Top

Published in:

01-01-2021 | Lymphoma | CME Review

IKAROS-Associated Diseases in 2020: Genotypes, Phenotypes, and Outcomes in Primary Immune Deficiency/Inborn Errors of Immunity

Authors: Hye Sun Kuehn, Cristiane J. Nunes-Santos, Sergio D. Rosenzweig

Published in: Journal of Clinical Immunology | Issue 1/2021

Abstract

IKAROS, encoded by IKZF1, is a zinc finger transcription factor and a critical regulator of hematopoiesis. Mutations in IKZF1 have been implicated in immune deficiency, autoimmunity, and malignancy in humans. Somatic IKZF1 loss-of-function mutations and deletions have been shown to increase predisposition to the development of B cell acute lymphoblastic leukemia (B-ALL) and associated with poor prognosis. In the last 4 years, germline heterozygous IKZF1 mutations have been reported in primary immune deficiency/inborn errors of immunity. These allelic variants, acting by either haploinsufficiency or dominant negative mechanisms affecting particular functions of IKAROS, are associated with common variable immunodeficiency, combined immunodeficiency, or primarily hematologic phenotypes in affected patients. In this review, we provide an overview of genetic, clinical, and immunological manifestations in patients with IKZF1 mutations, and the molecular and cellular mechanisms that contribute to their disease as a consequence of IKAROS dysfunction.

Lo K, Landau NR, Smale ST. LyF-1, a transcriptional regulator that interacts with a novel class of promoters for lymphocyte-specific genes. Mol Cell Biol. 1991;11(10):5229–43. https://doi.org/10.1128/mcb.11.10.5229.CrossRefPubMedPubMedCentral

Georgopoulos K, Moore DD, Derfler B. Ikaros, an early lymphoid-specific transcription factor and a putative mediator for T cell commitment. Science. 1992;258(5083):808–12. https://doi.org/10.1126/science.1439790.CrossRefPubMed

Georgopoulos K, Bigby M, Wang JH, Molnar A, Wu P, Winandy S, et al. The Ikaros gene is required for the development of all lymphoid lineages. Cell. 1994;79(1):143–56.CrossRef

Winandy S, Wu P, Georgopoulos K. A dominant mutation in the Ikaros gene leads to rapid development of leukemia and lymphoma. Cell. 1995;83(2):289–99.CrossRef

Wang JH, Nichogiannopoulou A, Wu L, Sun L, Sharpe AH, Bigby M, et al. Selective defects in the development of the fetal and adult lymphoid system in mice with an Ikaros null mutation. Immunity. 1996;5(6):537–49. https://doi.org/10.1016/s1074-7613(00)80269-1.CrossRefPubMed

Francis OL, Payne JL, Su RJ, Payne KJ. Regulator of myeloid differentiation and function: the secret life of Ikaros. World J Biol Chem. 2011;2(6):119–25. https://doi.org/10.4331/wjbc.v2.i6.119.CrossRefPubMedPubMedCentral

Allman D, Dalod M, Asselin-Paturel C, Delale T, Robbins SH, Trinchieri G, et al. Ikaros is required for plasmacytoid dendritic cell differentiation. Blood. 2006;108(13):4025–34. https://doi.org/10.1182/blood-2006-03-007757.CrossRefPubMedPubMedCentral

Dijon M, Bardin F, Murati A, Batoz M, Chabannon C, Tonnelle C. The role of Ikaros in human erythroid differentiation. Blood. 2008;111(3):1138–46. https://doi.org/10.1182/blood-2007-07-098202.CrossRefPubMed

Papathanasiou P, Perkins AC, Cobb BS, Ferrini R, Sridharan R, Hoyne GF, et al. Widespread failure of hematolymphoid differentiation caused by a recessive niche-filling allele of the Ikaros transcription factor. Immunity. 2003;19(1):131–44.CrossRef

10.

Malinge S, Thiollier C, Chlon TM, Dore LC, Diebold L, Bluteau O, et al. Ikaros inhibits megakaryopoiesis through functional interaction with GATA-1 and NOTCH signaling. Blood. 2013;121(13):2440–51. https://doi.org/10.1182/blood-2012-08-450627.CrossRefPubMedPubMedCentral

11.

Morgan B, Sun L, Avitahl N, Andrikopoulos K, Ikeda T, Gonzales E, et al. Aiolos, a lymphoid restricted transcription factor that interacts with Ikaros to regulate lymphocyte differentiation. EMBO J. 1997;16(8):2004–13. https://doi.org/10.1093/emboj/16.8.2004.CrossRefPubMedPubMedCentral

12.

Kelley CM, 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(9):508–15.CrossRef

13.

Honma Y, Kiyosawa H, Mori T, Oguri A, Nikaido T, Kanazawa K, et al. Eos: a novel member of the Ikaros gene family expressed predominantly in the developing nervous system. FEBS Lett. 1999;447(1):76–80. https://doi.org/10.1016/s0014-5793(99)00265-3.CrossRefPubMed

14.

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(49):38347–54. https://doi.org/10.1074/jbc.M005457200.CrossRefPubMed

15.

Hahm K, Cobb BS, McCarty AS, Brown KE, Klug CA, Lee R, et al. Helios, a T cell-restricted Ikaros family member that quantitatively associates with Ikaros at centromeric heterochromatin. Genes Dev. 1998;12(6):782–96. https://doi.org/10.1101/gad.12.6.782.CrossRefPubMedPubMedCentral

16.

Molnar A, Georgopoulos K. The Ikaros gene encodes a family of functionally diverse zinc finger DNA-binding proteins. Mol Cell Biol. 1994;14(12):8292–303. https://doi.org/10.1128/mcb.14.12.8292.CrossRefPubMedPubMedCentral

17.

Sun L, Liu A, Georgopoulos K. Zinc finger-mediated protein interactions modulate Ikaros activity, a molecular control of lymphocyte development. EMBO J. 1996;15(19):5358–69.CrossRef

18.

Georgopoulos K, Winandy S, Avitahl N. The role of the Ikaros gene in lymphocyte development and homeostasis. Annu Rev Immunol. 1997;15:155–76. https://doi.org/10.1146/annurev.immunol.15.1.155.CrossRefPubMed

19.

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(2):680–5. https://doi.org/10.1073/pnas.96.2.680.CrossRefPubMedPubMedCentral

20.

Mullighan CG, Miller CB, Radtke I, Phillips LA, Dalton J, Ma J, et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature. 2008;453(7191):110–4. https://doi.org/10.1038/nature06866.CrossRefPubMed

21.

Nakase K, Ishimaru F, Avitahl N, Dansako H, Matsuo K, Fujii K, et al. Dominant negative isoform of the Ikaros gene in patients with adult B-cell acute lymphoblastic leukemia. Cancer Res. 2000;60(15):4062–5.PubMed

22.

Meleshko AN, Movchan LV, Belevtsev MV, Savitskaja TV. Relative expression of different Ikaros isoforms in childhood acute leukemia. Blood Cells Mol Dis. 2008;41(3):278–83. https://doi.org/10.1016/j.bcmd.2008.06.006.CrossRefPubMed

23.

John LB, Ward AC. The Ikaros gene family: transcriptional regulators of hematopoiesis and immunity. Mol Immunol. 2011;48(9–10):1272–8. https://doi.org/10.1016/j.molimm.2011.03.006.CrossRefPubMed

24.

Thomas RM, Chen C, Chunder N, Ma L, Taylor J, Pearce EJ, et al. Ikaros silences T-bet expression and interferon-gamma production during T helper 2 differentiation. J Biol Chem. 2010;285(4):2545–53. https://doi.org/10.1074/jbc.M109.038794.CrossRefPubMed

25.

Heizmann B, Sellars M, Macias-Garcia A, Chan S, Kastner P. Ikaros limits follicular B cell activation by regulating B cell receptor signaling pathways. Biochem Biophys Res Commun. 2016;470(3):714–20. https://doi.org/10.1016/j.bbrc.2016.01.060.CrossRefPubMed

26.

Dumortier A, Kirstetter P, Kastner P, Chan S. Ikaros regulates neutrophil differentiation. Blood. 2003;101(6):2219–26. https://doi.org/10.1182/blood-2002-05-1336.CrossRefPubMed

27.

Rao KN, Smuda C, Gregory GD, Min B, Brown MA. Ikaros limits basophil development by suppressing C/EBP-alpha expression. Blood. 2013;122(15):2572–81. https://doi.org/10.1182/blood-2013-04-494625.CrossRefPubMedPubMedCentral

28.

Heizmann B, Kastner P, Chan S. The Ikaros family in lymphocyte development. Curr Opin Immunol. 2018;51:14–23. https://doi.org/10.1016/j.coi.2017.11.005.CrossRefPubMed

29.

Mullighan CG, Su X, Zhang J, Radtke I, Phillips LA, Miller CB, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009;360(5):470–80. https://doi.org/10.1056/NEJMoa0808253.CrossRefPubMedPubMedCentral

30.

Kastner P, Dupuis A, Gaub MP, Herbrecht R, Lutz P, Chan S. Function of Ikaros as a tumor suppressor in B cell acute lymphoblastic leukemia. Am J Blood Res. 2013;3(1):1–13.PubMedPubMedCentral

31.

Goldman FD, Gurel Z, Al-Zubeidi D, Fried AJ, Icardi M, Song C, et al. Congenital pancytopenia and absence of B lymphocytes in a neonate with a mutation in the Ikaros gene. Pediatr Blood Cancer. 2012;58(4):591–7. https://doi.org/10.1002/pbc.23160.CrossRefPubMed

32.

Kuehn HS, Boisson B, Cunningham-Rundles C, Reichenbach J, Stray-Pedersen A, Gelfand EW, et al. Loss of B cells in patients with heterozygous mutations in IKAROS. N Engl J Med. 2016;374(11):1032–43. https://doi.org/10.1056/NEJMoa1512234.CrossRefPubMedPubMedCentral

33.

Hoshino A, Okada S, Yoshida K, Nishida N, Okuno Y, Ueno H, et al. Abnormal hematopoiesis and autoimmunity in human subjects with germline IKZF1 mutations. J Allergy Clin Immunol. 2017;140(1):223–31. https://doi.org/10.1016/j.jaci.2016.09.029.CrossRefPubMed

34.

Bogaert DJ, Kuehn HS, Bonroy C, Calvo KR, Dehoorne J, Vanlander AV, et al. A novel IKAROS haploinsufficiency kindred with unexpectedly late and variable B-cell maturation defects. J Allergy Clin Immunol. 2018;141(1):432–5 e7. https://doi.org/10.1016/j.jaci.2017.08.019.CrossRefPubMed

35.

Dieudonne Y, Guffroy A, Vollmer O, Carapito R, Korganow AS. IKZF1 loss-of-function variant causes autoimmunity and severe familial antiphospholipid syndrome. J Clin Immunol. 2019;39(4):353–7. https://doi.org/10.1007/s10875-019-00643-2.CrossRefPubMed

36.

Van Nieuwenhove E, Garcia-Perez JE, Helsen C, Rodriguez PD, van Schouwenburg PA, Dooley J, et al. A kindred with mutant IKAROS and autoimmunity. J Allergy Clin Immunol. 2018;142(2):699–702 e12. https://doi.org/10.1016/j.jaci.2018.04.008.CrossRefPubMedPubMedCentral

37.

Sriaroon P, Chang Y, Ujhazi B, Csomos K, Joshi HR, Zhou Q, et al. Familial immune thrombocytopenia associated with a novel variant in IKZF1. Front Pediatr. 2019;7:139. https://doi.org/10.3389/fped.2019.00139.CrossRefPubMedPubMedCentral

38.

Groth DJ, Lakkaraja MM, Ferreira JO, Feuille EJ, Bassetti JA, Kaicker SM. Management of chronic immune thrombocytopenia and presumed autoimmune hepatitis in a child with IKAROS haploinsufficiency. J Clin Immunol. 2020;40(4):653–7. https://doi.org/10.1007/s10875-020-00781-y.CrossRefPubMed

39.

Eskandarian Z, Fliegauf M, Bulashevska A, Proietti M, Hague R, Smulski CR, et al. Assessing the functional relevance of variants in the IKAROS family zinc finger protein 1 (IKZF1) in a cohort of patients with primary immunodeficiency. Front Immunol. 2019;10:568. https://doi.org/10.3389/fimmu.2019.00568.CrossRefPubMedPubMedCentral

40.

Chen QY, Wang XC, Wang WJ, Zhou QH, Liu DR, Wang Y. B-cell deficiency: a de novo IKZF1 patient and review of the literature. J Investig Allergol Clin Immunol. 2018;28(1):53–6. https://doi.org/10.18176/jiaci.0207.CrossRefPubMed

41.

Kuehn HS, Niemela JE, Stoddard J, Ciullini Mannurita S, Shahin T, Goel S, et al. Germline IKAROS dimerization haploinsufficiency causes hematologic cytopenias and malignancies. Blood. 2020. https://doi.org/10.1182/blood.2020007292.

42.

Boutboul D, Kuehn HS, Van de Wyngaert Z, Niemela JE, Callebaut I, Stoddard J, et al. Dominant-negative IKZF1 mutations cause a T, B, and myeloid cell combined immunodeficiency. J Clin Invest. 2018;128(7):3071–87. https://doi.org/10.1172/JCI98164.CrossRefPubMedPubMedCentral

43.

Nunes-Santos CJ, Kuehn HS, Rosenzweig SD. IKAROS family zinc finger 1-associated diseases in primary immunodeficiency patients. Immunol Allergy Clin N Am. 2020;40(3):461–70. https://doi.org/10.1016/j.iac.2020.04.004.CrossRef

44.

Iacobucci I, Storlazzi CT, Cilloni D, Lonetti A, Ottaviani E, Soverini S, et al. Identification and molecular characterization of recurrent genomic deletions on 7p12 in the IKZF1 gene in a large cohort of BCR-ABL1-positive acute lymphoblastic leukemia patients: on behalf of Gruppo Italiano Malattie Ematologiche dell'Adulto Acute Leukemia Working Party (GIMEMA AL WP). Blood. 2009;114(10):2159–67. https://doi.org/10.1182/blood-2008-08-173963.CrossRefPubMed

45.

Vairy S, Tran TH. IKZF1 alterations in acute lymphoblastic leukemia: the good, the bad and the ugly. Blood Rev. 2020:100677. https://doi.org/10.1016/j.blre.2020.100677.

46.

Olsson L, Johansson B. Ikaros and leukaemia. Br J Haematol. 2015;169(4):479–91. https://doi.org/10.1111/bjh.13342.CrossRefPubMed

47.

Iacobucci I, Iraci N, Messina M, Lonetti A, Chiaretti S, Valli E, et al. IKAROS deletions dictate a unique gene expression signature in patients with adult B-cell acute lymphoblastic leukemia. PLoS One. 2012;7(7):e40934. https://doi.org/10.1371/journal.pone.0040934.CrossRefPubMedPubMedCentral

48.

Martinelli G, Iacobucci I, Storlazzi CT, Vignetti M, Paoloni F, Cilloni D, et al. IKZF1 (Ikaros) deletions in BCR-ABL1-positive acute lymphoblastic leukemia are associated with short disease-free survival and high rate of cumulative incidence of relapse: a GIMEMA AL WP report. J Clin Oncol. 2009;27(31):5202–7. https://doi.org/10.1200/JCO.2008.21.6408.CrossRefPubMed

49.

van der Veer A, Zaliova M, Mottadelli F, De Lorenzo P, Te Kronnie G, Harrison CJ, et al. IKZF1 status as a prognostic feature in BCR-ABL1-positive childhood ALL. Blood. 2014;123(11):1691–8. https://doi.org/10.1182/blood-2013-06-509794.CrossRefPubMed

50.

Churchman ML, Qian M, Te Kronnie G, Zhang R, Yang W, Zhang H, et al. Germline genetic IKZF1 variation and predisposition to childhood acute lymphoblastic leukemia. Cancer Cell. 2018;33(5):937–48 e8. https://doi.org/10.1016/j.ccell.2018.03.021.CrossRefPubMedPubMedCentral

51.

Cytlak U, Resteu A, Bogaert D, Kuehn HS, Altmann T, Gennery A, et al. Ikaros family zinc finger 1 regulates dendritic cell development and function in humans. Nat Commun. 2018;9(1):1239. https://doi.org/10.1038/s41467-018-02977-8.CrossRefPubMedPubMedCentral

52.

Kellner ES, Krupski C, Kuehn HS, Rosenzweig SD, Yoshida N, Kojima S, et al. Allogeneic hematopoietic stem cell transplant outcomes for patients with dominant-negative IKFZ1/IKAROS mutations. J Allergy Clin Immunol. 2019;144:339–42. https://doi.org/10.1016/j.jaci.2019.03.025.CrossRefPubMed

Title: IKAROS-Associated Diseases in 2020: Genotypes, Phenotypes, and Outcomes in Primary Immune Deficiency/Inborn Errors of Immunity
Authors: Hye Sun Kuehn
Cristiane J. Nunes-Santos
Sergio D. Rosenzweig
Publication date: 01-01-2021
Publisher: Springer US
Keywords: Lymphoma
Acute Lymphoblastic Leukemia
Immunodeficiency
Published in: Journal of Clinical Immunology / Issue 1/2021
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI: https://doi.org/10.1007/s10875-020-00936-x

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

IKAROS-Associated Diseases in 2020: Genotypes, Phenotypes, and Outcomes in Primary Immune Deficiency/Inborn Errors of Immunity

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2021

Infections in Infants with SCID: Isolation, Infection Screening, and Prophylaxis in PIDTC Centers

Expanding the Clinical Phenotype of Chronic Granulomatous Disease: a Female Patient with a De Novo Mutation in CYBB

Persistent Unexplained Transaminitis in COPA Syndrome

A Novel CYBB Variant Causing X-Linked Chronic Granulomatous Disease in a Patient with Empyema

Developmental Adaptive Immune Defects Associated with STAT5B Deficiency in Three Young Siblings

Pathogenic TLR3 Variant in a Patient with Recurrent Herpes Simplex Virus 1–Triggered Erythema Multiforme

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page