochromatin (PC-HC) localization and DNA binding. Point mutations abolishing Ikaros-PP1 interaction decrease DNA binding, prevent PC-HC localization, and accelerate proteasomal degradation of Ikaros via the ubiquitin pathway. Co-immunoprecipitation, RVXF motif mutagenesis, subcellular localization imaging, DNA-binding assays, protein stability (half-life) assays, ubiquitin co-immunoprecipitation The Journal of biological chemistry High 19282287
2011 CK2 kinase phosphorylates Ikaros at four specific sites; phosphomimetic mutations at these CK2 sites inhibit Ikaros localization to pericentromeric heterochromatin, reduce DNA binding to target gene promoters (e.g., TdT), and promote proteasomal degradation of Ikaros. Phosphoresistant mutations at CK2 sites restore DNA binding, PC-HC localization, and prevent accelerated degradation. Ikaros phosphomimetic and phosphoresistant mutants, subcellular localization assays, ChIP, DNA-binding assays, protein stability assays Molecular and cellular biochemistry High 21750978
2010 Ikaros and Aiolos bind directly to the c-Myc promoter in pre-B cells in vivo and suppress c-Myc expression. Downregulation of c-Myc is necessary for the growth-inhibitory effect of Ikaros/Aiolos, and precedes p27 induction and cyclin D3 downregulation. ChIP, siRNA knockdown, overexpression, cell proliferation assays, time-course expression analysis Molecular and cellular biology High 20566697
2015 Ikaros forms a complex with Polycomb Repressive Complex 2 (PRC2) in CD4−CD8− thymocytes, enabling PRC2 binding to >500 developmentally regulated loci including haematopoietic stem cell and Notch pathway genes. Loss of Ikaros in these cells reduces H3K27 trimethylation and causes ectopic gene expression. Ikaros interaction with PRC2 is independent of the NuRD complex. Conditional genetic inactivation, ChIP-seq, co-immunoprecipitation, H3K27me3 assays Nature communications High 26549758
1999 Upon T cell activation, Ikaros proteins localize to a higher-order chromatin structure at pericentromeric heterochromatin where they colocalize with components of the DNA replication machinery. T cells with reduced Ikaros activity show chromosome abnormalities when proliferating, implicating Ikaros in chromosome propagation during cell cycle. Immunofluorescence/nuclear localization imaging, chromosome analysis in proliferating T cells, TCR and IL-2 signaling assays Immunity Medium 10204489
2008 Endogenous Ikaros is recruited to the human beta-globin locus and targets HDAC1 and Mi-2 to gamma-globin promoters, contributing to gamma-globin gene silencing. Ikaros physically interacts with GATA-1 and enhances GATA-1 binding to regulatory regions, and their combined action impairs proximity between the locus control region and gamma-globin genes. ChIP, co-immunoprecipitation, reporter assays, chromosome conformation capture (3C) Molecular and cellular biology High 19114560
2011 Ikaros physically interacts with Cdk9 (a component of P-TEFb) via its N-terminal zinc finger domain and with GATA factors via its C-terminal zinc finger domain. These interactions promote transcription elongation of Ikaros target genes (including gamma-globin) by facilitating Cdk9 and GATA recruitment to promoters and conversion of RNA Pol II to the elongation-competent form. The oncogenic isoform Ik6 fails to interact with Cdk9 or GATA and perturbs Pol II elongation. Co-immunoprecipitation, domain mapping/mutagenesis, ChIP, in vivo transcription elongation assays Nucleic acids research High 21245044
2013 Direct protein-protein interactions between Ikaros C-terminal zinc fingers and GATA1/GATA2/GATA3 C-terminal zinc fingers, and between Ikaros N-terminal zinc fingers and the kinase/T-loop domain of Cdk9, are required for transcriptional activation of Ikaros target genes in hematopoietic cells. The Ik6 oncogenic isoform does not efficiently interact with Cdk9 or GATA proteins in vivo, perturbing P-TEFb recruitment and transcription elongation. Co-immunoprecipitation, domain deletion/mutagenesis, ChIP, transcriptional reporter assays in COS-7 and primary hematopoietic cells Molecular and cellular biology High 23732910
2005 Reintroduction of Ikaros into Ikaros-null T leukemia cells causes G0/G1 cell cycle arrest with upregulation of p27kip1, induction of T cell differentiation markers, and global and locus-specific increase in histone H3 acetylation, demonstrating Ikaros has tumor suppressor properties in T cells. Ikaros overexpression in leukemia cell line, flow cytometry (cell cycle), Western blot, immunofluorescence, histone acetylation assays Molecular and cellular biology Medium 15713624
2009 Ikaros directly occupies the tbx21 (T-bet) promoter in Th2 cells to repress T-bet expression and prevent IFNγ production. Loss of Ikaros DNA-binding in Th2 conditions leads to T-bet expression and IFNγ production. Ikaros is also required for epigenetic imprinting of the ifng locus during Th2 polarization. ChIP (endogenous Ikaros occupancy), dominant-negative Ikaros inhibition, cytokine production assays, in vivo parasite model The Journal of biological chemistry Medium 19923223
2006 Disruption of Ikaros in chicken DT40 B cells causes B cell receptor (BCR) signaling defects including reduced PLCγ2 phosphorylation, impaired intracellular calcium mobilization, and hyperphosphorylation of Cbl following BCR activation. These defects are rescued by Ikaros reintroduction. Gene disruption in DT40 cells, Ikaros reintroduction, phosphorylation assays, calcium mobilization assays European journal of immunology Medium 16482514
2012 Ikaros overexpression decreases NOTCH-induced megakaryocytic specification and represses megakaryocytic genes including GATA-1. Combined loss of Ikzf1 and Gata1 produces synthetic lethality in vivo with expansion of megakaryocyte progenitors, demonstrating a functional interplay between Ikaros, GATA factors, and the NOTCH pathway in megakaryopoiesis. Overexpression, genetic knockout (single and double), in vivo mouse models, flow cytometry Blood Medium 23335373
2021 In myeloid cells, IKZF1 regulates pyroptosis via canonical inflammasome signaling in a SIRT1-dependent manner. Ikaros negatively regulates SIRT1 through an AMPK-dependent pathway. Myeloid-specific Ikaros signaling augments hepatic pyroptosis and pro-inflammatory responses in vivo. Ikaros silencing/overexpression in BMM cultures, myeloid-specific Sirt1-KO mice, in vivo liver ischemia-reperfusion model, inflammasome signaling assays Journal of hepatology Medium 34871625
2006 Human Ikaros isoforms hIK-VI and hIK-H differ in DNA-binding affinity and subcellular localization: hIK-VI localizes exclusively to pericentromeric heterochromatin (PC-HC) while hIK-H shows dual centromeric and non-centromeric localization. Mutational analysis defined amino acids responsible for hIK-H's distinct DNA binding and localization. Co-expression of hIK-H with hIK-VI alters the DNA-binding specificity of Ikaros complexes toward PC-HC sequences. Isoform expression, mutational analysis, subcellular localization imaging, DNA-binding assays (EMSA), ChIP The Journal of biological chemistry Medium 17135265
2020 Ikaros antagonizes STAT5 DNA binding in pre-B cells by competing for overlapping GGAA binding motifs at >60% of STAT5 target genomic regions, causing widespread loss of STAT5 chromatin binding within two hours of Ikaros induction. Ikaros does not alter STAT5 protein levels or phosphorylation, nor does it physically associate with STAT5. ChIP-seq (genomic distribution of Ikaros and STAT5), inducible Ikaros expression system, Western blot, co-immunoprecipitation (negative for STAT5 interaction) PloS one Medium 33180866
2023 IKAROS assembles lineage-specific chromatin organization at multiple scales in B cell precursors, including interactions across megabase distances that override CTCF-imposed boundaries and build lineage-specific regulatory units. IKAROS-bound enhancers drive these long-range interactions. Gain-of-function in epithelial cells confirms IKAROS' direct ability to reconfigure chromatin architecture. IKAROS is also required for Igκ locus compaction in lymphocytes. Loss-of-function (conditional KO in B cell precursors), gain-of-function (ectopic expression in epithelial cells), Hi-C/chromatin conformation capture, ChIP-seq Cell High 37995656
2014 Ikaros binds to a variant site in the first intron of PP2A and represses PP2A (PP2Ac) expression at the mRNA and protein level. This repression is at least partially dependent on recruitment of HDAC1 to the intronic binding site. Silencing of Ikaros enhances PP2A expression. ChIP, siRNA knockdown, overexpression, luciferase reporter assays, Western blot, RT-PCR The Journal of biological chemistry Medium 24692537
2019 Ikaros controls B cell receptor anergy by regulating anergy-associated genes including Zfp318 (which promotes IgD expression in anergic B cells). In Ikaros-deficient mature B cells, TLR-MyD88-NF-κB signaling is hyperactive due to failure to upregulate feedback inhibitors. Loss of MyD88 in Ikaros-deficient B cells prevents systemic autoimmunity. Conditional KO in mature B cells, genetic epistasis (MyD88 deletion), gene expression analysis, BCR/TLR signaling assays Nature immunology High 31591571
2018 IKZF1 directly regulates CD34+ cell fate by being degraded via CRBN E3 ligase upon IMiD treatment, reducing IKZF1-dependent PU.1 transcription factor expression. ChIP shows IKZF1 directly binds the PU.1 promoter. CRBN knockdown reverses IMiD-induced IKZF1 downregulation. An IKZF1-Q146H mutation blocks CRBN binding and prevents IKZF1 ubiquitination. ChIP, thalidomide analog bead pull-down, CRBN knockdown (shRNA), IKZF1 Q146H mutant overexpression, colony-formation assays, xenograft model Blood advances High 29496670
2024 IKZF1 directly represses Cish (a negative regulator of IL-15 receptor signaling) in NK cells; Ikzf1-null NK cells have impaired IL-15 receptor signaling and increased BIM-mediated apoptosis. IKZF1 and IKZF3 directly bind AP-1 family members (Jun/Fos); deletion of both Ikzf1 and Ikzf3 in NK cells further reduces Jun/Fos expression and causes complete loss of peripheral NK cells. Conditional genetic inactivation (Ikzf1 KO, Ikzf1/Ikzf3 double KO, Ikzf1/Bcl2l11 co-deletion), ChIP-seq (direct AP-1 binding), cytokine signaling assays, flow cytometry Nature immunology High 38182668
2024 IKZF1 drives T cell exhaustion via epigenetic modulation; degradation of IKZF1 by iberdomide prevents exhaustion by blocking chromatin remodeling at T cell effector enhancers and preserving binding of AP-1, NF-κB, and NFAT transcription factors. Antigen-specific T cell exhaustion assay, epigenetic screen, ATAC-seq/chromatin accessibility, iberdomide treatment, transcription factor occupancy assays Cell reports. Medicine Medium 39486420
2019 In zebrafish, Ikzf1 directly regulates Ccr9a and Irf4a expression, which are required for thymic migration and T cell differentiation of hematopoietic stem/progenitor cells respectively. Restoration of ccr9a in ikzf1 mutants rescues thymic homing but not T cell differentiation; additional irf4a restoration rescues differentiation. Zebrafish genetic ablation (ikzf1 mutant), genetic rescue (ccr9a and irf4a reintroduction), ChIP/direct target validation, flow cytometry of thymic populations The Journal of biological chemistry Medium 31511326
2021 Germline IKZF1 variants affecting the C-terminal dimerization domain disrupt IKZF1 homo- and heterodimerization (completely or partially) without affecting wild-type allele function. These dimerization-defective mutants alter IKZF1 sumoylation, protein stability, and recruitment of the NuRD complex, contrasting with N-terminal DNA-binding defect mutants, which do not affect these mechanisms. Dimerization assays, sumoylation assays, protein stability assays, NuRD complex co-immunoprecipitation, patient germline variant characterization Blood Medium 32845957
2010 Ikaros-1 is expressed at the boundary of the striatal germinal zone/mantle zone during neurogenesis, where it induces cell cycle arrest of neural progenitors by upregulating p21Cip1/Waf1 and promotes differentiation of enkephalin-positive neurons. Ikaros-1 acts downstream of Dlx1/2 transcription factors in the striatum. Ikaros-KO mouse analysis, overexpression in primary striatal cultures, Dlx1/2 double-KO analysis, immunohistochemistry The Journal of comparative neurology Medium 19950118
2024 A germline IKZF1 variant in IgG4-RD patients increases binding to the FYN promoter, resulting in higher FYN transcription in T cells. Elevated FYN stabilizes JunB and biases T cells toward Th2 polarization. This mechanistic chain accounts for atopic/autoimmune manifestations linked to IKZF1 risk variants. Functional characterization of patient germline variant, promoter binding assay (increased FYN binding), T cell differentiation assays, T cell receptor transduction assay The Journal of clinical investigation Medium 38885295
2025 IKAROS regulates surface expression of CD19 and CD22 in a dose-dependent and reversible manner in B-ALL cells. IKAROSlow B-ALL cells undergo epigenetic and transcriptional changes reducing B-cell identity, which leads to reduced CD19 and CD22 surface expression and resistance to CAR T cell therapies. Single-cell analysis of 61 patient samples, IKAROS dose-dependent overexpression/knockdown experiments, epigenetic assays (ATAC-seq), antigen expression assays Nature communications Medium 40268897

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 The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science (New York, N.Y.) 1258 24292623
2010 Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia 419 20428194
1995 A dominant mutation in the Ikaros gene leads to rapid development of leukemia and lymphoma. Cell 419 7585946
2002 Haematopoietic cell-fate decisions, chromatin regulation and ikaros. Nature reviews. Immunology 256 11913067
1997 The role of the Ikaros gene in lymphocyte development and homeostasis. Annual review of immunology 219 9143685
1991 LyF-1, a transcriptional regulator that interacts with a novel class of promoters for lymphocyte-specific genes. Molecular and cellular biology 206 1922043
1994 The lymphoid transcription factor LyF-1 is encoded by specific, alternatively spliced mRNAs derived from the Ikaros gene. Molecular and cellular biology 192 7935426
2011 The Ikaros gene family: transcriptional regulators of hematopoiesis and immunity. Molecular immunology 185 21477865
2018 Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia. Cancer cell 169 29681510
2015 Efficacy of Retinoids in IKZF1-Mutated BCR-ABL1 Acute Lymphoblastic Leukemia. Cancer cell 155 26321221
1999 Ikaros sets thresholds for T cell activation and regulates chromosome propagation. Immunity 137 10204489
2002 Ikaros is critical for B cell differentiation and function. European journal of immunology 129 11870616
2018 The many faces of IKZF1 in B-cell precursor acute lymphoblastic leukemia. Haematologica 122 29519871
2024 Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127. Science (New York, N.Y.) 119 38301010
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
2017 The Ikaros family in lymphocyte development. Current opinion in immunology 103 29278858
2021 Myeloid Ikaros-SIRT1 signaling axis regulates hepatic inflammation and pyroptosis in ischemia-stressed mouse and human liver. Journal of hepatology 97 34871625
2005 Ikaros SUMOylation: switching out of repression. Molecular and cellular biology 88 15767674
2009 Ikaros stability and pericentromeric localization are regulated by protein phosphatase 1. The Journal of biological chemistry 78 19282287
2019 Suppression of Aiolos and Ikaros expression by lenalidomide reduces human ILC3-ILC1/NK cell transdifferentiation. European journal of immunology 76 31151137
2002 Ikaros regulates neutrophil differentiation. Blood 76 12406904
2018 Ikaros family zinc finger 1 regulates dendritic cell development and function in humans. Nature communications 72 29588478
2002 Aiolos and Ikaros: regulators of lymphocyte development, homeostasis and lymphoproliferation. Apoptosis : an international journal on programmed cell death 68 11997672
2015 Ikaros mediates gene silencing in T cells through Polycomb repressive complex 2. Nature communications 67 26549758
2014 Ikaros fingers on lymphocyte differentiation. International journal of hematology 65 25085254
2015 Ikaros and leukaemia. British journal of haematology 64 25753742
2019 Ikaros prevents autoimmunity by controlling anergy and Toll-like receptor signaling in B cells. Nature immunology 63 31591571
1993 Both LyF-1 and an Ets protein interact with a critical promoter element in the murine terminal transferase gene. Molecular and cellular biology 59 8474456
2008 Ikaros and GATA-1 combinatorial effect is required for silencing of human gamma-globin genes. Molecular and cellular biology 58 19114560
2005 Ikaros induces quiescence and T-cell differentiation in a leukemia cell line. Molecular and cellular biology 58 15713624
2012 GATA-1 utilizes Ikaros and polycomb repressive complex 2 to suppress Hes1 and to promote erythropoiesis. Molecular and cellular biology 54 22778136
2009 Ikaros silences T-bet expression and interferon-gamma production during T helper 2 differentiation. The Journal of biological chemistry 53 19923223
2007 Ikaros and chromatin regulation in early hematopoiesis. Current opinion in immunology 53 17307348
2017 The making of a lymphocyte: the choice among disparate cell fates and the IKAROS enigma. Genes & development 52 28385788
2016 The Ikaros family of zinc-finger proteins. Acta pharmaceutica Sinica. B 51 27818917
2011 Ikaros and tumor suppression in acute lymphoblastic leukemia. Critical reviews in oncogenesis 51 22150303
2020 IKZF1 alterations in acute lymphoblastic leukemia: The good, the bad and the ugly. Blood reviews 50 32245541
2010 Ikaros in immune receptor signaling, lymphocyte differentiation, and function. FEBS letters 50 20888815
2013 Ikaros inhibits megakaryopoiesis through functional interaction with GATA-1 and NOTCH signaling. Blood 49 23335373
2011 Ikaros, CK2 kinase, and the road to leukemia. Molecular and cellular biochemistry 49 21750978
2023 Inborn errors of human IKAROS: LOF and GOF variants associated with primary immunodeficiency. Clinical and experimental immunology 48 36433803
2021 Germline IKAROS dimerization haploinsufficiency causes hematologic cytopenias and malignancies. Blood 48 32845957
2021 The IKZF1-IRF4/IRF5 Axis Controls Polarization of Myeloma-Associated Macrophages. Cancer immunology research 43 33563611
2010 Awakening lineage potential by Ikaros-mediated transcriptional priming. Current opinion in immunology 42 20299195
2022 Discovery of a dual WDR5 and Ikaros PROTAC degrader as an anti-cancer therapeutic. Oncogene 41 35525905
2006 Human Ikaros function in activated T cells is regulated by coordinated expression of its largest isoforms. The Journal of biological chemistry 41 17135265
2018 A kindred with mutant IKAROS and autoimmunity. The Journal of allergy and clinical immunology 39 29705243
2023 Lineage-specific 3D genome organization is assembled at multiple scales by IKAROS. Cell 38 37995656
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
2020 Established and emergent roles for Ikaros transcription factors in lymphoid cell development and function. Immunological reviews 37 33331000
2016 Ikaros: Exploiting and targeting the hematopoietic stem cell niche in B-progenitor acute lymphoblastic leukemia. Experimental hematology 35 27865806
2016 Regulation of cellular proliferation in acute lymphoblastic leukemia by Casein Kinase II (CK2) and Ikaros. Advances in biological regulation 33 27666503
2006 Ikaros has a crucial role in regulation of B cell receptor signaling. European journal of immunology 33 16482514
1998 Ikaros in hemopoietic lineage determination and homeostasis. Seminars in immunology 33 9618757
2023 Structural rationalization of GSPT1 and IKZF1 degradation by thalidomide molecular glue derivatives. RSC medicinal chemistry 32 36970148
2010 Ikaros-1 couples cell cycle arrest of late striatal precursors with neurogenesis of enkephalinergic neurons. The Journal of comparative neurology 32 19950118
2022 Overcoming IMiD resistance in T-cell lymphomas through potent degradation of ZFP91 and IKZF1. Blood 31 34936696
2019 Ikzf1 regulates embryonic T lymphopoiesis via Ccr9 and Irf4 in zebrafish. The Journal of biological chemistry 31 31511326
2011 Ikaros interacts with P-TEFb and cooperates with GATA-1 to enhance transcription elongation. Nucleic acids research 29 21245044
2024 IKZF1 Alterations and Therapeutic Targeting in B-Cell Acute Lymphoblastic Leukemia. Biomedicines 27 38255194
2021 Germline IKZF1 mutations and their impact on immunity: IKAROS-associated diseases and pathophysiology. Expert review of clinical immunology 27 33691560
2019 Lack of Ikaros Deregulates Inflammatory Gene Programs in T Cells. Journal of immunology (Baltimore, Md. : 1950) 27 30635395
2014 Gene-gene interactions of IRF5, STAT4, IKZF1 and ETS1 in systemic lupus erythematosus. Tissue antigens 27 24697319
2020 The specific distribution pattern of IKZF1 mutation in acute myeloid leukemia. Journal of hematology & oncology 26 33081843
2012 IKZF1: a critical role in the pathogenesis of systemic lupus erythematosus? Modern rheumatology 26 22782532
2024 IKAROS and AIOLOS directly regulate AP-1 transcriptional complexes and are essential for NK cell development. Nature immunology 25 38182668
2023 Ikaros family proteins redundantly regulate temporal patterning in the developing mouse retina. Development (Cambridge, England) 25 36537580
2020 IKAROS Family Zinc Finger 1-Associated Diseases in Primary Immunodeficiency Patients. Immunology and allergy clinics of North America 25 32654692
2020 Chromatin Protein PC4 Orchestrates B Cell Differentiation by Collaborating with IKAROS and IRF4. Cell reports 25 33357426
2018 IMiD compounds affect CD34+ cell fate and maturation via CRBN-induced IKZF1 degradation. Blood advances 25 29496670
2018 Aberrant ARID5B expression and its association with Ikaros dysfunction in acute lymphoblastic leukemia. Oncogenesis 25 30420689
2024 A noncoding regulatory variant in IKZF1 increases acute lymphoblastic leukemia risk in Hispanic/Latino children. Cell genomics 24 38537633
2023 Ikzf1 as a novel regulator of microglial homeostasis in inflammation and neurodegeneration. Brain, behavior, and immunity 24 36702234
2016 Ikaros Is a Negative Regulator of B1 Cell Development and Function. The Journal of biological chemistry 24 26841869
2018 Multiple functions of Ikaros in hematological malignancies, solid tumor and autoimmune diseases. Gene 22 30352248
2015 IKAROS: a multifunctional regulator of the polymerase II transcription cycle. Trends in genetics : TIG 22 26049627
2020 Quantitative expression of Ikaros, IRF4, and PSMD10 proteins predicts survival in VRD-treated patients with multiple myeloma. Blood advances 21 33284947
2014 Transcription factor Ikaros represses protein phosphatase 2A (PP2A) expression through an intronic binding site. The Journal of biological chemistry 21 24692537
2002 The Ikaros family protein Eos associates with C-terminal-binding protein corepressors. European journal of biochemistry 21 12444977
2007 Notch and Ikaros: not only converging players in T cell leukemia. Cell cycle (Georgetown, Tex.) 20 18032925
2000 Ikaros expression in human hematopoietic lineages. Experimental hematology 19 11063871
2017 The transcription factor Ikaros inhibits cell proliferation by downregulating ANXA4 expression in hepatocellular carcinoma. American journal of cancer research 18 28670491
2003 Upstream of Ikaros. Trends in immunology 18 14596876
2021 Inborn errors of IKAROS and AIOLOS. Current opinion in immunology 17 34265590
2019 RAG1 high expression associated with IKZF1 dysfunction in adult B-cell acute lymphoblastic leukemia. Journal of Cancer 17 31333801
2024 Degradation of IKZF1 prevents epigenetic progression of T cell exhaustion in an antigen-specific assay. Cell reports. Medicine 16 39486420
2018 Pan-PIM kinase inhibitors enhance Lenalidomide's anti-myeloma activity via cereblon-IKZF1/3 cascade. Cancer letters 16 30312729
2013 Direct protein interactions are responsible for Ikaros-GATA and Ikaros-Cdk9 cooperativeness in hematopoietic cells. Molecular and cellular biology 16 23732910
2024 IKZF1 and UBR4 gene variants drive autoimmunity and Th2 polarization in IgG4-related disease. The Journal of clinical investigation 15 38885295
2021 Ikaros-Associated Diseases: From Mice to Humans and Back Again. Frontiers in pediatrics 15 34354970
2013 Ectopic Ikaros expression positively correlates with lung cancer progression. Anatomical record (Hoboken, N.J. : 2007) 15 23580163
2023 The clinical impact of IKZF1 mutation in acute myeloid leukemia. Experimental hematology & oncology 14 36997950
2020 Ikaros antagonizes DNA binding by STAT5 in pre-B cells. PloS one 14 33180866
2018 Ikaros cooperates with Notch activation and antagonizes TGFβ signaling to promote pDC development. PLoS genetics 14 30001316
2015 IKZF1 rs4132601 polymorphism and acute lymphoblastic leukemia susceptibility: a meta-analysis. Leukemia & lymphoma 14 25012940
2025 IKAROS levels are associated with antigen escape in CD19- and CD22-targeted therapies for B-cell malignancies. Nature communications 13 40268897
2024 CCL2 mediated IKZF1 expression promotes M2 polarization of glioma-associated macrophages through CD84-SHP2 pathway. Oncogene 13 39112517
2016 Protein signaling and regulation of gene transcription in leukemia: role of the Casein Kinase II-Ikaros axis. Journal of investigative medicine : the official publication of the American Federation for Clinical Research 13 26912004

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