IKZF1 explained

DNA-binding protein Ikaros also known as Ikaros family zinc finger protein 1 is a protein that in humans is encoded by the IKZF1 gene.^{[1] [2] [3]}

Ikaros - transcription factor

Ikaros is a transcription factor that is encoded by the IKZF genes of the Ikaros family zinc finger group. Zinc finger is a small structural motif of protein that allows protein binding to DNA or RNA molecule that is characterized by the coordination of one or more zinc ions (Zn²⁺) in order to stabilize the fold.

Ikaros displays crucial functions in the hematopoietic system and is a known regulator of immune cells development, mainly in early B cells, CD4+ T cells. Its dysfunction has been linked to the development of chronic lymphocytic leukemia.^{[4] [5]} In particular, Ikaros has been found in recent years to be a major tumor suppressor involved in human B-cell acute lymphoblastic leukemia and that it also has a part in the differentiation and function of individual T helper cells.^[6]

Ikaros also has a role during the later stages of B cell development during VDJ recombination in switch class of the antibody isotypes and expression of the B cell receptor.^[7]

In Ikaros knockout mice, T cells but not B cells are generated late in mouse development due to late compensatory expression of the related gene Aiolos (IKZF3).^[8] Ikaros point mutant mice are embryonic lethal due to anemia; they have severe defects in terminal erythrocyte and granulocyte differentiation, and excessive macrophage formation.^[9] SNPs located near the 3' region of IKZF1 in humans have been linked to susceptibility to childhood acute lymphoblastic leukemia (ALL)^[10] as well as type 1 diabetes.^[11] The two effects appear to be in opposite directions, with the allele marking susceptibility to ALL protecting from T1D and vice versa.

Further evidence shows that Ikaros regulates the development of medullary thymic epithelial cells (mTECs). Conditional deletion of Ikzf1 in thymic epithelial cells by Foxn1-Cre in mice, results in the dysregulation of various mTEC subsets, including the loss of Aire+ mTECs. The loss of Aire (Autoimmune regulator) expressing mTECs also causes global loss of tissue restricted antigens (TRAs) and Aire-dependent mimetic cell populations, with the loss of TRAs eventually leading to breakdown of immune tolerance.^[12]

Genes of the Ikaros Zinc Finger Family group

The Ikaros Zinc Finger (IkZF) family of transcription factors are known regulators of hematopoietic cell development and many immune cells including that of CD4⁺ T cells.

The IkZF family consists of five members: Ikaros (encoded by the gene Ikzf1), Helios (Ikzf2), Aiolos (Ikzf3), Eos (Ikzf4), and Pegasus (Ikzf5). These factors contain N-terminal zinc finger (ZF) domains, which are responsible for mediating direct interactions with DNA, and C-terminal ZFs, which facilitate homo- and heterodimerization between IkZF family members. ^[13]

IKZF1 is upregulated in granulocytes, B cells, CD4 and CD8 T cells, and NK cells, and downregulated in erythroblasts, megakaryocytes and monocytes.^[14]

Ikaros deficiency

The mutation in the IKZF1 gene can cause dysfunction of the Ikaros transcription factor. The dysfunction affects expression in B cells that can lead to deregulation of the BCR signaling during B cell development and is associated with B cell transformation. The deregulation then can result in low proliferation rate and increased apoptosis of the B cells. The deregulation may be related with lymphoproliferative disorders and different forms of leukemia. ^[15]

Interactions

IKZF1 has been shown to interact with:

• CTBP1,^[16]
• HDAC1,
• HDAC7A,
• Histone deacetylase 5,^[17]
• IKZF2,^[18]
• IKZF3,^{[19] [20] [21]}
• IKZF4,^{[22] [23]}
• SIN3A,^{[20] [17] [24]}
• Cereblon
• SIN3B.^{[20] [17]}
• GATA2^[25]

References

Further reading

• Tonnelle C, Calmels B, Maroc C, Gabert J, Chabannon C . Ikaros gene expression and leukemia . Leukemia & Lymphoma . 43 . 1 . 29–35 . January 2002 . 11908734 . 10.1080/10428190210186 . 23932398 .
• Westman BJ, Mackay JP, Gell D . Ikaros: a key regulator of haematopoiesis . The International Journal of Biochemistry & Cell Biology . 34 . 10 . 1304–7 . October 2002 . 12127581 . 10.1016/S1357-2725(02)00070-5 .
• Molnár A, Wu P, Largespada DA, Vortkamp A, Scherer S, Copeland NG, Jenkins NA, Bruns G, Georgopoulos K . The Ikaros gene encodes a family of lymphocyte-restricted zinc finger DNA binding proteins, highly conserved in human and mouse . Journal of Immunology . 156 . 2 . 585–92 . January 1996 . 10.4049/jimmunol.156.2.585 . 8543809 . 24893140 . free .
• Nietfeld W, Meyerhans A . Cloning and sequencing of hIk-1, a cDNA encoding a human homologue of mouse Ikaros/LyF-1 . Immunology Letters . 49 . 1–2 . 139–41 . January 1996 . 8964602 . 10.1016/0165-2478(95)02479-4 .
• Morgan B, Sun L, Avitahl N, Andrikopoulos K, Ikeda T, Gonzales E, Wu P, Neben S, Georgopoulos K . Aiolos, a lymphoid restricted transcription factor that interacts with Ikaros to regulate lymphocyte differentiation . The EMBO Journal . 16 . 8 . 2004–13 . April 1997 . 9155026 . 1169803 . 10.1093/emboj/16.8.2004 .
• Kelley CM, Ikeda T, Koipally J, Avitahl N, Wu L, Georgopoulos K, Morgan BA . Helios, a novel dimerization partner of Ikaros expressed in the earliest hematopoietic progenitors . Current Biology . 8 . 9 . 508–15 . April 1998 . 9560339 . 10.1016/S0960-9822(98)70202-7 . 17835058 . free . 1998CBio....8..508K .
• Sun L, Heerema N, Crotty L, Wu X, Navara C, Vassilev A, Sensel M, Reaman GH, Uckun FM . Expression of dominant-negative and mutant isoforms of the antileukemic transcription factor Ikaros in infant acute lymphoblastic leukemia . Proceedings of the National Academy of Sciences of the United States of America . 96 . 2 . 680–5 . January 1999 . 9892693 . 15196 . 10.1073/pnas.96.2.680 . 1999PNAS...96..680S . free .
• Kim J, Sif S, Jones B, Jackson A, Koipally J, Heller E, Winandy S, Viel A, Sawyer A, Ikeda T, Kingston R, Georgopoulos K . Ikaros DNA-binding proteins direct formation of chromatin remodeling complexes in lymphocytes . Immunity . 10 . 3 . 345–55 . March 1999 . 10204490 . 10.1016/S1074-7613(00)80034-5 . free .
• Honma Y, Kiyosawa H, Mori T, Oguri A, Nikaido T, Kanazawa K, Tojo M, Takeda J, Tanno Y, Yokoya S, Kawabata I, Ikeda H, Wanaka A . Eos: a novel member of the Ikaros gene family expressed predominantly in the developing nervous system . FEBS Letters . 447 . 1 . 76–80 . March 1999 . 10218586 . 10.1016/S0014-5793(99)00265-3 . 28898354 . free .
• Koipally J, Renold A, Kim J, Georgopoulos K . Repression by Ikaros and Aiolos is mediated through histone deacetylase complexes . The EMBO Journal . 18 . 11 . 3090–100 . June 1999 . 10357820 . 1171390 . 10.1093/emboj/18.11.3090 .
• Sun L, Goodman PA, Wood CM, Crotty ML, Sensel M, Sather H, Navara C, Nachman J, Steinherz PG, Gaynon PS, Seibel N, Vassilev A, Juran BD, Reaman GH, Uckun FM . Expression of aberrantly spliced oncogenic ikaros isoforms in childhood acute lymphoblastic leukemia . Journal of Clinical Oncology . 17 . 12 . 3753–66 . December 1999 . 10577847 . 10.1200/JCO.1999.17.12.3753 .
• Hosokawa Y, Maeda Y, Ichinohasama R, Miura I, Taniwaki M, Seto M . The Ikaros gene, a central regulator of lymphoid differentiation, fuses to the BCL6 gene as a result of t(3;7)(q27;p12) translocation in a patient with diffuse large B-cell lymphoma . Blood . 95 . 8 . 2719–21 . April 2000 . 10753856 . 10.1182/blood.V95.8.2719.
• Koipally J, Georgopoulos K . Ikaros interactions with CtBP reveal a repression mechanism that is independent of histone deacetylase activity . The Journal of Biological Chemistry . 275 . 26 . 19594–602 . June 2000 . 10766745 . 10.1074/jbc.M000254200 . free .
• Perdomo J, Holmes M, Chong B, Crossley M . Eos and pegasus, two members of the Ikaros family of proteins with distinct DNA binding activities . The Journal of Biological Chemistry . 275 . 49 . 38347–54 . December 2000 . 10978333 . 10.1074/jbc.M005457200 . free .
• Payne KJ, Nicolas JH, Zhu JY, Barsky LW, Crooks GM . Cutting edge: predominant expression of a novel Ikaros isoform in normal human hemopoiesis . Journal of Immunology . 167 . 4 . 1867–70 . August 2001 . 11489963 . 10.4049/jimmunol.167.4.1867 . free .
• Koipally J, Heller EJ, Seavitt JR, Georgopoulos K . Unconventional potentiation of gene expression by Ikaros . The Journal of Biological Chemistry . 277 . 15 . 13007–15 . April 2002 . 11799125 . 10.1074/jbc.M111371200 . free .
• Dorsam G, Goetzl EJ . Vasoactive intestinal peptide receptor-1 (VPAC-1) is a novel gene target of the hemolymphopoietic transcription factor Ikaros . The Journal of Biological Chemistry . 277 . 16 . 13488–93 . April 2002 . 11812772 . 10.1074/jbc.M107922200 . free .

Notes and References

1. Georgopoulos K, Moore DD, Derfler B . Ikaros, an early lymphoid-specific transcription factor and a putative mediator for T cell commitment . Science . 258 . 5083 . 808–12 . October 1992 . 1439790 . 10.1126/science.1439790 . 1992Sci...258..808G .
2. Hahm K, Ernst P, Lo K, Kim GS, Turck C, Smale ST . The lymphoid transcription factor LyF-1 is encoded by specific, alternatively spliced mRNAs derived from the Ikaros gene . Molecular and Cellular Biology . 14 . 11 . 7111–23 . November 1994 . 7935426 . 359245 . 10.1128/mcb.14.11.7111 .
3. Web site: Entrez Gene: IKZF1 IKAROS family zinc finger 1 (Ikaros).
4. Kastner P, Chan S . Role of Ikaros in T-cell acute lymphoblastic leukemia . World Journal of Biological Chemistry . 2 . 6 . 108–114 . June 2011 . 21765975 . 3135856 . 10.4331/wjbc.v2.i6.108 . free .
5. Oliveira VC, Lacerda MP, Moraes BB, Gomes CP, Maricato JT, Souza OF, Schenkman S, Pesquero JB, Moretti NS, Rodrigues CA, Popi AF . Deregulation of Ikaros expression in B-1 cells: New insights in the malignant transformation to chronic lymphocytic leukemia . Journal of Leukocyte Biology . 106 . 3 . 581–594 . September 2019 . 31299112 . 10.1002/JLB.MA1118-454R . 196350761 .
6. Powell MD, Read KA, Sreekumar BK, Oestreich KJ . Ikaros Zinc Finger Transcription Factors: Regulators of Cytokine Signaling Pathways and CD4⁺ T Helper Cell Differentiation . Frontiers in Immunology . 10 . 1299 . 2019 . 31244845 . 6563078 . 10.3389/fimmu.2019.01299 . free .
7. Sellars M, Kastner P, Chan S. June 2011. Ikaros in B cell development and function. World Journal of Biological Chemistry. 2. 6. 132–9. 10.4331/wjbc.v2.i6.132. 3135860. 21765979 . free .
8. Georgopoulos K, Winandy S, Avitahl N . The role of the Ikaros gene in lymphocyte development and homeostasis . Annual Review of Immunology . 15 . 155–76 . 1997 . 9143685 . 10.1146/annurev.immunol.15.1.155 .
9. Papathanasiou P, Perkins AC, Cobb BS, Ferrini R, Sridharan R, Hoyne GF, Nelms KA, Smale ST, Goodnow CC . Widespread failure of hematolymphoid differentiation caused by a recessive niche-filling allele of the Ikaros transcription factor . Immunity . 19 . 1 . 131–44 . July 2003 . 12871645 . 10.1016/s1074-7613(03)00168-7 . free .
10. Papaemmanuil E, Hosking FJ, Vijayakrishnan J, Price A, Olver B, Sheridan E, Kinsey SE, Lightfoot T, Roman E, Irving JA, Allan JM, Tomlinson IP, Taylor M, Greaves M, Houlston RS . Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia . Nature Genetics . 41 . 9 . 1006–10 . September 2009 . 19684604 . 4915548 . 10.1038/ng.430 .
11. Swafford AD, Howson JM, Davison LJ, Wallace C, Smyth DJ, Schuilenburg H, Maisuria-Armer M, Mistry T, Lenardo MJ, Todd JA . An allele of IKZF1 (Ikaros) conferring susceptibility to childhood acute lymphoblastic leukemia protects against type 1 diabetes . Diabetes . 60 . 3 . 1041–4 . March 2011 . 21270240 . 3046822 . 10.2337/db10-0446 .
12. Sin JH, Sucharov J, Kashyap S, Wang Y, Proekt I, Liu X, Parent AV, Gupta A, Kastner P, Chan S, Gardner JM, Ntranos V, Miller CN, Anderson MS, Schjerven H, Waterfield MR . Ikaros is a principal regulator of Aire⁺ mTEC homeostasis, thymic mimetic cell diversity, and central tolerance . Science Immunology . 8 . 88 . eabq3109 . October 2023 . 37889983 . 10.1126/sciimmunol.abq3109 . 264518068 .
13. Powell MD, Read KA, Sreekumar BK, Oestreich KJ . + T Helper Cell Differentiation . Frontiers in Immunology . 10 . 1299 . 2019-06-06 . 31244845 . 6563078 . 10.3389/fimmu.2019.01299 . free .
14. Watkins NA, Gusnanto A, de Bono B, De S, Miranda-Saavedra D, Hardie DL, Angenent WG, Attwood AP, Ellis PD, Erber W, Foad NS, Garner SF, Isacke CM, Jolley J, Koch K, Macaulay IC, Morley SL, Rendon A, Rice KM, Taylor N, Thijssen-Timmer DC, Tijssen MR, van der Schoot CE, Wernisch L, Winzer T, Dudbridge F, Buckley CD, Langford CF, Teichmann S, Göttgens B, Ouwehand WH . A HaemAtlas: characterizing gene expression in differentiated human blood cells . Blood . 113 . 19 . e1–e9 . May 2009 . 19228925 . 2680378 . 10.1182/blood-2008-06-162958 .
15. Oliveira VC, Lacerda MP, Moraes BB, Gomes CP, Maricato JT, Souza OF, Schenkman S, Pesquero JB, Moretti NS, Rodrigues CA, Popi AF . Deregulation of Ikaros expression in B-1 cells: New insights in the malignant transformation to chronic lymphocytic leukemia . Journal of Leukocyte Biology . July 2019 . 106 . 3 . 581–594 . 31299112 . 10.1002/JLB.MA1118-454R . 196350761 .
16. Koipally J, Georgopoulos K . Ikaros interactions with CtBP reveal a repression mechanism that is independent of histone deacetylase activity . The Journal of Biological Chemistry . 275 . 26 . 19594–602 . June 2000 . 10766745 . 10.1074/jbc.M000254200 . free .
17. Koipally J, Georgopoulos K . A molecular dissection of the repression circuitry of Ikaros . The Journal of Biological Chemistry . 277 . 31 . 27697–705 . August 2002 . 12015313 . 10.1074/jbc.M201694200 . free .
18. Kelley CM, Ikeda T, Koipally J, Avitahl N, Wu L, Georgopoulos K, Morgan BA . Helios, a novel dimerization partner of Ikaros expressed in the earliest hematopoietic progenitors . Current Biology . 8 . 9 . 508–15 . April 1998 . 9560339 . 10.1016/s0960-9822(98)70202-7 . 17835058 . free . 1998CBio....8..508K .
19. Morgan B, Sun L, Avitahl N, Andrikopoulos K, Ikeda T, Gonzales E, Wu P, Neben S, Georgopoulos K . Aiolos, a lymphoid restricted transcription factor that interacts with Ikaros to regulate lymphocyte differentiation . The EMBO Journal . 16 . 8 . 2004–13 . April 1997 . 9155026 . 1169803 . 10.1093/emboj/16.8.2004 .
20. Koipally J, Renold A, Kim J, Georgopoulos K . Repression by Ikaros and Aiolos is mediated through histone deacetylase complexes . The EMBO Journal . 18 . 11 . 3090–100 . June 1999 . 10357820 . 1171390 . 10.1093/emboj/18.11.3090 .
21. Kim J, Sif S, Jones B, Jackson A, Koipally J, Heller E, Winandy S, Viel A, Sawyer A, Ikeda T, Kingston R, Georgopoulos K . Ikaros DNA-binding proteins direct formation of chromatin remodeling complexes in lymphocytes . Immunity . 10 . 3 . 345–55 . March 1999 . 10204490 . 10.1016/s1074-7613(00)80034-5 . free .
22. Honma Y, Kiyosawa H, Mori T, Oguri A, Nikaido T, Kanazawa K, Tojo M, Takeda J, Tanno Y, Yokoya S, Kawabata I, Ikeda H, Wanaka A . Eos: a novel member of the Ikaros gene family expressed predominantly in the developing nervous system . FEBS Letters . 447 . 1 . 76–80 . March 1999 . 10218586 . 10.1016/s0014-5793(99)00265-3 . Wanaka A . 28898354 . free .
23. Perdomo J, Holmes M, Chong B, Crossley M . Eos and pegasus, two members of the Ikaros family of proteins with distinct DNA binding activities . The Journal of Biological Chemistry . 275 . 49 . 38347–54 . December 2000 . 10978333 . 10.1074/jbc.M005457200 . free .
24. Koipally J, Georgopoulos K . Ikaros-CtIP interactions do not require C-terminal binding protein and participate in a deacetylase-independent mode of repression . The Journal of Biological Chemistry . 277 . 26 . 23143–9 . June 2002 . 11959865 . 10.1074/jbc.M202079200 . free .
25. Katsumura KR, Bresnick EH . The GATA factor revolution in hematology . Blood . 129 . 15 . 2092–2102 . April 2017 . 28179282 . 5391619 . 10.1182/blood-2016-09-687871 .