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. [5] [6] [7]
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. [5] [6] [7]
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]
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. [11]
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]
IKZF1 has been shown to interact with: