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.[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 individual T 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 terminal erythrocyte and granulocyte differentiation, and excessive macrophage formation.[13] SNPs located near the 3' region of IKZF1 in humans have been linked to susceptibility to childhood acute lymphoblastic leukemia (ALL)[14] as well as type 1 diabetes.[15] The two effects appear to be in opposite directions, with the allele marking susceptibility to ALL protecting from T1D and vice versa.[15]
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.[16]
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. [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 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. [19]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Georgopoulos K, Moore DD, Derfler B (October 1992). "Ikaros, an early lymphoid-specific transcription factor and a putative mediator for T cell commitment". Science. 258 (5083): 808–12. Bibcode:1992Sci...258..808G. doi:10.1126/science.1439790. PMID1439790.
^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.
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.
