Affinage

IKZF1

DNA-binding protein Ikaros · UniProt Q13422

Length
519 aa
Mass
57.5 kDa
Annotated
2026-04-28
100 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IKZF1 (Ikaros) is a zinc finger transcription factor that serves as a master regulator of lymphoid lineage specification, hematopoietic cell fate decisions, and 3D genome architecture at lymphocyte-specific loci. It encodes alternatively spliced isoforms whose N-terminal zinc fingers mediate sequence-specific DNA binding at regulatory elements, while C-terminal zinc fingers mediate homo- and heterodimerization with family members such as Helios; DNA-binding-competent isoforms localize to the nucleus and pericentromeric heterochromatin, where they function as both transcriptional activators (recruiting P-TEFb/CDK9 and BRG1 to promote elongation) and repressors (recruiting NuRD/Mi-2-HDAC and mSin3-HDAC complexes to induce histone deacetylation) at target loci including Hes1, T-bet, γ-globin, POMC, PU.1, and Cish (PMID:7969165, PMID:10357820, PMID:21245044, PMID:18852286, PMID:38182668). IKZF1 is essential for the development of all lymphoid lineages (T, B, and NK cells), plasmacytoid dendritic cells, and proper V(D)J recombination; it also establishes lineage-specific chromatin accessibility, enhancer/super-enhancer formation, and megabase-scale 3D genome organization that overrides CTCF boundaries in B cell precursors (PMID:7923373, PMID:37995656, PMID:31073152, PMID:22291095). Its DNA-binding activity is negatively regulated by CK2-mediated phosphorylation and restored by PP1-mediated dephosphorylation, while immunomodulatory drugs (lenalidomide, thalidomide derivatives) redirect the CRBN-CRL4 E3 ubiquitin ligase to ubiquitinate and degrade IKZF1 as a neo-substrate via a β-hairpin degron containing a critical glycine, a mechanism that is both necessary and sufficient for IMiD therapeutic activity in myeloma and IMiD-induced neutropenia (PMID:24292625, PMID:24292623, PMID:21750978, PMID:36970148, PMID:29496670).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1994 High

    Cloning of IKZF1 established that it encodes a family of alternatively spliced zinc finger transcription factors, resolving how a single locus could produce isoforms with distinct DNA-binding, subcellular localization, and transcriptional activation properties — the functional isoforms (Ik-1/Ik-2) bind lymphocyte-specific regulatory elements while shorter isoforms (Ik-3/Ik-4) lack DNA-binding capacity and act as weak activators.

    Evidence EMSA, immunofluorescence, reporter assays characterizing multiple splice isoforms

    PMID:7969165

    Open questions at the time
    • Full repertoire of isoform-specific target genes not defined
    • Regulation of alternative splicing not elucidated in this study
  2. 1994 High

    Germline disruption of the IKZF1 DNA-binding domain demonstrated that IKZF1 is absolutely required for all lymphoid lineage development (T, B, and NK cells), establishing it as a master regulator of lymphopoiesis while showing dispensability for erythroid and myeloid development.

    Evidence Germline knockout mouse, flow cytometry, histology

    PMID:7923373

    Open questions at the time
    • Mechanism of lymphoid specification versus alternative lineage exclusion not resolved
    • Direct transcriptional targets mediating this phenotype not identified
  3. 1998 High

    Biochemical purification of endogenous IKZF1 complexes revealed stable association with the family member Helios and colocalization at pericentromeric heterochromatin, establishing that Ikaros functions within multimeric complexes at specific nuclear compartments.

    Evidence Immunoaffinity chromatography, co-IP, confocal microscopy in T cells

    PMID:9512513

    Open questions at the time
    • Functional significance of pericentromeric targeting not established
    • Full composition of endogenous IKZF1 complexes not determined
  4. 1999 High

    Identification of two repression domains in IKZF1 that recruit mSin3 and Mi-2-HDAC co-repressor complexes established the molecular mechanism of IKZF1-mediated transcriptional repression as chromatin modification through histone deacetylation.

    Evidence Reporter assays, co-IP (in vivo and in vitro), HDAC inhibitor treatment, histone acetylation analysis

    PMID:10357820

    Open questions at the time
    • Genome-wide identification of repressed targets not performed
    • Relative contribution of mSin3 versus NuRD complexes to specific loci unknown
  5. 2006 High

    Multiple studies expanded IKZF1's functional scope beyond lymphopoiesis: it was shown to regulate pituitary POMC expression and corticomelanotroph differentiation, BCR signaling through control of PLCγ2 phosphorylation and calcium flux, and plasmacytoid dendritic cell differentiation, revealing IKZF1 as a broadly acting hematopoietic and neuroendocrine transcription factor.

    Evidence ChIP and reporter assays in pituitary cells plus Ikaros KO mice (POMC); gene disruption in DT40 B cells with calcium flux assays (BCR signaling); Ikaros hypomorphic mice with flow cytometry and bone marrow reconstitution (pDC)

    PMID:15841184 PMID:16482514 PMID:16912230

    Open questions at the time
    • Whether pituitary and neuronal functions are direct or involve intermediate transcription factors
    • BCR signaling mechanism is indirect — direct IKZF1 targets mediating this phenotype only partially identified
  6. 2008 High

    ChIP-based studies demonstrated that IKZF1 directly binds the Hes-1 promoter (competing with RBP-Jκ for Notch target repression) and the β-globin locus (recruiting HDAC1 and Mi-2 to γ-globin promoters), establishing IKZF1 as a sequence-specific repressor at defined developmental gene loci with locus-specific epigenetic consequences.

    Evidence ChIP assays, reporter assays, H3K27me3 analysis in Ikaros-deficient mice (Hes-1); ChIP, Co-IP, chromosome conformation capture, siRNA knockdown (β-globin)

    PMID:18852286 PMID:19114560

    Open questions at the time
    • Genome-wide extent of IKZF1–Notch antagonism not mapped
    • Temporal dynamics of IKZF1-mediated γ-globin silencing during ontogeny not fully resolved
  7. 2011 High

    CK2 was identified as a kinase that phosphorylates IKZF1 at four sites to inhibit its DNA binding, pericentromeric localization, and stability, while PP1 counteracts this via an RVXF motif; separately, IKZF1 was shown to recruit P-TEFb (CDK9) and BRG1 to activate transcription elongation at γ-globin genes, revealing IKZF1 as both an activator and repressor regulated by a phosphorylation switch.

    Evidence In vitro kinase assays, phosphomimetic/phosphoresistant mutants, EMSA, confocal microscopy, PP1 interaction mapping (CK2/PP1); Co-IP, ChIP, Pol II Ser2 phosphorylation analysis in primary erythroid cells (P-TEFb)

    PMID:21245044 PMID:21750978

    Open questions at the time
    • In vivo regulation of the CK2-PP1 switch in specific developmental contexts not established
    • Whether P-TEFb recruitment is a general IKZF1 activation mechanism or specific to the globin locus
  8. 2012 High

    FoxO1 was found to regulate IKZF1 at the level of mRNA splicing (not transcription) in pro-B cells, and IKZF1 was shown to cooperate with Pax5 for distal VH gene rearrangement, placing IKZF1 within a defined regulatory hierarchy controlling V(D)J recombination.

    Evidence Genetic epistasis analysis in Pten-deficient pro-B cells, mRNA splicing analysis, V(D)J recombination assays

    PMID:22291095

    Open questions at the time
    • Mechanism by which FoxO1 regulates splicing of IKZF1 not determined
    • How IKZF1 makes distal VH genes accessible at the chromatin level not resolved
  9. 2013 High

    The discovery that lenalidomide redirects the CRBN-CRL4 E3 ubiquitin ligase to ubiquitinate and degrade IKZF1 (and IKZF3) as neo-substrates — and that this is both necessary and sufficient for lenalidomide's myeloma and T-cell immunostimulatory effects — transformed understanding of IMiD pharmacology and established IKZF1 as a drug-induced degradation target.

    Evidence Quantitative proteomics, ubiquitination assays, point-mutant resistance experiments, genetic rescue in myeloma cells, T-cell functional assays, published simultaneously by two independent labs

    PMID:24292623 PMID:24292625

    Open questions at the time
    • Structural basis of CRBN–IKZF1 recognition not yet solved at this point
    • Downstream transcriptional consequences of IMiD-induced IKZF1 loss in different cell types not comprehensively mapped
  10. 2013 High

    IKZF1 was shown to regulate hematopoietic lineage decisions beyond lymphopoiesis by repressing GATA-1 to inhibit megakaryopoiesis and by directly binding Cebpa and Hes1 loci with opposing epigenetic effects (promoting H3K4me3 at Cebpa while reducing it at Hes1) to suppress basophil differentiation.

    Evidence Overexpression/knockdown, Ikzf1/Gata1 double KO mice, colony assays (megakaryopoiesis); ChIP, conditional Ikaros KO mice, histone modification analysis (basophil)

    PMID:23335373 PMID:23990620

    Open questions at the time
    • Whether IKZF1-mediated lineage suppression is direct transcriptional repression or involves intermediate factors at all loci
    • Genome-wide map of IKZF1-dependent histone modifications in megakaryocyte and basophil progenitors not available
  11. 2015 High

    CK2 inhibition in leukemia cells was shown to restore IKZF1 DNA-binding activity, pericentromeric localization, and tumor-suppressive transcriptional repression of cell cycle and PI3K pathway genes, establishing the CK2-IKZF1 axis as a therapeutically targetable mechanism in ALL.

    Evidence ChIP, gene expression analysis, CK2 inhibitor treatment, patient-derived xenograft models

    PMID:26219304

    Open questions at the time
    • Clinical significance of CK2-IKZF1 axis in patient outcomes not established
    • Whether CK2 inhibitor effects are fully IKZF1-dependent not formally excluded
  12. 2017 High

    Crystal structures of cereblon with next-generation IMiDs (CC-220) revealed that compound potency for IKZF1 degradation correlates with increased CRBN-compound contacts, providing structural rationalization for designing more potent IKZF1 degraders.

    Evidence Crystal structure determination, biochemical binding assays, cellular degradation assays

    PMID:28425720

    Open questions at the time
    • Ternary CRBN–compound–IKZF1 crystal structure not solved
    • Kinetics of neo-substrate ubiquitination not measured
  13. 2018 High

    IKZF1 was shown to form distinct transcription factor complexes with IRF4 at composite DNA elements (ZICEs and EICEs) in plasma cells, mediating either repression or activation depending on the co-factor (PU.1), and separately, IMiD-induced IKZF1 degradation in hematopoietic progenitors was found to reduce PU.1 expression and cause neutropenia.

    Evidence IRF4 ChIP-seq, Co-IP, gene expression analysis (plasma cells); thalidomide-bead pulldown, ChIP, CRBN-binding mutant, colony assays, NOD/SCID model (neutropenia)

    PMID:29496670 PMID:29669755

    Open questions at the time
    • Genome-wide map of IKZF1-IRF4 co-occupied sites and their functional consequences incomplete
    • Whether neutropenia is solely PU.1-dependent or involves additional IKZF1 targets
  14. 2019 High

    Genome-wide studies revealed IKZF1 possesses pioneering activity — directly establishing de novo enhancers and super-enhancers and increasing chromatin accessibility in T-ALL — and that IKZF1 regulates B cell tolerance by controlling anergy-associated gene programs and restraining TLR/MyD88-NF-κB signaling.

    Evidence ChIP-seq, ATAC-seq, RNA-seq with IKZF1 re-introduction into IKZF1-null T-ALL cells (pioneering); B cell-specific conditional KO, genetic epistasis with MyD88 deletion (anergy)

    PMID:31073152 PMID:31591571

    Open questions at the time
    • Mechanism of IKZF1 pioneering activity (co-factors, chromatin remodelers involved) not resolved
    • Whether autoimmunity in IKZF1-deleted B cells is fully TLR-dependent
  15. 2021 Medium

    Characterization of germline IKZF1 C-terminal dimerization domain mutations in patients revealed that these disrupt homo/heterodimerization, alter sumoylation and protein stability, and impair NuRD complex recruitment — mechanisms distinct from N-terminal DNA-binding mutations — demonstrating genotype-specific molecular pathology.

    Evidence Dimerization assays, sumoylation assays, NuRD recruitment assays, patient germline variant characterization

    PMID:32845957

    Open questions at the time
    • Clinical penetrance and phenotypic spectrum of C-terminal mutations not fully delineated
    • Whether sumoylation loss is causative or correlative
    • Single study; independent confirmation needed
  16. 2023 High

    Structural work on thalidomide derivatives solved the molecular basis of CRBN neo-substrate selectivity: a β-hairpin degron in IKZF1 containing a critical glycine mediates key contacts for CRBN recognition, with compound-specific SAR distinguishing IKZF1 from GSPT1 degradation; separately, Hi-C studies showed IKZF1 organizes megabase-scale 3D chromatin architecture in B cell precursors, overriding CTCF boundaries to create lineage-specific regulatory units and compact the Igκ locus for V(D)J recombination.

    Evidence Crystal structures, molecular dynamics, SAR across 14 analogs, cell-based degradation assays (degron); Hi-C, ChIP-seq, loss- and gain-of-function (3D genome)

    PMID:36970148 PMID:37995656

    Open questions at the time
    • Full ternary structure of CRBN–IMiD–IKZF1 at atomic resolution still lacking
    • Whether IKZF1-mediated 3D genome organization requires co-factors or is autonomous
    • Mechanism by which IKZF1 overrides CTCF boundaries not determined
  17. 2024 High

    IKZF1 was shown to directly repress Cish (a negative regulator of IL-15R signaling) in NK cells and to physically interact with AP-1 family members, with combined loss of IKZF1 and IKZF3 causing complete peripheral NK cell loss, establishing IKZF1 as essential for NK cell homeostasis through cytokine signaling and AP-1-dependent transcription.

    Evidence Conditional Ikzf1 KO, Ikzf1/Ikzf3 double conditional KO, ChIP, RNA-seq, apoptosis assays in NK cells

    PMID:38182668

    Open questions at the time
    • Whether IKZF1–AP-1 interaction is direct DNA co-occupancy or protein–protein interaction at all sites
    • Relative contributions of IKZF1 versus IKZF3 to individual NK cell gene programs not fully separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the atomic-resolution ternary structure of CRBN–IMiD–IKZF1, the mechanism by which IKZF1 acts as a chromatin pioneer factor, the full spectrum of IKZF1 isoform-specific functions across tissues, and how IKZF1 overrides CTCF-mediated boundary elements to establish lineage-specific 3D genome topology.
  • No ternary CRBN–IMiD–IKZF1 co-crystal structure published
  • Pioneer factor mechanism (co-factors, chromatin remodelers) undefined
  • Isoform-specific transcriptional programs not mapped genome-wide across tissues

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 13 GO:0003677 DNA binding 8 GO:0042393 histone binding 4
Localization
GO:0005634 nucleus 5 GO:0000228 nuclear chromosome 4 GO:0005654 nucleoplasm 2
Pathway
R-HSA-74160 Gene expression (Transcription) 10 R-HSA-4839726 Chromatin organization 6 R-HSA-1643685 Disease 5 R-HSA-1266738 Developmental Biology 4 R-HSA-168256 Immune System 4
Partners
CDK9CRBNCSNK2A1GATA1IKZF2IKZF3IRF4PPP1CA
Complex memberships
CRBN-CRL4 (as neo-substrate)NuRD/Mi-2-HDACmSin3-HDAC

Evidence

Reading pass · 34 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) by redirecting the CRBN-CRL4 E3 ubiquitin ligase to target these transcription factors as neo-substrates. A single amino acid substitution in IKZF3 conferred resistance to lenalidomide-induced degradation, confirming the specificity of this mechanism. Quantitative proteomics, ubiquitination assays, rescue experiments with point mutant IKZF3, cell growth assays Science High 24292623 24292625
2013 Lenalidomide-bound cereblon 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, and lenalidomide-induced IL-2 production in T cells is also due to IKZF1/IKZF3 depletion. Cereblon biochemistry, genetic rescue experiments in myeloma cell lines, T-cell functional assays Science High 24292623 24292625
1994 IKZF1 encodes a family of alternatively spliced zinc finger transcription factors; isoforms Ik-1 and Ik-2 contain sufficient N-terminal zinc fingers to bind DNA at lymphocyte-specific regulatory elements, localize to the nucleus, and strongly activate transcription, whereas Ik-3 and Ik-4 lack these fingers, are predominantly cytoplasmic, and are weak activators. Alternate splicing characterization, DNA-binding assays (EMSA), subcellular localization by immunofluorescence, transcription activation reporter assays Molecular and Cellular Biology High 7969165
1994 IKZF1 is required for the development of all lymphoid lineages (T, B, and NK cells) and their earliest progenitors; mice with a germline mutation in the IKZF1 DNA-binding domain completely lack these lineages while erythroid and myeloid lineages remain intact. Germline mouse knockout (DNA-binding domain mutation), flow cytometry, histology Cell High 7923373
1999 IKZF1 represses transcription through two repression domains that recruit the mSin3 family of co-repressors, which in turn bind histone deacetylases; this repression correlates with histone hypoacetylation at target promoters and is relieved by HDAC inhibitors. IKZF1 also associates with the Mi-2-HDAC complex. Reporter gene assays, in vivo and in vitro co-immunoprecipitation, HDAC inhibitor treatment, chromatin histone acetylation analysis EMBO Journal High 10357820
1998 IKZF1 proteins exist in highly stable complexes in T cells; immunoaffinity purification identified Helios (a T-cell-restricted Ikaros family member) as a stoichiometric component. IKZF1-Helios complexes colocalize to centromeric heterochromatin regions in T cell nuclei. Immunoaffinity chromatography/purification, co-immunoprecipitation, immunofluorescence/confocal microscopy Genes & Development High 9512513
2011 CK2 kinase phosphorylates IKZF1 at four specific sites, and this phosphorylation inhibits IKZF1's localization to pericentromeric heterochromatin, reduces its DNA-binding affinity, and promotes its degradation by the ubiquitin/proteasome pathway. Protein phosphatase 1 (PP1) dephosphorylates IKZF1 via an RVXF consensus binding motif, counteracting CK2. In vitro kinase assays, phosphomimetic and phosphoresistant mutant analysis, EMSA, confocal microscopy, phosphopeptide mapping, PP1 interaction mapping Molecular and Cellular Biochemistry High 21750978
2015 CK2 kinase impairs IKZF1's function as a transcriptional repressor in leukemia by phosphorylating it; CK2 inhibition restores IKZF1 DNA-binding activity, its ability to repress cell cycle and PI3K pathway genes, and its pericentromeric localization. ChIP assays, gene expression analysis, CK2 inhibitor treatment, patient-derived xenograft models Blood High 26219304
2008 IKZF1 represses the Notch target gene Hes-1 in T-cell development by competing with RBP-Jκ for binding to two elements in the Hes-1 promoter; IKZF1 binding to the Hes-1 promoter increases at the DN4 stage and correlates with reduced trimethylated H3K27 at this locus in IKZF1-deficient cells. ChIP assays, reporter gene assays, T-cell developmental stage analysis, Ikaros-deficient mouse model, H3K27me3 chromatin analysis Molecular and Cellular Biology High 18852286
2008 IKZF1 is recruited to the human β-globin locus and targets HDAC1 and Mi-2 to γ-globin gene promoters to contribute to γ-globin gene silencing. IKZF1 interacts with GATA-1, enhances GATA-1 binding to regulatory regions, and impairs LCR-γ-globin proximity. ChIP assays in primary cells, co-immunoprecipitation, 3C (chromosome conformation capture), siRNA knockdown Molecular and Cellular Biology High 19114560
2011 IKZF1 interacts with P-TEFb (specifically CDK9) and cooperates with GATA-1 to promote transcription elongation of γ-globin genes in yolk sac erythroid cells, facilitating conversion of RNA Pol II to its elongation-competent phospho-Ser2 form; IKZF1 also promotes BRG1 recruitment to the LCR and γ-globin promoters. Co-immunoprecipitation, ChIP assays in primary cells, RNA Pol II phosphorylation analysis, BRG1 recruitment assays Nucleic Acids Research High 21245044
2009 IKZF1 directly binds the tbx21 (T-bet) promoter in Th2 cells, repressing T-bet expression and preventing IFN-γ production; Ikaros is also required for epigenetic imprinting of the IFN-γ locus during Th2 polarization. ChIP assays, inhibition of IKZF1 DNA binding, gene expression analysis, in vivo Th response analysis Journal of Biological Chemistry High 19923223
2017 Crystal structure of cereblon in complex with DDB1 and the cereblon modulator CC-220 reveals that increased potency of IKZF1/IKZF3 degradation correlates with increased contacts between the compound and cereblon away from the modeled substrate binding site, confirming that E3 ligase binding affinity modulates neo-substrate degradation efficiency. Crystal structure determination, biochemical binding assays, cellular IKZF1/IKZF3 degradation assays Journal of Medicinal Chemistry High 28425720
2019 IKZF1 directly regulates the de novo formation and activation of enhancers and super-enhancers genome-wide, and exhibits pioneering activity by regulating chromatin accessibility in T-ALL cells; these functions underlie its tumor suppressor activity, resulting in cessation of proliferation and induction of T-cell differentiation. ChIP-seq, ATAC-seq, RNA-seq, re-introduction of IKZF1 into IKZF1-null T-ALL cells Leukemia High 31073152
2023 IKZF1 assembles lineage-specific 3D genome organization in B cell precursors by establishing interactions across megabase distances from IKZF1-bound enhancers, overriding CTCF-imposed boundaries to create lineage-specific regulatory units; IKZF1 also compacts the Igκ locus to enable V(D)J recombination. Hi-C, ChIP-seq, IKZF1 loss-of-function in B cell precursors, gain-of-function in epithelial cells Cell High 37995656
2013 IKZF1 inhibits megakaryopoiesis by repressing GATA-1 expression and decreasing NOTCH-induced megakaryocytic specification; IKZF1 expression is differentially regulated by GATA-2 and GATA-1 during megakaryocytic differentiation, and combined loss of Ikzf1 and Gata1 causes synthetic lethality in vivo. Overexpression/knockdown, gene expression analysis, mouse genetic models (Ikzf1/Gata1 double knockout), colony assays Blood High 23335373
2013 IKZF1 directly binds regulatory sites within the Cebpa and Hes1 loci and regulates permissive H3K4 trimethylation at the Cebpa locus while reducing H3K4me3 at the Hes1 promoter, thereby suppressing basophil differentiation. ChIP assays, conditional Ikaros knockout mice, bone marrow culture, histone modification analysis Blood High 23990620
2006 Disruption of IKZF1 in DT40 B cells induces a BCR signaling defect characterized by reduced PLCγ2 phosphorylation and impaired intracellular calcium mobilization, and causes hyperphosphorylation of Cbl; these defects are restored by IKZF1 reintroduction. Gene disruption in DT40 chicken B cells, calcium flux assays, phosphorylation assays, rescue by IKZF1 reintroduction European Journal of Immunology High 16482514
2010 IKZF1 binds to the promoter of the INPP5D gene (encoding SHIP) and positively regulates SHIP expression; loss of IKZF1 leads to upregulation of SHIP, whereas loss of Helios leads to downregulation, demonstrating that IKZF1 and Helios cooperate to control BCR signaling through SHIP. ChIP assays, Helios-deficient DT40 B cell line characterization, calcium flux assays, phosphorylation analysis European Journal of Immunology High 20602434
2012 FoxO1 promotes proper IKZF1 mRNA splicing (not transcription) in pro-B cells; FoxO1-induced IKZF1 expression mediates proximal VH-to-DJH gene rearrangement, while IKZF1 cooperates with Pax5 to activate distal VH gene rearrangement. Pro-B cell genetic analysis (Pten-deficient cells), mRNA splicing analysis, V(D)J recombination assays, FoxO1 and Pax5 genetic manipulation Journal of Experimental Medicine High 22291095
2014 IKZF1 represses PP2A expression by binding to a variant site in the first intron of the PP2A gene; IKZF1-mediated repression involves recruitment of HDAC1 to this intronic site. Exogenous IKZF1 reduces PP2Ac mRNA and protein, while IKZF1 silencing enhances PP2A expression. ChIP, reporter assays, siRNA knockdown, exogenous expression, HDAC1 co-recruitment assay Journal of Biological Chemistry Medium 24692537
2018 In plasma cells, IKZF1 forms complexes with IRF4 at zinc finger-IRF composite elements (ZICEs), repressing target genes such as Ebf1; Ikaros (but not Aiolos) is essential for IRF4 binding to the ZICE sequence. In contrast, an Ikaros/PU.1/IRF4 complex at EICE motifs activates target gene expression. IRF4 ChIP-seq, gene expression analysis, co-immunoprecipitation, ChIP assays Blood Advances High 29669755
2006 IKZF1 is expressed in pituitary corticomelanotroph cells, binds the proopiomelanocortin (POMC) promoter, and regulates endogenous POMC gene expression; loss of IKZF1 in vivo results in contraction of the corticomelanotroph population and adrenal glucocorticoid insufficiency. ChIP, reporter assays, Ikaros knockout mouse analysis, ACTH/glucocorticoid measurements Journal of Clinical Investigation High 15841184
2007 IKZF1 (Ik-1/Ik-2 isoforms) is expressed in developing striatal neurons, binds Ikaros recognition elements in the enkephalin (ENK) gene, and acts as a positive regulator of ENK gene expression; mice lacking the IKZF1 DNA-binding domain show reduced enkephalin-positive neurons. DNA-binding assays, blocking of IKZF1 DNA-binding in striatal cultures, Ikaros knockout mouse analysis, in situ hybridization Journal of Neurochemistry Medium 17504264
2019 IKZF1 regulates BCR anergy by controlling anergy-associated genes including Zfp318 (which promotes IgD expression in anergic B cells); Ikaros also restrains TLR/MyD88-NF-κB signaling by upregulating feedback inhibitors of this pathway. B cell-specific deletion of Ikaros leads to systemic autoimmunity. B cell-specific conditional knockout mice, gene expression profiling, BCR and TLR signaling assays, genetic epistasis with MyD88 deletion Nature Immunology High 31591571
2006 Low-level expression of IKZF1 isoforms in Ik(L/L) mice causes a cell-intrinsic block in plasmacytoid dendritic cell (pDC) differentiation at the Ly-49Q- stage; this block leads to failure to produce type I IFN upon viral challenge. Global gene expression profiling reveals upregulation of genes normally silenced in WT pDCs. Ikaros hypomorphic mouse model (Ik(L/L)), flow cytometry, Flt-3L stimulation, bone marrow reconstitution, gene expression profiling Blood High 16912230
2011 Cell cycle-specific phosphorylation by CK2 during S phase reduces IKZF1's DNA-binding affinity for regulatory regions of target genes while preserving pericentromeric heterochromatin binding; these changes are controlled by the CK2 kinase pathway and are observed in human ALL cells. EMSA, confocal microscopy, phosphopeptide mapping, cell cycle synchronization Pediatric Blood & Cancer Medium 22106042
2014 Full-length IKZF1 (IK-1) maintains EBV latency in B cells through indirect mechanisms—by sustaining Oct-2 and Bcl-6 expression that inhibit EBV reactivation—and physically associates with the EBV immediate early R protein (co-IP), partially colocalizing within cells; R protein association relieves IK-1-mediated repression. shRNA knockdown, ChIP-seq, co-immunoprecipitation, ectopic expression, immunofluorescence colocalization Journal of Virology Medium 24522918
2021 In myeloid macrophages, IKZF1 negatively regulates SIRT1 in an AMPK-dependent manner; IKZF1-regulated pyroptosis via canonical inflammasome signaling is SIRT1-dependent. Myeloid-specific IKZF1 signaling augments hepatic pyroptosis and pro-inflammatory responses in vivo. Ikaros silencing/overexpression in BMMs, myeloid-specific Sirt1 KO mice, CD11b-DTR mice, AMPK pathway analysis Journal of Hepatology Medium 34871625
2023 Structural analysis of thalidomide derivatives with cereblon (CRBN) reveals that the β-hairpin degron of IKZF1 containing a critical glycine mediates key contacts required for CRBN recognition and subsequent ubiquitination; compound-specific structure-activity relationships for IKZF1 vs. GSPT1 degradation were delineated. Crystal structures, computational docking, molecular dynamics, cell-based IKZF1 and GSPT1 degradation assays with 14 analogs RSC Medicinal Chemistry High 36970148
2021 Germline IKZF1 C-terminal dimerization domain mutations disrupt homo- and heterodimerization without affecting the wild-type allele, and alter IKZF1 sumoylation, protein stability, and recruitment of the NuRD (nucleosome remodeling and deacetylase) complex—mechanisms distinct from those of N-terminal DNA-binding domain mutations. Dimerization assays, sumoylation assays, NuRD complex recruitment assays, protein stability analysis, patient germline variant characterization Blood Medium 32845957
2018 IMiD compounds cause CRBN-dependent ubiquitination and degradation of IKZF1 in CD34+ hematopoietic progenitor cells; IKZF1 directly binds the PU.1 promoter (ChIP), and its degradation reduces PU.1 expression, leading to neutropenia. A CRBN-binding mutant IKZF1 (Q146H) is resistant to IMiD-induced degradation. Thalidomide-bead pulldown, CRBN knockdown, colony formation assays, ChIP, NOD/SCID mouse model Blood Advances High 29496670
2019 In zebrafish, Ikzf1 directly controls Ccr9a and Irf4a expression (direct transcriptional targets) in hematopoietic stem/progenitor cells; Ccr9a mediates thymic migration of HSPCs downstream of Ikzf1, while Irf4a drives HSPC proliferation and T-cell differentiation; restoration of both partially rescues T lymphopoiesis in ikzf1 mutants. Zebrafish ikzf1 mutant, genetic rescue with ccr9a and irf4a, HSPC thymic homing assays, gene expression analysis Journal of Biological Chemistry Medium 31511326
2024 IKZF1 directly represses Cish (a negative regulator of IL-15 receptor signaling) in NK cells; IKZF1 and IKZF3 directly bind AP-1 family members (Jun/Fos), and combined deletion of Ikzf1 and Ikzf3 in NK cells causes further reductions in AP-1 expression and complete loss of peripheral NK cells. Conditional Ikzf1 knockout mice, Ikzf1/Ikzf3 double conditional knockout, ChIP, RNA-seq, apoptosis assays Nature Immunology High 38182668

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.) 1469 24292625
2013 The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science (New York, N.Y.) 1241 24292623
1994 The Ikaros gene is required for the development of all lymphoid lineages. Cell 822 7923373
1994 The Ikaros gene encodes a family of functionally diverse zinc finger DNA-binding proteins. Molecular and cellular biology 376 7969165
1999 Repression by Ikaros and Aiolos is mediated through histone deacetylase complexes. The EMBO journal 258 10357820
2002 Haematopoietic cell-fate decisions, chromatin regulation and ikaros. Nature reviews. Immunology 256 11913067
1998 Helios, a T cell-restricted Ikaros family member that quantitatively associates with Ikaros at centromeric heterochromatin. Genes & development 223 9512513
1997 The role of the Ikaros gene in lymphocyte development and homeostasis. Annual review of immunology 219 9143685
2017 A Cereblon Modulator (CC-220) with Improved Degradation of Ikaros and Aiolos. Journal of medicinal chemistry 214 28425720
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