Germline IKZF1 mutations and their impact on immunity: IKAROS-associated diseases and pathophysiology

References

• 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):5229–5243.
   PubMed Web of Science ®Google Scholar
• 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):808–812.
   PubMed Web of Science ®Google Scholar
• Morgan B, Sun L, Avitahl N, et al. Aiolos, a lymphoid restricted transcription factor that interacts with Ikaros to regulate lymphocyte differentiation. Embo J. 1997;16(8):2004–2013. .
   PubMed Web of Science ®Google Scholar
• Kelley CM, Ikeda T, Koipally J, et al. Helios, a novel dimerization partner of Ikaros expressed in the earliest hematopoietic progenitors. Curr Biol. 1998;8(9):508–515. .
   PubMed Web of Science ®Google Scholar
• Honma Y, Kiyosawa H, Mori T, 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. .
   PubMed Web of Science ®Google Scholar
• Perdomo J, Holmes M, Chong B, et al. Eos and pegasus, two members of the Ikaros family of proteins with distinct DNA binding activities. J Biol Chem. 2000;275(49):38347–38354.
   PubMed Web of Science ®Google Scholar
• Hahm K, Cobb BS, McCarty AS, et al. Helios, a T cell-restricted Ikaros family member that quantitatively associates with Ikaros at centromeric heterochromatin. Genes Dev. 1998;12(6):782–796. .
   PubMed Web of Science ®Google Scholar
• Wang JH, Nichogiannopoulou A, Wu L, 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):537–549. .
   PubMed Web of Science ®Google Scholar
• Wu L, Nichogiannopoulou A, Shortman K, et al. Cell-autonomous defects in dendritic cell populations of Ikaros mutant mice point to a developmental relationship with the lymphoid lineage. Immunity. 1997;7(4):483–492.
   PubMed Web of Science ®Google Scholar
• 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):289–299.
   PubMed Web of Science ®Google Scholar
• Malinge S, Thiollier C, Chlon TM, et al. Ikaros inhibits megakaryopoiesis through functional interaction with GATA-1 and NOTCH signaling. Blood. 2013;121(13):2440–2451. .
   PubMed Web of Science ®Google Scholar
• Francis OL, Payne JL, Su RJ, et al. Regulator of myeloid differentiation and function: the secret life of Ikaros. World J Biol Chem. 2011;2(6):119–125.
   PubMedGoogle Scholar
• Dijon M, Bardin F, Murati A, et al. The role of Ikaros in human erythroid differentiation. Blood. 2008;111(3):1138–1146.
   PubMed Web of Science ®Google Scholar
• Molnar A, Georgopoulos K. The Ikaros gene encodes a family of functionally diverse zinc finger DNA-binding proteins. Mol Cell Biol. 1994;14(12):8292–8303.
   PubMed Web of Science ®Google Scholar
• Powell MD, Read KA, Sreekumar BK, et al. Ikaros zinc finger transcription factors: regulators of cytokine signaling pathways and CD4(+) T helper cell differentiation. Front Immunol. 2019;10:1299.
   PubMed Web of Science ®Google Scholar
• Ochiai K, Kondo H, Okamura Y, et al. Zinc finger-IRF composite elements bound by Ikaros/IRF4 complexes function as gene repression in plasma cell. Blood Adv. 2018;2(8):883–894. .
   PubMed Web of Science ®Google Scholar
• Kim J, Sif S, Jones B, et al. Ikaros DNA-binding proteins direct formation of chromatin remodeling complexes in lymphocytes. Immunity. 1999;10(3):345–355. .
   PubMed Web of Science ®Google Scholar
• Heizmann B, Kastner P, Chan S. The Ikaros family in lymphocyte development. Curr Opin Immunol. 2018;51(14–23):14–23.
   PubMedGoogle Scholar
• Mullighan CG, Miller CB, Radtke I, et al., BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature. 2008;453(7191):110–114. .
   PubMed Web of Science ®Google Scholar
• Churchman ML, Qian M, Te Kronnie G, et al., Germline genetic IKZF1 variation and predisposition to childhood acute lymphoblastic leukemia. Cancer Cell. 2018;33(5):937–948 e938. .
   PubMed Web of Science ®Google Scholar
• Kastner P, Dupuis A, Gaub MP, et al. Function of Ikaros as a tumor suppressor in B cell acute lymphoblastic leukemia. Am J Blood Res. 2013;3(1):1–13.
   PubMedGoogle Scholar
• Kuehn HS, Niemela JE, Stoddard J, et al. Germline IKAROS dimerization haploinsufficiency causes hematologic cytopenias and malignancies. Blood. 2020;137(3):349-363.
   Google Scholar
• Boutboul D, Kuehn HS, Van De Wyngaert Z, et al., Dominant-negative IKZF1 mutations cause a T, B, and myeloid cell combined immunodeficiency. J Clin Invest. 2018;128(7):3071–3087. .
   PubMed Web of Science ®Google Scholar
• Kuehn HS, Boisson B, Cunningham-Rundles C, et al., Loss of B cells in patients with heterozygous mutations in IKAROS. N Engl J Med. 2016;374(11):1032–1043. .
   PubMed Web of Science ®Google Scholar
• Hoshino A, Okada S, Yoshida K, et al. Abnormal hematopoiesis and autoimmunity in human subjects with germline IKZF1 mutations. J Allergy Clin Immunol. 2017;140(1):223–231. .
   PubMed Web of Science ®Google Scholar
• Groth DJ, Lakkaraja MM, Ferreira JO, et al. Management of chronic immune thrombocytopenia and presumed autoimmune hepatitis in a child with IKAROS haploinsufficiency. J Clin Immunol. 2020;40(4):653–657.
   PubMed Web of Science ®Google Scholar
• Dieudonne Y, Guffroy A, Vollmer O, et al. IKZF1 loss-of-function variant causes autoimmunity and severe familial antiphospholipid syndrome. J Clin Immunol. 2019;39(4):353–357.
   PubMed Web of Science ®Google Scholar
• Goldman FD, Gurel Z, Al-Zubeidi D, 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):591–597. .
   PubMed Web of Science ®Google Scholar
• Chen QY, Wang XC, Wang WJ, et al. B-cell deficiency: a De Novo IKZF1 patient and review of the literature. J Investig Allergol Clin Immunol. 2018;28(1):53–56.
   PubMed Web of Science ®Google Scholar
• Van Nieuwenhove E, Garcia-Perez JE, Helsen C, et al. A kindred with mutant IKAROS and autoimmunity. J Allergy Clin Immunol. 2018;142(2):699–702 e612. .
   PubMed Web of Science ®Google Scholar
• Bogaert DJ, Kuehn HS, Bonroy C, et al. A novel IKAROS haploinsufficiency kindred with unexpectedly late and variable B-cell maturation defects. J Allergy Clin Immunol. 2018;141(1):432–435 e437. .
   PubMed Web of Science ®Google Scholar
• Eskandarian Z, Fliegauf M, Bulashevska A, 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.
   PubMed Web of Science ®Google Scholar
• Banday AZ, Jindal AK, Kaur A, et al. Cutaneous IgA vasculitis-presenting manifestation of a novel mutation in the IKZF1 gene. Rheumatology (Oxford). 2020. DOI:10.1093/rheumatology/keaa081.
   PubMedGoogle Scholar
• Sriaroon P, Chang Y, Ujhazi B, et al. Familial immune thrombocytopenia associated with a novel variant in IKZF1. Front Pediatr. 2019;7:139.
   PubMed Web of Science ®Google Scholar
• Yilmaz E, Kuehn HS, Odakir E, et al. Common variable immunodeficiency, autoimmune hemolytic anemia, and pancytopenia associated with a defect in IKAROS. J Pediatr Hematol Oncol. 2020;Publish Ahead of Print. DOI:10.1097/MPH.0000000000001976.
   Google Scholar
• Okano T, Imai K, Naruto T, et al. Whole-exome sequencing-based approach for germline mutations in patients with inborn errors of immunity. J Clin Immunol. 2020;40(5):729–740. .
   PubMed Web of Science ®Google Scholar
• Belot A, Rice GI, Omarjee SO. Contribution of rare and predicted pathogenic gene variants to childhood-onset lupus: a large, genetic panel analysis of British and French cohorts (vol 2, pg e99, 2020). Lancet Rheumatol. 2020;2(11):E664–E664.
   Google Scholar
• Thaventhiran JED, Lango Allen H, Burren OS, et al. Publisher correction: whole-genome sequencing of a sporadic primary immunodeficiency cohort. Nature. 2020;584(7819):E2. .
   PubMedGoogle Scholar
• Brown KE, Guest SS, Smale ST, et al. Association of transcriptionally silent genes with Ikaros complexes at centromeric heterochromatin. Cell. 1997;91(6):845–854.
   PubMed Web of Science ®Google Scholar
• Koipally J, Heller EJ, Seavitt JR, et al. Unconventional potentiation of gene expression by Ikaros. J Biol Chem. 2002;277(15):13007–13015.
   PubMed Web of Science ®Google Scholar
• Cobb BS, Morales-Alcelay S, Kleiger G, et al. Targeting of Ikaros to pericentromeric heterochromatin by direct DNA binding. Genes Dev. 2000;14(17):2146–2160.
   PubMed Web of Science ®Google Scholar
• Georgopoulos K, Bigby M, Wang JH, et al. The Ikaros gene is required for the development of all lymphoid lineages. Cell. 1994;79(1):143–156. .
   PubMed Web of Science ®Google Scholar
• Allman D, Dalod M, Asselin-Paturel C, et al. Ikaros is required for plasmacytoid dendritic cell differentiation. Blood. 2006;108(13):4025–4034. .
   PubMed Web of Science ®Google Scholar
• Cytlak U, Resteu A, Bogaert D, et al. Ikaros family zinc finger 1 regulates dendritic cell development and function in humans. Nat Commun. 2018;9(1):1239. .
   PubMedGoogle Scholar
• Kellner ES, Krupski C, Kuehn HS, et al. Allogeneic hematopoietic stem cell transplant outcomes for patients with dominant-negative IKFZ1/IKAROS mutations. J Allergy Clin Immunol. 2019;144(1):339–342. .
   PubMed Web of Science ®Google Scholar
• Han JW, Zheng HF, Cui Y, et al. Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat Genet. 2009;41(11):1234–1237. .
   PubMed Web of Science ®Google Scholar
• Cunninghame Graham DS, Morris DL, Bhangale TR, et al. Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with systemic lupus erythematosus. PLoS Genet. 2011;7(10):e1002341. .
   PubMed Web of Science ®Google Scholar
• Nunes-Santos CJ, Kuehn HS, Rosenzweig SD, et al. Finger 1-associated diseases in primary immunodeficiency patients. Immunol Allergy Clin North Am. 2020;40(3):461–470.
   PubMed Web of Science ®Google Scholar
• Schwickert TA, Tagoh H, Schindler K, et al. Ikaros prevents autoimmunity by controlling anergy and Toll-like receptor signaling in B cells. Nat Immunol. 2019;20(11):1517–1529.
   PubMed Web of Science ®Google Scholar
• Macias-Garcia A, Heizmann B, Sellars M, et al. Ikaros is a negative regulator of B1 cell development and function. J Biol Chem. 2016;291(17):9073–9086. .
   PubMed Web of Science ®Google Scholar
• Marke R, Van Leeuwen FN, Scheijen B. The many faces of IKZF1 in B-cell precursor acute lymphoblastic leukemia. Haematologica. 2018;103(4):565–574.
   PubMed Web of Science ®Google Scholar
• Marcais A, Jeannet R, Hernandez L, et al. Genetic inactivation of Ikaros is a rare event in human T-ALL. Leuk Res. 2010;34(4):426–429. .
   PubMed Web of Science ®Google Scholar
• Payne KJ, Dovat S. Ikaros and tumor suppression in acute lymphoblastic leukemia. Crit Rev Oncog. 2011;16(1–2):3–12.
   PubMedGoogle Scholar
• Mullighan CG, Su X, Zhang J, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009;360(5):470–480. .
   PubMed Web of Science ®Google Scholar
• Yoshida N, Sakaguchi H, Muramatsu H, et al. Germline IKAROS mutation associated with primary immunodeficiency that progressed to T-cell acute lymphoblastic leukemia. Leukemia. 2017;31(5):1221–1223. .
   PubMed Web of Science ®Google Scholar
• Ng S, Fanta C, Okam M, et al. NK-cell and B-cell deficiency with a thymic mass. N Engl J Med. 2011;364(6):586–588.
   PubMed Web of Science ®Google Scholar
• Higgins E, Al Shehri T, McAleer MA, et al. Use of ruxolitinib to successfully treat chronic mucocutaneous candidiasis caused by gain-of-function signal transducer and activator of transcription 1 (STAT1) mutation. J Allergy Clin Immunol. 2015;135(2):551–553. .
   PubMed Web of Science ®Google Scholar
• Fink EC, Ebert BL. The novel mechanism of lenalidomide activity. Blood. 2015;126(21):2366–2369.
   PubMed Web of Science ®Google Scholar