ikaros transcription factor

Summary

Summary: A transcription factor that plays a role as a key regulator of HEMATOPOIESIS. Aberrant Ikaros expression has been associated with LYMPHOBLASTIC LEUKEMIA.

Top Publications

  1. Papathanasiou P, Perkins A, Cobb B, Ferrini R, Sridharan R, Hoyne G, et al. Widespread failure of hematolymphoid differentiation caused by a recessive niche-filling allele of the Ikaros transcription factor. Immunity. 2003;19:131-44 pubmed
  2. Sezaki N, Ishimaru F, Takata M, Tabayashi T, Nakase K, Kozuka T, et al. Over-expression of the dominant-negative isoform of Ikaros confers resistance to dexamethasone-induced and anti-IgM-induced apoptosis. Br J Haematol. 2003;121:165-9 pubmed
    ..Further investigations of the mechanism of leukaemogenesis associated with the over-expression of Ik-6 are warranted. ..
  3. Kano G, Morimoto A, Takanashi M, Hibi S, Sugimoto T, Inaba T, et al. Ikaros dominant negative isoform (Ik6) induces IL-3-independent survival of murine pro-B lymphocytes by activating JAK-STAT and up-regulating Bcl-xl levels. Leuk Lymphoma. 2008;49:965-73 pubmed publisher
  4. Iacobucci I, Lonetti A, Cilloni D, Messa F, Ferrari A, Zuntini R, et al. Identification of different Ikaros cDNA transcripts in Philadelphia-positive adult acute lymphoblastic leukemia by a high-throughput capillary electrophoresis sizing method. Haematologica. 2008;93:1814-21 pubmed publisher
    ..Our findings demonstrate that both aberrant splicing and genomic deletion leading to different non-DNA-binding Ikaros cDNA transcripts are common features of Philadelphia chromosome-positive acute lymphoblastic leukemia. ..
  5. Schwab C, Jones L, Morrison H, Ryan S, Yigittop H, Schouten J, et al. Evaluation of multiplex ligation-dependent probe amplification as a method for the detection of copy number abnormalities in B-cell precursor acute lymphoblastic leukemia. Genes Chromosomes Cancer. 2010;49:1104-13 pubmed publisher
  6. Waanders E, van der Velden V, van der Schoot C, van Leeuwen F, van Reijmersdal S, de Haas V, et al. Integrated use of minimal residual disease classification and IKZF1 alteration status accurately predicts 79% of relapses in pediatric acute lymphoblastic leukemia. Leukemia. 2011;25:254-8 pubmed publisher
  7. Uckun F, Ma H, Zhang J, Ozer Z, Dovat S, Mao C, et al. Serine phosphorylation by SYK is critical for nuclear localization and transcription factor function of Ikaros. Proc Natl Acad Sci U S A. 2012;109:18072-7 pubmed publisher
    ..Mechanistically, we establish that SYK-induced Ikaros activation is essential for its nuclear localization and optimal transcription factor function. ..
  8. Ma S, Pathak S, Trinh L, Lu R. Interferon regulatory factors 4 and 8 induce the expression of Ikaros and Aiolos to down-regulate pre-B-cell receptor and promote cell-cycle withdrawal in pre-B-cell development. Blood. 2008;111:1396-403 pubmed
    ..Thus, IRF4,8 orchestrate the transition from large pre-B to small pre-B cells by inducing the expression of Ikaros and Aiolos. ..
  9. Gómez del Arco P, Kashiwagi M, Jackson A, Naito T, Zhang J, Liu F, et al. Alternative promoter usage at the Notch1 locus supports ligand-independent signaling in T cell development and leukemogenesis. Immunity. 2010;33:685-98 pubmed publisher
    ..Thus, a network of epigenetic and transcriptional regulators controls conventional and unconventional Notch signaling during normal development and leukemogenesis. ..

More Information

Publications62

  1. Roberts K, Mullighan C. How new advances in genetic analysis are influencing the understanding and treatment of childhood acute leukemia. Curr Opin Pediatr. 2011;23:34-40 pubmed publisher
    ..Future studies will be increasingly reliant on comprehensive genomic sequencing to reveal the spectrum of genetic alterations in this disease, with the ultimate aim of improving the treatment outcome for leukemia patients. ..
  2. Sun L, Heerema N, Crotty L, Wu X, Navara C, Vassilev A, et al. Expression of dominant-negative and mutant isoforms of the antileukemic transcription factor Ikaros in infant acute lymphoblastic leukemia. Proc Natl Acad Sci U S A. 1999;96:680-5 pubmed
    ..These results implicate the expression of dominant-negative Ikaros isoforms and the disruption of normal Ikaros function in the leukemogenesis of ALL in infants. ..
  3. Kelley C, Ikeda T, Koipally J, Avitahl N, Wu L, Georgopoulos K, et al. Helios, a novel dimerization partner of Ikaros expressed in the earliest hematopoietic progenitors. Curr Biol. 1998;8:508-15 pubmed
    Normal hematopoietic development depends on the activity of the Ikaros transcription factor, which contains distinct zinc-finger domains that mediate DNA binding and protein dimerization...
  4. John L, Ward A. The Ikaros gene family: transcriptional regulators of hematopoiesis and immunity. Mol Immunol. 2011;48:1272-8 pubmed publisher
    ..This review describes the key roles of Ikaros proteins in development and disease, their mechanisms of action and gene targets, as well as explaining their evolutionary origins and role in the emergence of adaptive immunity. ..
  5. Perdomo J, Holmes M, Chong B, Crossley M. Eos and pegasus, two members of the Ikaros family of proteins with distinct DNA binding activities. J Biol Chem. 2000;275:38347-54 pubmed
    ..Our results suggest that these proteins may associate with previously described Ikaros family proteins in lymphoid cells and play additional roles in other tissues. ..
  6. Kurreeman F, Stahl E, Okada Y, Liao K, Diogo D, Raychaudhuri S, et al. Use of a multiethnic approach to identify rheumatoid- arthritis-susceptibility loci, 1p36 and 17q12. Am J Hum Genet. 2012;90:524-32 pubmed publisher
  7. Klug C, Morrison S, Masek M, Hahm K, Smale S, Weissman I. Hematopoietic stem cells and lymphoid progenitors express different Ikaros isoforms, and Ikaros is localized to heterochromatin in immature lymphocytes. Proc Natl Acad Sci U S A. 1998;95:657-62 pubmed
    ..Unexpectedly, we found Ikaros localized to heterochromatin in Abelson-transformed pre-B lymphocytes by using immunogold electron microscopy. These observations suggest a complex role for Ikaros in lymphoid development. ..
  8. Kaufmann C, Yoshida T, Perotti E, Landhuis E, Wu P, Georgopoulos K. A complex network of regulatory elements in Ikaros and their activity during hemo-lymphopoiesis. EMBO J. 2003;22:2211-23 pubmed
  9. Marçais A, Jeannet R, Hernandez L, Soulier J, Sigaux F, Chan S, et al. Genetic inactivation of Ikaros is a rare event in human T-ALL. Leuk Res. 2010;34:426-9 pubmed publisher
    ..Thus, inactivation of Ikaros by deletion or mutation is rare in human T-ALL. ..
  10. Koipally J, Georgopoulos K. A molecular dissection of the repression circuitry of Ikaros. J Biol Chem. 2002;277:27697-705 pubmed
    ..Finally, we show that, barring CtBP, the Ikaros family members Aiolos, Helios, and Eos can associate with all of the identified corepressors of Ikaros including its newly identified interactors, Class II HDACs. ..
  11. Trageser D, Iacobucci I, Nahar R, Duy C, von Levetzow G, Klemm L, et al. Pre-B cell receptor-mediated cell cycle arrest in Philadelphia chromosome-positive acute lymphoblastic leukemia requires IKAROS function. J Exp Med. 2009;206:1739-53 pubmed publisher
  12. Hahm K, Ernst P, Lo K, Kim G, Turck C, Smale S. The lymphoid transcription factor LyF-1 is encoded by specific, alternatively spliced mRNAs derived from the Ikaros gene. Mol Cell Biol. 1994;14:7111-23 pubmed
    ..These data reveal that the LyF-1 protein is encoded by specific mRNAs derived from the alternatively-spliced Ikaros gene, suggesting that this gene may be important for the early stages of both B- and T-lymphocyte development. ..
  13. Payne K, Dovat S. Ikaros and tumor suppression in acute lymphoblastic leukemia. Crit Rev Oncog. 2011;16:3-12 pubmed
    ..This review summarizes currently available data regarding the structure and function of Ikaros, the clinical relevance of genetic inactivation of Ikzf1, and signal transduction pathways that regulate Ikaros function. ..
  14. Antica M, Cicin Sain L, Sain L, Kapitanovic S, Matulic M, Dzebro S, et al. Aberrant Ikaros, Aiolos, and Helios expression in Hodgkin and non-Hodgkin lymphoma. Blood. 2008;111:3296-7 pubmed publisher
  15. Winandy S, Wu P, Georgopoulos K. A dominant mutation in the Ikaros gene leads to rapid development of leukemia and lymphoma. Cell. 1995;83:289-99 pubmed
    ..A decrease in Ikaros activity below the first threshold causes the rapid accumulation of T lymphoblasts, whereas a further decrease leads to neoplastic transformation. ..
  16. Kleinmann E, Geimer Le Lay A, Sellars M, Kastner P, Chan S. Ikaros represses the transcriptional response to Notch signaling in T-cell development. Mol Cell Biol. 2008;28:7465-75 pubmed publisher
    ..How these genes are repressed remains poorly understood. We report here that the Ikaros transcription factor plays a crucial role in repressing the transcriptional response to Notch signaling in T-cell ..
  17. Ma S, Pathak S, Mandal M, Trinh L, Clark M, Lu R. Ikaros and Aiolos inhibit pre-B-cell proliferation by directly suppressing c-Myc expression. Mol Cell Biol. 2010;30:4149-58 pubmed publisher
    ..Collectively, our studies identify a pre-B-cell receptor signaling induced inhibitory network, orchestrated by Ikaros and Aiolos, which functions to terminate pre-B-cell expansion. ..
  18. Merkenschlager M. Ikaros in immune receptor signaling, lymphocyte differentiation, and function. FEBS Lett. 2010;584:4910-4 pubmed publisher
  19. He L, Xu H, Gu Z, Liu C, Chen G, Wang Y, et al. Ikaros is degraded by proteasome-dependent mechanism in the early phase of apoptosis induction. Biochem Biophys Res Commun. 2011;406:430-4 pubmed publisher
    ..These data might shed new insight on the role of IK1 in apoptosis and the post-translational regulation of IK1. ..
  20. Molnar A, Georgopoulos K. The Ikaros gene encodes a family of functionally diverse zinc finger DNA-binding proteins. Mol Cell Biol. 1994;14:8292-303 pubmed
    ..The ability of the Ikaros gene to generate functionally diverse proteins that may participate in distinct regulatory pathways substantiates its role as a master regulator during lymphocyte development. ..
  21. McCarty A, Kleiger G, Eisenberg D, Smale S. Selective dimerization of a C2H2 zinc finger subfamily. Mol Cell. 2003;11:459-70 pubmed
    ..These results demonstrate that the C2H2 motif provides a versatile platform for both sequence-specific protein-nucleic acid interactions and highly specific dimerization. ..
  22. Dovat S, Ronni T, Russell D, Ferrini R, Cobb B, Smale S. A common mechanism for mitotic inactivation of C2H2 zinc finger DNA-binding domains. Genes Dev. 2002;16:2985-90 pubmed
    ..Phosphomimetic substitutions abolished DNA-binding and pericentromeric localization. A linker within Sp1 was also phosphorylated, suggesting that linker phosphorylation provides a global mechanism for inactivation of the C2H2 family. ..
  23. Tonnelle C, Bardin F, Maroc C, Imbert A, Campa F, Dalloul A, et al. Forced expression of the Ikaros 6 isoform in human placental blood CD34(+) cells impairs their ability to differentiate toward the B-lymphoid lineage. Blood. 2001;98:2673-80 pubmed
  24. Koipally J, Heller E, Seavitt J, Georgopoulos K. Unconventional potentiation of gene expression by Ikaros. J Biol Chem. 2002;277:13007-15 pubmed
    ..Thus, potentiation of gene expression by Ikaros correlates strongly with its ability to localize to PC-HC in combination with the chromatin remodeler Mi-2beta. ..
  25. Takanashi M, Yagi T, Imamura T, Tabata Y, Morimoto A, Hibi S, et al. Expression of the Ikaros gene family in childhood acute lymphoblastic leukaemia. Br J Haematol. 2002;117:525-30 pubmed
    ..Only one case of T lineage ALL expressed a small-sized isoform of Helios (designated as He6). It was also found that the expression of Ai1 and He1 was low in Ik6-positive patients (Fisher's exact test; Ai1 P = 0.005, Hel P = 0.035). ..
  26. Yoshida T, Ng S, Zuniga Pflucker J, Georgopoulos K. Early hematopoietic lineage restrictions directed by Ikaros. Nat Immunol. 2006;7:382-91 pubmed
    ..Using this approach, we identify previously unknown pivotal functions for Ikaros in distinct fate 'decisions' in the early hematopoietic hierarchy. ..
  27. Schjerven H, McLaughlin J, Arenzana T, Frietze S, Cheng D, Wadsworth S, et al. Selective regulation of lymphopoiesis and leukemogenesis by individual zinc fingers of Ikaros. Nat Immunol. 2013;14:1073-83 pubmed publisher
    ..The subcategorization of functions and target genes by mutagenesis of individual zinc fingers will facilitate efforts to understand how zinc-finger transcription factors regulate development, immunity and disease. ..
  28. Lessard C, Adrianto I, Ice J, Wiley G, Kelly J, Glenn S, et al. Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as susceptibility loci for systemic lupus erythematosus in a large-scale multiracial replication study. Am J Hum Genet. 2012;90:648-60 pubmed publisher
    ..The results of this study increase the number of confirmed SLE risk loci and identify others warranting further investigation. ..
  29. Liu P, Lin Z, Qian S, Qiao C, Qiu H, Wu Y, et al. Expression of dominant-negative Ikaros isoforms and associated genetic alterations in Chinese adult patients with leukemia. Ann Hematol. 2012;91:1039-49 pubmed publisher
    ..In conclusion, this study provides a rationale for the integration of aberrant Ikaros isoforms, notably Ik6 and Ik10, in the evaluation of adult ALL, particularly in Ph(+)ALL patients. ..
  30. Wang J, Avitahl N, Cariappa A, Friedrich C, Ikeda T, Renold A, et al. Aiolos regulates B cell activation and maturation to effector state. Immunity. 1998;9:543-53 pubmed
    ..In sharp contrast to conventional B cells, B cells of the peritoneum, of the marginal zone, and the recirculating bone marrow population are greatly reduced. ..
  31. Winandy S, Wu L, Wang J, Georgopoulos K. Pre-T cell receptor (TCR) and TCR-controlled checkpoints in T cell differentiation are set by Ikaros. J Exp Med. 1999;190:1039-48 pubmed
    ..We conclude that Ikaros regulates T cell differentiation, selection, and homeostasis by providing signaling thresholds for pre-TCR and TCR. ..
  32. Ashworth T, Pear W, Chiang M, Blacklow S, Mastio J, Xu L, et al. Deletion-based mechanisms of Notch1 activation in T-ALL: key roles for RAG recombinase and a conserved internal translational start site in Notch1. Blood. 2010;116:5455-64 pubmed publisher
    ..Thus, like human T-ALL, murine T-ALL is often associated with acquired mutations that cause ligand-independent Notch1 activation. ..
  33. Yoshida T, Ng S, Georgopoulos K. Awakening lineage potential by Ikaros-mediated transcriptional priming. Curr Opin Immunol. 2010;22:154-60 pubmed publisher
    ..Loss of Ikaros removes the lymphoid leg of the immune system and may confer aberrant self-renewing properties to myeloid progenitors. ..
  34. Umetsu S, Winandy S. Ikaros is a regulator of Il10 expression in CD4+ T cells. J Immunol. 2009;183:5518-25 pubmed publisher
    ..Thus, we provide evidence for Ikaros as a regulator of Il10 and Ifng gene expression and suggest a role for Ikaros in directing lineage-specific cytokine gene activation and repression. ..
  35. Koipally J, Georgopoulos K. Ikaros-CtIP interactions do not require C-terminal binding protein and participate in a deacetylase-independent mode of repression. J Biol Chem. 2002;277:23143-9 pubmed
    ..Finally, we show that CtIP and CtBP can interact with the general transcription factors, TATA binding protein and transcription factor IIB, which suggests a possible mechanism for their deacetylase-independent mode of repression. ..
  36. Mullighan C, Zhang J, Harvey R, Collins Underwood J, Schulman B, Phillips L, et al. JAK mutations in high-risk childhood acute lymphoblastic leukemia. Proc Natl Acad Sci U S A. 2009;106:9414-8 pubmed publisher
    ..These results suggest that inhibition of JAK signaling is a logical target for therapeutic intervention in JAK mutated ALL. ..
  37. Rebollo A, Schmitt C. Ikaros, Aiolos and Helios: transcription regulators and lymphoid malignancies. Immunol Cell Biol. 2003;81:171-5 pubmed
    ..The direct involvement of aberrant protein expression of Ikaros family members in human haematological malignancies is discussed. ..
  38. Thomas R, Chunder N, Chen C, Umetsu S, Winandy S, Wells A. Ikaros enforces the costimulatory requirement for IL2 gene expression and is required for anergy induction in CD4+ T lymphocytes. J Immunol. 2007;179:7305-15 pubmed
    ..These results establish Ikaros as a transcriptional repressor of the IL2 gene that functions through modulation of chromatin structure and has an obligate role in the induction of anergy. ..
  39. Nichogiannopoulou A, Trevisan M, Neben S, Friedrich C, Georgopoulos K. Defects in hemopoietic stem cell activity in Ikaros mutant mice. J Exp Med. 1999;190:1201-14 pubmed
  40. Georgopoulos K, Moore D, Derfler B. Ikaros, an early lymphoid-specific transcription factor and a putative mediator for T cell commitment. Science. 1992;258:808-12 pubmed
    ..The pattern of Ikaros gene expression and its ability to stimulate CD3 delta transcription support the model that Ikaros functions in the specification and maturation of the T lymphocyte. ..
  41. Georgopoulos K, Bigby M, Wang J, Molnar A, Wu P, Winandy S, et al. The Ikaros gene is required for the development of all lymphoid lineages. Cell. 1994;79:143-56 pubmed
    ..In the absence of a functional Ikaros gene, these stem cells are exclusively diverted into the erythroid and myeloid lineages. ..
  42. Wu L, Nichogiannopoulou A, Shortman K, Georgopoulos K. Cell-autonomous defects in dendritic cell populations of Ikaros mutant mice point to a developmental relationship with the lymphoid lineage. Immunity. 1997;7:483-92 pubmed
    ..The complete lack of DCs in the lymphoid organs of Ikaros DN-/- micke points to an essential role for the Ikaros gene family in the development of all DCs. ..
  43. Reynaud D, Demarco I, Reddy K, Schjerven H, Bertolino E, Chen Z, et al. Regulation of B cell fate commitment and immunoglobulin heavy-chain gene rearrangements by Ikaros. Nat Immunol. 2008;9:927-36 pubmed publisher
    ..Thus, Ikaros is an obligate component of a network that regulates B cell fate commitment and immunoglobulin heavy-chain gene recombination. ..
  44. Ruiz A, Williams O, Brady H. The Ikaros splice isoform, Ikaros 6, immortalizes murine haematopoietic progenitor cells. Int J Cancer. 2008;123:1240-5 pubmed publisher
    ..Using an in vivo transplantation assay, we found that Ik6 favours reconstitution by haematopoietic precursors. These findings suggest that Ik6 may play an important role in the generation of the leukaemic phenotype. ..
  45. Papathanasiou P, Attema J, Karsunky H, Hosen N, Sontani Y, Hoyne G, et al. Self-renewal of the long-term reconstituting subset of hematopoietic stem cells is regulated by Ikaros. Stem Cells. 2009;27:3082-92 pubmed publisher
  46. Westman B, Mackay J, Gell D. Ikaros: a key regulator of haematopoiesis. Int J Biochem Cell Biol. 2002;34:1304-7 pubmed
    ..In addition, nuclear localisation is important for Ikaros function--unlike most transcription factors, Ikaros is localised to discrete nuclear foci in lymphoid cells, suggesting it employs novel mechanisms to regulate transcription. ..
  47. Nishii K, Katayama N, Miwa H, Shikami M, Usui E, Masuya M, et al. Non-DNA-binding Ikaros isoform gene expressed in adult B-precursor acute lymphoblastic leukemia. Leukemia. 2002;16:1285-92 pubmed
    ..The predominant expression of Ik-6, which is the result of post-transcription dysregulation, is characteristic of adult pre-B ALL, especially CD10(+) pre-B ALL. ..
  48. Yagi T, Hibi S, Takanashi M, Kano G, Tabata Y, Imamura T, et al. High frequency of Ikaros isoform 6 expression in acute myelomonocytic and monocytic leukemias: implications for up-regulation of the antiapoptotic protein Bcl-XL in leukemogenesis. Blood. 2002;99:1350-5 pubmed
    ..Thus, the pathogenesis of myelomonocytic/monocytic AML may involve aberrant regulation of apoptosis due to unscheduled expression of the Ik6 isoform. ..
  49. Kirstetter P, Thomas M, Dierich A, Kastner P, Chan S. Ikaros is critical for B cell differentiation and function. Eur J Immunol. 2002;32:720-30 pubmed
    ..In the periphery, mature B cells exhibit a lower activation threshold but form fewer germinal centers in response to antigenic stimulation. Our results show that Ikaros controls multiple aspects of B cell differentiation and function. ..
  50. Getnet D, Grosso J, Goldberg M, Harris T, Yen H, Bruno T, et al. A role for the transcription factor Helios in human CD4(+)CD25(+) regulatory T cells. Mol Immunol. 2010;47:1595-600 pubmed publisher
    ..Taken together, these data suggest that Helios may play an important role in regulatory T cell function and support the concept that Helios may be a novel target to manipulate Treg activity in a clinical setting. ..
  51. Bottardi S, Ross J, Bourgoin V, Fotouhi Ardakani N, Affar E, Trudel M, et al. Ikaros and GATA-1 combinatorial effect is required for silencing of human gamma-globin genes. Mol Cell Biol. 2009;29:1526-37 pubmed publisher
    ..Since the absence of Ikaros also affects GATA-1 recruitment to GATA-2 promoter, we propose that the combinatorial effect of Ikaros and GATA-1 is not restricted to globin gene regulation. ..
  52. Wojcik H, Griffiths E, Staggs S, Hagman J, Winandy S. Expression of a non-DNA-binding Ikaros isoform exclusively in B cells leads to autoimmunity but not leukemogenesis. Eur J Immunol. 2007;37:1022-32 pubmed
    ..We also show that deregulation of Ikaros activity does not rapidly result in B cell leukemogenesis as it does with 100% penetrance within the T cell lineage. ..
  53. Dumortier A, Jeannet R, Kirstetter P, Kleinmann E, Sellars M, dos Santos N, et al. Notch activation is an early and critical event during T-Cell leukemogenesis in Ikaros-deficient mice. Mol Cell Biol. 2006;26:209-20 pubmed
    The Ikaros transcription factor is both a key regulator of lymphocyte differentiation and a tumor suppressor in T lymphocytes. Mice carrying a hypomorphic mutation (Ik(L/L)) in the Ikaros gene all develop thymic lymphomas...