Discovery of Ikaros

The Ikaros protein was discovered in 1991 [1], and the murine gene (Ikzf1) was first cloned in 1992 [2] (see entry for the murine Ikzf1 gene). The murine and the human genes are highly homologous, however, the human IKZF1 gene encodes an alternatively spliced exon that is not found in the mouse Ikaros gene (Ikzf1) [3]. Ikaros is the founding member of the Ikaros family of transcription factors, which includes Helios (IKZF2), Aiolos (IKZF3), Eos (IKZF4) and Pegasus (IKZF5).

Disease relevance of IKZF1

• Ikaros is an important tumor suppressor in the lymphoid lineage in both mice and humans. While Ikaros mutant mice develop spontaneous thymic lymphoma, with the tumor suppressor function dependent on the fourth DNA-binding zinc finger (ZnF4) [4], Ikaros tumor suppressor function in human leukemia is most recognized in the B-cell lineage [5][6]

• Acute lymphoblastic leukemia in a patient with Greig cephalopolysyndactyly and interstitial deletion of chromosome 7 del(7)(p11.2 p14) involving the GLI3 and ZNFN1A1 genes [7].
• Ikaros, a zinc finger-containing DNA-binding protein, is required for normal lymphocyte development, and germline mutant mice that express only non-DNA binding dominant-negative "leukemogenic" Ikaros isoforms lacking critical N-terminal zinc fingers develop an aggressive form of lymphoblastic leukemia 3-6 months after birth [8].
• High frequency of Ikaros isoform 6 expression in acute myelomonocytic and monocytic leukemias: implications for up-regulation of the antiapoptotic protein Bcl-XL in leukemogenesis [9].
• 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 [10].
• Adult acute myeloid leukemia cells do not express nonfunctional Ikaros isoforms [11].

High impact information on IKZF1

• Here we found that mice lacking finger 1 or finger 4 of Ikaros exhibited distinct subsets of the hematological defects of Ikaros-null mice [4].

• Some factors that control early lymphoid development are discussed, including IL-7 and the Ikaros transcription factors [12].
• The predicted protein sequence has two potential nuclear localization signals and an unusual combination of different zinc-finger motifs, including IKAROS-like and GATA-binding sequences [13].
• The Ikaros-dependent down-regulation event and the observed chromatin alterations appear to precede pericentromeric repositioning [14].
• Ikaros is a unique regulator of lymphopoiesis that associates with pericentromeric heterochromatin and has been implicated in heritable gene inactivation [14].
• Current models propose that the functions of Ikaros should be disrupted by a small isoform that retains the dimerization domain and lacks the DNA-binding domain [14].

Chemical compound and disease context of IKZF1

• Chronic angiotensin II stimulation in the heart produces an acquired long QT syndrome associated with IK1 potassium current downregulation [15].
• These data suggest that cardiac Ang II overproduction leads to the emergence of a long QT syndrome resulting from an IK1-dependent prolongation of the action potential duration through modulation of channel subunit expression [15].

Biological context of IKZF1

• Pegasus is related to other Ikaros proteins in its C-terminal dimerization domain but contains a divergent N-terminal zinc finger domain [16].
• The human VPAC-1 5'-flanking region (1.4 kb) contains four high affinity Ikaros (IK) consensus sequences [17].
• Transactivation, electrophoretic mobility shift assay and RNA interference-mediated gene knockdown experiments revealed that Ik is involved in the regulation of STAT4 in human T cells [18].
• Sequence comparison of the 5' flanking regions of human, mouse and pufferfish (Fugu rubripes) Stat4 genes revealed a high frequency of Ikaros (Ik) binding elements in all three species [18].
• Analysis of the FAAH promoter showed an Ikaros binding site, and mutation of this site prevented FAAH activation by progesterone in transient expression assays [19].

Anatomical context of IKZF1

• Our results suggest that these proteins may associate with previously described Ikaros family proteins in lymphoid cells and play additional roles in other tissues [16].
• We then investigated the role of Ik binding elements in the human STAT4 promoter using Jurkat T cells [18].
• PATIENTS AND METHODS: We studied Ikaros gene expression in normal human bone marrow, normal thymocytes, normal fetal liver-derived immature lymphocyte precursor cell lines, eight different ALL cell lines, and leukemic cells from 69 children with ALL (T-lineage ALL, n = 18; B-lineage ALL, n = 51) [20].
• Ikaros is expressed in human extravillous trophoblasts and involved in their migration and invasion [21].
• In order to search for molecular markers specific for cellular components of the adaptive immune system in lampreys, we used the polymerase chain reaction (PCR) to identify genes for transcription factors of the Ikaros family in genomic DNA and cDNA libraries from two species of lampreys, Petromyzon marinus and Lampetra fluviatilis [22].

Associations of IKZF1 with chemical compounds

• The activation of FAAH by progesterone was paralleled by a decrease (down to 60%) of the cellular levels of anandamide and involved increased nuclear levels of the transcription factor Ikaros [19].
• We identified a single nucleotide polymorphism (SNP) affecting the third base of the triplet codon for a proline (CCC or CCA) in the highly conserved bipartite activation region (viz, A or C at position 1002 numbering from the translation start site of Ik-1) within our Ikaros clones [20].
• Electromobility shift assay revealed that dexamethasone abolished the binding of nuclear transcription factors to the Ikaros binding site and reduced AP-1 binding activity [23].
• Consistent with this, there was a time-dependent increase in colocalization between IK1 and the lipid raft ganglioside GM1 on the plasma membrane, which subsequently decreased with volume recovery [24].
• The negative inotropic effect of ACh in ventricular muscle is associated with a reduction of Isi; there is no important effect of ACh on IK1 in ventricular muscle [25].

Physical interactions of IKZF1

• Consistent with this expectation, we show that Ikaros can interact with a CtBP-interacting protein (CtIP), which has also been linked to a deacetylase-independent strategy of repression [26].
• LyF-1 also interacts with an element in the immunoglobulin mu enhancer, called microB, that was recently shown to be important for lymphocyte-specific enhancer activity [1].
• Ikaros DNA-binding proteins are critical for the development of lymphocytes and other hematopoietic lineages, but it remains unclear how they cooperate with other regulators of signaling and transcription to achieve ordered gene expression during development [27].
• Our results suggest that Ikaros targets two types of chromatin-remodeling factors-activators (SWI/SNF) and repressors (NuRD)-in a single complex (PYR complex) to the beta-globin locus in adult erythroid cells [28].
• These results indicate that dexamethasone is able to abrogate the transcriptional activity of the human granzyme B gene promoter by inhibiting the binding of nuclear factors at the AP-1 and Ikaros sites [23].

Regulatory relationships of IKZF1

• We have previously shown that Ikaros can repress transcription through the recruitment of histone deacetylase complexes [29].
• BCR-ABL1 induces aberrant splicing of IKAROS and lineage infidelity in pre-B lymphoblastic leukemia cells [30].
• Thus, dominant-negative Ikaros isoforms may inhibit the normal transcriptional regulation of hematopoietic cell development [9].
• Overexpression of dominant-negative Ikaros 6 protein is restricted to a subset of B common adult acute lymphoblastic leukemias that express high levels of the CD34 antigen [31].
• Ap-2 and Ikaros regulate transcription of human placental leucine aminopeptidase/oxytocinase gene [32].

Other interactions of IKZF1

• Here we describe two additional Ikaros family proteins, Eos and Pegasus [16].
• STAT4 is a target of the hematopoietic zinc-finger transcription factor Ikaros in T cells [18].
• Mutations in Ikaros that prevent CtBP interactions reduce its ability to repress transcription [29].
• Consistent with this, BCR-ABL1+ pre-B lymphoblastic leukemia cells exhibit defective expression of IKAROS, a transcription factor needed for early lymphoid lineage commitment [30].
• In the present study, we analyzed expression of the Ikaros family genes Ikaros, Aiolos, and Helios in a panel of human T-cell leukemia/lymphoma cell lines and bone marrow samples of patients with T-cell acute lymphoblastic leukemia [33].

Analytical, diagnostic and therapeutic context of IKZF1

• A molecular dissection of the repression circuitry of Ikaros [34].
• PCR cloning and nucleotide sequencing were used to identify the specific Ikaros isoforms and detect Ikaros gene mutations in these cells [8].
• Reverse transcription-polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH) analyses of a patient sample established that the t(3;7)(q27;p12) results in fusion of the Ikaros and BCL6 genes [10].
• Expression of Ikaros protein and its subcellular localization were examined by immunoblotting and confocal laser-scanning microscopy, respectively [20].
• In leukemic cells expressing the aberrant Ikaros coding sequences with the 30-base-pair deletion, genomic sequence analysis of the intron-exon junctions between exons 6 and 7 yielded the wild-type sequence [20].

References