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Gene Review

Ikzf1  -  IKAROS family zinc finger 1

Mus musculus

Synonyms: 5832432G11Rik, DNA-binding protein Ikaros, Ikaros, Ikaros family zinc finger protein 1, LyF-1, ...
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Discovery of Ikaros (Ikzf1)

The Ikaros protein was described in 1991 as a protein binding to lymphocyte specific genes, and was initially named LyF-1 [1]. The gene encoding Ikaros, Ikzf1, was cloned the next year [2] and when it later was discovered that LyF-1 was encoded by the Ikzf1 gene, the name of LyF-1 was abandoned, and the protein thereafter named Ikaros [3].


Ikaros is a zinc finger transcription factor

Ikaros belongs to the largest class of mammalian transcription factors as defined by the DNA-binding domain: the zinc finger (ZnF) family. Ikaros contains four DNA-binding N-terminal ZnFs (where the two central fingers, ZnF2 and ZnF3, are required for binding to DNA) and two C-terminal ZnFs that mediate protein dimerization. Biochemical studies have demonstrated that ZnF proteins only require two or three tandem ZnFs to mediate stable DNA binding, and thus the presence of multiple tandem ZnFs in the many ZnF transcription factors indicate an added layer of function or regulation. Within one multi-fingered transcription factor, several ZnFs might function to recognize extended regions of DNA for highly specific protein-DNA interactions, or the protein could use different subsets of the DNA-binding ZnFs to bind different subsets of DNA-recognition sites. Support for the latter was recently shown for Ikaros, where mutant mice demonstrated in vivo functional difference between Ikaros lacking the exon encoding the first DNA-binding ZnF (Ikzf1ΔF1/ΔF1) and mice lacking the fourth DNA-binding ZnF (Ikzf1ΔF4/ΔF4) [4]. These two mutant mice strains displayed different phenotypes, indicating different functional requirement for the two flanking DNA-binding ZnFs.


The Ikaros Family

Ikaros is the founding member of a family of transcription factors including Helios (Ikzf2), Aiolos (Ikzf3), Eos (Ikzf4) and Pegasus (Ikzf5).


Ikaros is critical for proper hematopoietic development

Ikaros is expressed throughout the hematopoietic system, and observations from Ikaros-mutant mice demonstrate that Ikaros has important roles in the development of several hematopoietic lineages. It is absolutely required for B-cell development, as Ikaros-null mutant mice do not have any B-cells at all, neither fetal, post natal or adult [5]. In addition to the critical role in the initiation of B-cell development, Ikaros has regulatory roles also at other stages of B-cell development [6]. Interestingly, the role in fetal and post-natal/adult B-cell development was separated with the study of Ikaros ZnF mutant mice [4]. It was found that Ikaros-ZnF4 mutant mice do not have fetal B-cells, while the Ikaro-ZnF1 mutant mice do. Furthermore, for adult B-cell development, both ZnF mutant mice had B-cells, although at reduced levels, and further analysis of early B-cell development in the BM revealed partial blocks in development at distinct staged. In addition to the critical role in B-cell development, Ikaros also have important roles in T-cell development, as well as other lymphoid lineages (see various references below).


Disease relevance of Ikzf1

  • Ikaros is a tumor suppressor in the lymphoid lineage. Various Ikaros mutant mice develop spontaneous thymic lymphoma, and the tumor suppressor function is independent of the first DNA-binding zinc finger, but requires the exon encoding the fourth DNA-binding zinc finger (ZnF4) [4]. Ikaros is also an important tumor suppressor in human lymphoid lineage leukemia, and a striking correlation was found in the BCR-ABL1+ subset of pre-B ALL, with more than 80% displaying mutation or deletion in the IKZF1 gene, encoding Ikaros [7].
  • Mice carrying a hypomorphic mutation (Ik(L/L)) in the Ikaros gene all develop thymic lymphomas [8].
  • Recombinant Ikaros expressed in Escherichia coli bound to the TdT promoter, and antisera directed against the recombinant protein specifically blocked the DNA-binding activity of LyF-1 in crude extracts [9].
  • When a mutated non-DNA-binding form of Ikaros was introduced into primary activated B cells by retrovirus transduction, the endogenous Ikaros clusters were disrupted [10].
  • This prompted us to investigate whether mutations in Ikaros play a role in human hematological malignancies [11].
  • In 9 of 17 samples of patients in blast crisis of CML, Ikaros activity had been reduced either by drastically reducing mRNA expression (4 of 17) or by overexpressing the dominant-negative isoform Ik-6 (5 of 17) [11].

High impact information on Ikzf1

  • Furthermore, Ikaros-null thymocytes hyperproliferate in response to T cell receptor (TCR) signaling; within days after their appearance in the thymus, clonally expanding populations are detected [12].
  • The dominant interference activity of Ikaros isoforms unable to bind DNA and their effects in lymphocyte development suggest that Ikaros works in concert with other factors [12].
  • The Ikaros gene, which encodes a family of hemopoietic-specific zinc finger proteins, is described as a central regulator of lymphocyte differentiation [12].
  • In addition, lack of natural killer cells and selective defects in gamma delta T cells and dendritic antigen-presenting cells point to Ikaros as an essential factor for the establishment of early branchpoints of the T cell pathway [12].
  • Deregulated TCR-mediated responses and the fast kinetics of tumor development in these mutant thymocytes implicate Ikaros as a central tumor suppressor gene for the T cell lineage [12].

Chemical compound and disease context of Ikzf1


Biological context of Ikzf1


Anatomical context of Ikzf1

  • Notch activation is an early and critical event during T-Cell leukemogenesis in Ikaros-deficient mice [8].
  • The role of the Ikaros gene in lymphocyte development and homeostasis [12].
  • In the absence of a functional Ikaros gene, these stem cells are exclusively diverted into the erythroid and myeloid lineages [18].
  • During development, Ikaros messenger RNA was first detected in the mouse fetal liver and the embryonic thymus when hematopoietic and lymphoid progenitors initially colonize these organs; no expression was observed in the spleen or the bone marrow [19].
  • Unlike the B cell results, however, only a fraction of the Ikaros, presumably the fraction associated with Helios, exhibited centromeric localization in T cells [20].

Associations of Ikzf1 with chemical compounds

  • In pre-B cells, one allele became preferentially packaged into an active chromatin structure characterized by histone acetylation and methylation of histone H3 lysine 4, while the other allele was recruited to heterochromatin, where it was associated with heterochromatin protein-gamma and Ikaros [21].
  • In Ikaros mutant mice, a decrease in expression of the tyrosine kinase receptors flk-2 and c-kit is observed in the lineage-depleted c-kit(+)Sca-1(+) population that is normally enriched for HSCs and may in part contribute to the early hemopoietic phenotypes manifested in the absence of Ikaros [22].
  • CONCLUSIONS: Distinct but overlapping expression patterns of members of the Ikaros gene family during hematopoiesis might result in the formation of different multimeric complexes that have specific roles in lineage progression [23].
  • Interestingly, 8 of the mutations were identified in the NH2-terminal zinc finger motifs, which are crucial for the DNA-binding function of Ikaros [14].
  • An intronic Ikaros-binding element mediates retinoic acid suppression of the kappa opioid receptor gene, accompanied by histone deacetylation on the promoters [24].

Physical interactions of Ikzf1

  • Ikaros interacts with the NURD complex (Mi2) [25] [26].
  • We give evidence that Ikaros can bind to several sites in the germline gamma1 and epsilon immunoglobulin heavy chain promoters, in a cooperative manner [10].
  • Silencing of lambda5 expression in mature B cells occurs through the action of Ikaros on the gene promoter where it may compete for binding of EBF and initiate the formation of a silent chromatin structure [27].
  • This is the first report of Ikaros mutations coupled with Mlh1 deficiency in lymphomagenesis [28].
  • In double-negative thymocytes, Ikaros binding to the Cd4 silencer contributed to its repressive activity [29].

Regulatory relationships of Ikzf1

  • To study the effect of Pax5 on the development of other hematopoietic lineages, we generated a heterozygous knockin mouse carrying a Pax5 minigene under the control of the Ikaros locus [30].
  • Furthermore, we have demonstrated that Ik-2 and upstream stimulatory factor synergize in trans-activating the dor promoter via the putative Ik-binding site and the E box, respectively [31].
  • Overexpression of Ikaros enhanced GHRH promoter activity and induced endogenous GHRH gene expression [32].
  • Aiolos encodes a zinc finger DNA-binding protein that is highly expressed in mature B cells and is homologous to Ikaros [33].
  • However, overexpression of GATA-1 or Lyf-1 repressed Npr1 basal promoter activity by 50% and 80%, respectively [34].
  • We provide evidence that Ikaros directly represses Hes1 in concert with the transcriptional repressor, RBP-Jkappa, allowing for cross-talk between Notch and Ikaros that impacts regulation of CD4 expression [35].

Other interactions of Ikzf1

  • He e we demonstrate that ectopic Pax5 expression from the Ikaros promote induces proximal rather than distal VH-DJH rearrangements in Ik(Pax5/+) thymocytes, thus recapitulating the loss-of-function phenotype of Pax5-/- pro-B cells [36].
  • In the present study, only a small fraction of tumours showed LOH in the Ikaros region, while a minority of lymphomas, but not acute myeloid leukaemias, showed allelic loss of the chromosome 11 segment encoding Trp53 [37].
  • Here we test whether Helios and Aiolos, two other members of the Ikaros gene family, are also involved in lymphomagenesis [38].
  • Genetic mapping and allelic loss analysis in mouse thymic lymphomas of Helios and Aiolos belonging to the Ikaros gene family [38].
  • Sequence analysis revealed that the most common nucleic acid substitutions were T>A (4/8) in p53, T>C (4/5) in Ikaros and G>A/T (8/9) in Kras, suggesting that the spectrum of mutations was gene dependent [13].

Analytical, diagnostic and therapeutic context of Ikzf1


  1. LyF-1, a transcriptional regulator that interacts with a novel class of promoters for lymphocyte-specific genes. Lo, K., Landau, N.R., Smale, S.T. Mol. Cell. Biol. (1991) [Pubmed]
  2. Ikaros, an early lymphoid-specific transcription factor and a putative mediator for T cell commitment. Georgopoulos, K., Moore, D.D., Derfler, B. Science. (1992) [Pubmed]
  3. The lymphoid transcription factor LyF-1 is encoded by specific, alternatively spliced mRNAs derived from the Ikaros gene. Hahm, K., Ernst, P., Lo, K., Kim, G.S., Turck, C., Smale, S.T. Mol. Cell. Biol. (1994) [Pubmed]
  4. Selective regulation of lymphopoiesis and leukemogenesis by individual zinc fingers of Ikaros. Schjerven, H., McLaughlin, J., Arenzana, T.L., Frietze, S., Cheng, D., Wadsworth, S.E., Lawson, G.W., Bensinger, S.J., Farnham, P.J., Witte, O.N., Smale, S.T. Nat. Immunol. (2013) [Pubmed]
  5. Selective defects in the development of the fetal and adult lymphoid system in mice with an Ikaros null mutation. Wang, J.H., Nichogiannopoulou, A., Wu, L., Sun, L., Sharpe, A.H., Bigby, M., Georgopoulos, K. Immunity. (1996) [Pubmed]
  6. Regulation of B cell fate commitment and immunoglobulin heavy-chain gene rearrangements by Ikaros. Reynaud, D., Demarco, I.A., Reddy, K.L., Schjerven, H., Bertolino, E., Chen, Z., Smale, S.T., Winandy, S., Singh, H. Nat. Immunol. (2008) [Pubmed]
  7. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Mullighan, C.G., Miller, C.B., Radtke, I., Phillips, L.A., Dalton, J., Ma, J., White, D., Hughes, T.P., Le Beau, M.M., Pui, C.H., Relling, M.V., Shurtleff, S.A., Downing, J.R. Nature. (2008) [Pubmed]
  8. Notch activation is an early and critical event during T-Cell leukemogenesis in Ikaros-deficient mice. Dumortier, A., Jeannet, R., Kirstetter, P., Kleinmann, E., Sellars, M., dos Santos, N.R., Thibault, C., Barths, J., Ghysdael, J., Punt, J.A., Kastner, P., Chan, S. Mol. Cell. Biol. (2006) [Pubmed]
  9. The lymphoid transcription factor LyF-1 is encoded by specific, alternatively spliced mRNAs derived from the Ikaros gene. Hahm, K., Ernst, P., Lo, K., Kim, G.S., Turck, C., Smale, S.T. Mol. Cell. Biol. (1994) [Pubmed]
  10. Binding of Ikaros to germline Ig heavy chain gamma1 and epsilon promoters. Ström, L., Lundgren, M., Severinson, E. Mol. Immunol. (2003) [Pubmed]
  11. Decreases in Ikaros activity correlate with blast crisis in patients with chronic myelogenous leukemia. Nakayama, H., Ishimaru, F., Avitahl, N., Sezaki, N., Fujii, N., Nakase, K., Ninomiya, Y., Harashima, A., Minowada, J., Tsuchiyama, J., Imajoh, K., Tsubota, T., Fukuda, S., Sezaki, T., Kojima, K., Hara, M., Takimoto, H., Yorimitsu, S., Takahashi, I., Miyata, A., Taniguchi, S., Tokunaga, Y., Gondo, H., Niho, Y., Harada, M. Cancer Res. (1999) [Pubmed]
  12. The role of the Ikaros gene in lymphocyte development and homeostasis. Georgopoulos, K., Winandy, S., Avitahl, N. Annu. Rev. Immunol. (1997) [Pubmed]
  13. Frequent retention of heterozygosity for point mutations in p53 and Ikaros in N-ethyl-N-nitrosourea-induced mouse thymic lymphomas. Kakinuma, S., Nishimura, M., Kubo, A., Nagai, J.Y., Amasaki, Y., Majima, H.J., Sado, T., Shimada, Y. Mutat. Res. (2005) [Pubmed]
  14. Point mutations and deletions in the znfn1a1/ikaros gene in chemically induced murine lymphomas. Karlsson, A., Söderkvist, P., Zhuang, S.M. Cancer Res. (2002) [Pubmed]
  15. Expression of dominant-negative Ikaros isoforms in T-cell acute lymphoblastic leukemia. Sun, L., Crotty, M.L., Sensel, M., Sather, H., Navara, C., Nachman, J., Steinherz, P.G., Gaynon, P.S., Seibel, N., Mao, C., Vassilev, A., Reaman, G.H., Uckun, F.M. Clin. Cancer Res. (1999) [Pubmed]
  16. The Ikaros gene encodes a family of lymphocyte-restricted zinc finger DNA binding proteins, highly conserved in human and mouse. Molnár, A., Wu, P., Largespada, D.A., Vortkamp, A., Scherer, S., Copeland, N.G., Jenkins, N.A., Bruns, G., Georgopoulos, K. J. Immunol. (1996) [Pubmed]
  17. The zinc finger Ikaros transcription factor regulates pituitary growth hormone and prolactin gene expression through distinct effects on chromatin accessibility. Ezzat, S., Yu, S., Asa, S.L. Mol. Endocrinol. (2005) [Pubmed]
  18. The Ikaros gene is required for the development of all lymphoid lineages. Georgopoulos, K., Bigby, M., Wang, J.H., Molnar, A., Wu, P., Winandy, S., Sharpe, A. Cell (1994) [Pubmed]
  19. Ikaros, an early lymphoid-specific transcription factor and a putative mediator for T cell commitment. Georgopoulos, K., Moore, D.D., Derfler, B. Science (1992) [Pubmed]
  20. Helios, a T cell-restricted Ikaros family member that quantitatively associates with Ikaros at centromeric heterochromatin. Hahm, K., Cobb, B.S., McCarty, A.S., Brown, K.E., Klug, C.A., Lee, R., Akashi, K., Weissman, I.L., Fisher, A.G., Smale, S.T. Genes Dev. (1998) [Pubmed]
  21. Epigenetic ontogeny of the Igk locus during B cell development. Goldmit, M., Ji, Y., Skok, J., Roldan, E., Jung, S., Cedar, H., Bergman, Y. Nat. Immunol. (2005) [Pubmed]
  22. Defects in hemopoietic stem cell activity in Ikaros mutant mice. Nichogiannopoulou, A., Trevisan, M., Neben, S., Friedrich, C., Georgopoulos, K. J. Exp. Med. (1999) [Pubmed]
  23. Helios, a novel dimerization partner of Ikaros expressed in the earliest hematopoietic progenitors. Kelley, C.M., Ikeda, T., Koipally, J., Avitahl, N., Wu, L., Georgopoulos, K., Morgan, B.A. Curr. Biol. (1998) [Pubmed]
  24. An intronic Ikaros-binding element mediates retinoic acid suppression of the kappa opioid receptor gene, accompanied by histone deacetylation on the promoters. Hu, X., Bi, J., Loh, H.H., Wei, L.N. J. Biol. Chem. (2001) [Pubmed]
  25. Predominant interaction of both Ikaros and Helios with the NuRD complex in immature thymocytes. Sridharan, R., Smale, S.T. J. Biol. Chem. (2007) [Pubmed]
  26. Harnessing of the nucleosome-remodeling-deacetylase complex controls lymphocyte development and prevents leukemogenesis. Zhang, J., Jackson, A.F., Naito, T., Dose, M., Seavitt, J., Liu, F., Heller, E.J., Kashiwagi, M., Yoshida, T., Gounari, F., Petrie, H.T., Georgopoulos, K. Nat. Immunol. (2011) [Pubmed]
  27. The lambda5-VpreB1 locus--a model system for studying gene regulation during early B cell development. Sabbattini, P., Dillon, N. Semin. Immunol. (2005) [Pubmed]
  28. Ikaros is a mutational target for lymphomagenesis in Mlh1-deficient mice. Kakinuma, S., Kodama, Y., Amasaki, Y., Yi, S., Tokairin, Y., Arai, M., Nishimura, M., Monobe, M., Kojima, S., Shimada, Y. Oncogene (2007) [Pubmed]
  29. Antagonistic interactions between Ikaros and the chromatin remodeler Mi-2beta determine silencer activity and Cd4 gene expression. Naito, T., Gómez-Del Arco, P., Williams, C.J., Georgopoulos, K. Immunity (2007) [Pubmed]
  30. Pax5 promotes B lymphopoiesis and blocks T cell development by repressing Notch1. Souabni, A., Cobaleda, C., Schebesta, M., Busslinger, M. Immunity (2002) [Pubmed]
  31. Transcriptional regulation of mouse delta-opioid receptor gene. Ikaros-2 and upstream stimulatory factor synergize in trans-activating mouse delta-opioid receptor gene in T cells. Sun, P., Loh, H.H. J. Biol. Chem. (2003) [Pubmed]
  32. An essential role for the hematopoietic transcription factor Ikaros in hypothalamic-pituitary-mediated somatic growth. Ezzat, S., Mader, R., Fischer, S., Yu, S., Ackerley, C., Asa, S.L. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  33. Aiolos regulates B cell activation and maturation to effector state. Wang, J.H., Avitahl, N., Cariappa, A., Friedrich, C., Ikeda, T., Renold, A., Andrikopoulos, K., Liang, L., Pillai, S., Morgan, B.A., Georgopoulos, K. Immunity (1998) [Pubmed]
  34. Transcriptional regulation of guanylyl cyclase/natriuretic peptide receptor-A gene. Kumar, P., Arise, K.K., Pandey, K.N. Peptides (2006) [Pubmed]
  35. Ikaros directly represses the notch target gene Hes1 in a leukemia T cell line: implications for CD4 regulation. Kathrein, K.L., Chari, S., Winandy, S. J. Biol. Chem. (2008) [Pubmed]
  36. Pax5 induces V-to-DJ rearrangements and locus contraction of the immunoglobulin heavy-chain gene. Fuxa, M., Skok, J., Souabni, A., Salvagiotto, G., Roldan, E., Busslinger, M. Genes Dev. (2004) [Pubmed]
  37. Analysis of loss of heterozygosity in lymphoma and leukaemia arising in F1 hybrid mice locates a common region of chromosome 4 loss. Meijne, E., Huiskamp, R., Haines, J., Moody, J., Finnon, R., Wilding, J., Spanjer, S., Bouffler, S., Edwards, A., Cox, R., Silver, A. Genes Chromosomes Cancer (2001) [Pubmed]
  38. Genetic mapping and allelic loss analysis in mouse thymic lymphomas of Helios and Aiolos belonging to the Ikaros gene family. Xu, H., Wakabayashi, Y., Okano, H., Saito, Y., Miyazawa, T., Kominami, R. Jpn. J. Cancer Res. (2001) [Pubmed]
  39. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. Mullighan, C.G., Su, X., Zhang, J., Radtke, I., Phillips, L.A., Miller, C.B., Ma, J., Liu, W., Cheng, C., Schulman, B.A., Harvey, R.C., Chen, I.M., Clifford, R.J., Carroll, W.L., Reaman, G., Bowman, W.P., Devidas, M., Gerhard, D.S., Yang, W., Relling, M.V., Shurtleff, S.A., Campana, D., Borowitz, M.J., Pui, C.H., Smith, M., Hunger, S.P., Willman, C.L., Downing, J.R. N. Engl. J. Med. (2009) [Pubmed]
  40. Control of lymphocyte development by the Ikaros gene family. Cortes, M., Wong, E., Koipally, J., Georgopoulos, K. Curr. Opin. Immunol. (1999) [Pubmed]
  41. Hematopoietic stem cells and lymphoid progenitors express different Ikaros isoforms, and Ikaros is localized to heterochromatin in immature lymphocytes. Klug, C.A., Morrison, S.J., Masek, M., Hahm, K., Smale, S.T., Weissman, I.L. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  42. Association of transcriptionally silent genes with Ikaros complexes at centromeric heterochromatin. Brown, K.E., Guest, S.S., Smale, S.T., Hahm, K., Merkenschlager, M., Fisher, A.G. Cell (1997) [Pubmed]
  43. Conservation of a master hematopoietic switch gene during vertebrate evolution: isolation and characterization of Ikaros from teleost and amphibian species. Hansen, J.D., Strassburger, P., Du Pasquier, L. Eur. J. Immunol. (1997) [Pubmed]
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