Ikaros is a transcription factor that is encoded by theIKZF genes of the Ikaros familyzinc 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 thehematopoietic system and is a known regulator ofimmune cells development, mainly in earlyB cells,CD4+ T cells. Its dysfunction has been linked to the development of chronic lymphocytic leukemia.[8][9] In particular, Ikaros has been found in recent years to be a major tumor suppressor involved in human B-cell acute lymphoblastic leukemia[8] and that it also has a part in the differentiation and function of individualT helper cells.[10]
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).[12] Ikaros point mutant mice are embryonic lethal due to anemia; they have severe defects in terminalerythrocyte andgranulocyte differentiation, and excessivemacrophage formation.[13] SNPs located near the3' region of IKZF1 in humans have been linked to susceptibility to childhoodacute lymphoblastic leukemia (ALL)[14] as well astype 1 diabetes.[15] The two effects appear to be in opposite directions, with the allele marking susceptibility toALL protecting fromT1D and vice versa.[15]
Further evidence shows that Ikaros regulates the development ofmedullary thymic epithelial cells (mTECs). Conditional deletion ofIkzf1 in thymic epithelial cells byFoxn1-Cre in mice, results in the dysregulation of various mTEC subsets, including the loss of Aire+ mTECs. The loss ofAire (Autoimmune regulator) expressing mTECs also causes global loss oftissue restricted antigens (TRAs) and Aire-dependentmimetic cell populations, with the loss of TRAs eventually leading to breakdown ofimmune tolerance.[16]
The Ikaros Zinc Finger (IkZF) family oftranscription 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 geneIkzf1), 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.[17]
IKZF1 is upregulated in granulocytes, B cells, CD4 and CD8 T cells, and NK cells, and downregulated in erythroblasts, megakaryocytes and monocytes.[18]
The mutation in theIKZF1 gene can cause dysfunction of the Ikaros transcription factor. The dysfunction affects expression inB 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 lowproliferation rate and increasedapoptosis of the B cells. The deregulation may be related withlymphoproliferative disorders and different forms ofleukemia.[19]
^Oliveira VC, Lacerda MP, Moraes BB, Gomes CP, Maricato JT, Souza OF, et al. (September 2019). "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.doi:10.1002/JLB.MA1118-454R.PMID31299112.S2CID196350761.
^Georgopoulos K, Winandy S, Avitahl N (1997). "The role of the Ikaros gene in lymphocyte development and homeostasis".Annual Review of Immunology.15:155–76.doi:10.1146/annurev.immunol.15.1.155.PMID9143685.
^Oliveira VC, Lacerda MP, Moraes BB, Gomes CP, Maricato JT, Souza OF, et al. (July 2019). "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.doi:10.1002/JLB.MA1118-454R.PMID31299112.S2CID196350761.
Westman BJ, Mackay JP, Gell D (October 2002). "Ikaros: a key regulator of haematopoiesis".The International Journal of Biochemistry & Cell Biology.34 (10):1304–7.doi:10.1016/S1357-2725(02)00070-5.PMID12127581.
Nietfeld W, Meyerhans A (January 1996). "Cloning and sequencing of hIk-1, a cDNA encoding a human homologue of mouse Ikaros/LyF-1".Immunology Letters.49 (1–2):139–41.doi:10.1016/0165-2478(95)02479-4.PMID8964602.
Sun L, Goodman PA, Wood CM, Crotty ML, Sensel M, Sather H, et al. (December 1999). "Expression of aberrantly spliced oncogenic ikaros isoforms in childhood acute lymphoblastic leukemia".Journal of Clinical Oncology.17 (12):3753–66.doi:10.1200/JCO.1999.17.12.3753.PMID10577847.
Hosokawa Y, Maeda Y, Ichinohasama R, Miura I, Taniwaki M, Seto M (April 2000). "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.doi:10.1182/blood.V95.8.2719.PMID10753856.
