Artículos de revistas: "Ikarios"

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Schock, Werner. "Ikarios und Erigone". Analytische Psychologie 17, n.º 4 (1986): 288–305. http://dx.doi.org/10.1159/000471116.

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2

Biles, Zachary. "Celebrating poetic victory: representations of epinikia in Classical Athens". Journal of Hellenic Studies 127 (noviembre de 2007): 19–37. http://dx.doi.org/10.1017/s0075426900001592.

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Abstract:Although we are fairly well informed about the general organization and important events of the dramatic competitions in Athens, there remain significant gaps in our knowledge on many points of detail. In no place is this more true than with regard to the epinikian celebration honouring members of the victorious performance, about which scarcely any unambiguous testimony has come down to us. This study aims to provide new insights into the problem by demonstrating a connection between the iconography preserved in several sculpted reliefs of the Roman period commonly referred to as Dionysos' visit to Ikarios and the representation of a celebration for poetic victory in Plato'sSymposium. Central to the combined testimony of these sources is the ideal of Dionysos’ epiphany to the poet in order to acknowledge and honour his victory in person. So identified as an element of victory celebration, related articulations of this imagined moment can then be detected in several additional representations on vases and in Aristophanic comedy, in both of which other independent elements likewise suggest the activation of an epinikian syntax. Practical matters about the celebration still elude us; what we gain, however, is a clearer sense of the religious ideals that were conveyed through these celebrations in connection with the worship of Dionysos, which formed a nucleus for the dramatic festivals.

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3

Fatourou, Katerina. "Experiencing Dance as Social Process: A Case Study of the Summer Paniyiri in Ikaria Island". Congress on Research in Dance Conference Proceedings 2016 (2016): 148–55. http://dx.doi.org/10.1017/cor.2016.21.

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The Ikarian paniyiri, one of the main cultural events in the island of Ikaria, has always acted as an important social process with various functions. Currently, it has also incorporated another role, acting as a cultural product aimed for touristic attraction. This transformation has affected the musical and dancing performance in the paniyiri, and especially the performance of the “ikariotiko,” the local dance of Ikaria. This presentation explores the multiple functions of dancing in the Ikarian paniyiri, the redefining of culture in a globalized setting, and also the process of participant integration through an intersubjective interpretation.

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4

Ruiz, Anna y Hugh J. M. Brady. "Ikaros 6 Immortalizes Murine Hematopoietic Precursors In Vitro." Blood 106, n.º 11 (16 de noviembre de 2005): 4354. http://dx.doi.org/10.1182/blood.v106.11.4354.4354.

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Abstract The Ikaros transcription factor has been shown to play an important role in the differentiation of both the myeloid and lymphoid lineages. The ikaros gene encodes for a zinc finger protein containing seven exons that can be alternatively spliced generating several isoforms with differing functional properties. Isoforms with less than three DNA binding domains act as dominant negative (DN) by forming complexes with longer isoforms and interfering with their DNA binding and transcriptional activation ability. Mice heterozygous for a DN ikaros isoform develop T cell leukemia and lymphoma with 100% penetrance. Overexpression of DN Ikaros isoforms has been found in some forms of leukemias. We have previously reported overexpression of the DN Ikaros6 (Ik6) isoform in a subset of leukemia patients harboring t(4;11) translocations. In addition, we inducibly expressed Ik6 in BaF3 cells and found that Ik6 overexpression delayed cell death after IL-3 withdrawal. To further investigate the leukemogenic properties of Ik6 overexpression, we have transduced murine hematopoietic precursors with a retroviral Ik6 expression vector and have analysed the effects on proliferation and differentiation of these precursors by in vitro colony formation assays. We have found that Ik6 can immortalize murine hematopopietic precursors in these in vitro assays. We are currently analysing the leukemogenic potential of Ik6 in vivo by transplanting Ik6 expressing cell lines into NOD/SCID mice.

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5

Zhang, Hong, Min Ye, Robert S. Welner y Daniel G. Tenen. "Sox4 Is Required for the Formation and Maintenance of Multipotent Progenitors". Blood 124, n.º 21 (6 de diciembre de 2014): 1577. http://dx.doi.org/10.1182/blood.v124.21.1577.1577.

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Abstract Introduction Hematopoiesis is maintained by a hierarchical system, whereas aberrant control of hematopoiesis is the underlying cause of many diseases. Within the hematopoietic hierarchy, hematopoietic stem cells (HSCs) give rise to multipotent progenitors that have lost their self-renewal capacity but remain multipotent to differentiate into mature blood cells. However, the precise molecular mechanisms that modulate this transition are not fully understood yet. Results We recently discovered that genetic ablation of SRY sex determining region Y-box 4 gene (Sox4) in the murine hematopoietic system resulted in dramatic loss of multipotent progenitor population (CD48+CD150-Lin-kit+Sca1+, or CD48+CD150-LSK) both relatively (to the total LSK population) and in absolute number. Interestingly, the absolute number of HSCs (CD48-CD150+Lin-kit+Sca1+, or SLAM+LSK) in these conditional Sox4-deficient mice was comparable to their wild-type counterparts. Transcriptional factor Sox4 belongs to the high-mobility group (HMG) domain superfamily which also includes other Sox proteins, TCF-1 (T-cell factor 1) and LEF-1 (lymphoid enhancer factor 1). Sox4 has been implicated in leukemogenesis and may potentially contribute to stem cell properties. Nevertheless, the precise roles of Sox4 in hematopoietic stem/progenitor cells and the underlying mechanisms have not been defined yet. Further analysis of stem/progenitor compartment defined by Flt3 and CD34 expression demonstrated a major loss in lymphoid-primed multipotent progenitors (LMPPs) (CD34+Flt3+LSK) with relatively normal formation of LT-HSCs (CD34-Flt3-LSK) and ST-HSCs (CD34+Flt3-LSK) upon the loss of Sox4, suggesting that Sox4 is essential for the development from HSCs to multipotent progenitors. Such observation is in line with the expression pattern of Sox4. Quantitative PCR (qPCR) analysis of wild-type mice revealed that expression of Sox4 increased from HSCs to multipotent progenitors which expressed Sox4 at the highest level among all the hematopoietic compartments. Studies of biological behaviors further indicateed that disruption of Sox4 had no effect on proliferative capacity of HSCs and multipotent progenitors, as evidenced by BrdU incorporation assay. However, Annexin V/propidium iodide staining revealed an increased frequency of apoptotic multipotent progenitors, but not that of HSCs upon the ablation of Sox4. In a transplantation setting, although Sox4-deficient LSKs homed appropriately to the bone marrow, they exhibited severely impaired ability to give rise to multipotent progenitors, but contributed normally to HSCs compared to the wild-type donors. Among a set of genes crucial to the biological properties of stem/progenitor cells, qPCR analysis revealed that upon the loss of Sox4, only the levels of Ikaros1 and Ikaros2, the two major Ikaros isoforms in stem/progenitor cells, were downregulated specifically in multipotent progenitors, but remained normal in HSCs. Intriguingly, in a reminiscent manner of Sox4-deficient mice, mice lacking both Ikaros 1 and Ikaros 2 proteins, also exhibited disrupted B cell development and selectively impaired LMPPs. Previous study identified an enhancer of Ikaros locus as the only cis-regulatory element that was capable of stimulating reporter expression in the LMPPs. Our sequence analysis revealed a highly conserved Sox4 binding motif within this enhancer, therefore potentially connecting Sox4 with the known regulatory networks that modulate the differentiation of HSCs. Currently, we are working on (1) confirming the direct transcriptional regulation of Ikaros by Sox4; (2) assessing whether Ikaros mediates the functions of Sox4 in the formation or maintenance of the multipotent progenitors population in vivo; and (3) delineating the downstream regulatory network of Sox4 in stem/progenitor cells. Conclusion In summary, out study reveals a novel role for Sox4 gene in early hematopoiesis and brings important insights into the regulatory mechanisms underlying the commitment of HSCs toward multipotent progenitors. Disclosures No relevant conflicts of interest to declare.

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6

Witkowski, Matthew T., Yifang Hu, Luisa Cimmino, Mark D. McKenzie, Grace J. Liu, Gordon K. Smyth y Ross A. Dickins. "Reversible Tumor Suppression By Ikzf1/Ikaros in Mouse Models of BCR-ABL1+ B-ALL". Blood 124, n.º 21 (6 de diciembre de 2014): 288. http://dx.doi.org/10.1182/blood.v124.21.288.288.

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Abstract Background: Loss-of-function mutations in the transcription factor IKZF1 (IKAROS) correlate with poor prognosis in B-progenitor acute lymphoblastic leukemia (B-ALL), and are particularly prevalent in the high-risk BCR-ABL1+ and BCR-ABL1-like disease subtypes. While recent studies using mouse models of Ikaros-deficient B-ALL have uncovered Ikaros-regulated genes, the mechanisms by which IKAROS loss promotes leukemogenesis and confers treatment resistance remain unclear. Results: We have generated a novel transgenic mouse model that allows tet-regulated, shRNA-mediated Ikaros knockdown or restoration in normal lymphocytes and leukemias in vivo. Ikaros knockdown significantly decreases disease latency in mouse models of B-ALL driven by transgenic or retroviral expression of the BCR-ABL1 fusion oncogene, recapitulating a common genetic interaction in high-risk pediatric B-ALL. Remarkably, we find that restoring endogenous Ikaros expression in established BCR-ABL1+ ALL causes rapid disease regression and sustained remission despite ongoing expression of BCR-ABL1, indicating that disabled Ikaros remains a critical disease driver in this context. Using integrated in vivo RNA-seq analysis we have identified a novel set of genes that are (1) differentially expressed in Ikaros-low versus Ikaros-wildtype leukemias and (2) concordantly differentially expressed upon acute Ikaros restoration in established Ikaros-low leukemias. We are now performing in vitro and in vivo loss-of-function genetic screens to interrogate these high confidence Ikaros-regulated genes, focusing on potential roles for Ikaros-activated genes in tumor suppression and Ikaros-repressed genes in promoting BCR-ABL1+ ALL self-renewal. Conclusions: Our results demonstrate that B-ALL driven by expression of BCR-ABL1 and Ikaros loss remains dependent on ongoing Ikaros suppression, suggesting that re-engaging or inhibiting critical components of the Ikaros-regulated gene expression program may provide new therapeutic avenues in this high-risk B-ALL subtype. Disclosures No relevant conflicts of interest to declare.

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7

Payne, Jonathon L., Chunhua Song, Yali Ding, Pavan Kumar Dhanyamraju, Yevgeniya Bamme, Joseph W. Schramm, Dhimant Desai, Arati Sharma, Chandrika Gowda y Sinisa Dovat. "Regulation of Small GTPase Rab20 by Ikaros in B-Cell Acute Lymphoblastic Leukemia". International Journal of Molecular Sciences 21, n.º 5 (3 de marzo de 2020): 1718. http://dx.doi.org/10.3390/ijms21051718.

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Ikaros is a DNA-binding protein that regulates gene expression and functions as a tumor suppressor in B-cell acute lymphoblastic leukemia (B-ALL). The full cohort of Ikaros target genes have yet to be identified. Here, we demonstrate that Ikaros directly regulates expression of the small GTPase, Rab20. Using ChIP-seq and qChIP we assessed Ikaros binding and the epigenetic signature at the RAB20 promoter. Expression of Ikaros, CK2, and RAB20 was determined by qRT-PCR. Overexpression of Ikaros was achieved by retroviral transduction, whereas shRNA was used to knockdown Ikaros and CK2. Regulation of transcription from the RAB20 promoter was analyzed by luciferase reporter assay. The results showed that Ikaros binds the RAB20 promoter in B-ALL. Gain-of-function and loss-of-function experiments demonstrated that Ikaros represses RAB20 transcription via chromatin remodeling. Phosphorylation by CK2 kinase reduces Ikaros’ affinity toward the RAB20 promoter and abolishes its ability to repress RAB20 transcription. Dephosphorylation by PP1 phosphatase enhances both Ikaros’ DNA-binding affinity toward the RAB20 promoter and RAB20 repression. In conclusion, the results demonstrated opposing effects of CK2 and PP1 on expression of Rab20 via control of Ikaros’ activity as a transcriptional regulator. A novel regulatory signaling network in B-cell leukemia that involves CK2, PP1, Ikaros, and Rab20 is identified.

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8

Muthusami, Sunil, Chunhua Song, Xiaokang Pan, Chandrika S. Gowda, Kimberly J. Payne y Sinisa Dovat. "Epigenetic Regulation of Cell Cycle-Promoting Genes By Ikaros and HDAC1 in Acute Lymphoblastic Leukemia". Blood 124, n.º 21 (6 de diciembre de 2014): 3571. http://dx.doi.org/10.1182/blood.v124.21.3571.3571.

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Abstract B-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood leukemia. Expression profiling has identified IKZF1 (Ikaros) as a major tumor suppressor in B-ALL and established reduced Ikaros function as a poor prognostic marker for this disease. Ikaros regulates expression of its target genes via chromatin remodeling. In vivo, Ikaros can form a complex with histone deacetylases HDAC1 and/or HDAC2 as well as the NuRD chromatin remodeling complex. The mechanisms by which Ikaros exerts its tumor suppressor function and regulates gene expression in B-ALL are unknown. Here we report the use of chromatin immunoprecipitation coupled with next generation sequencing (ChIP-SEQ) to identify genes that are regulated by Ikaros in vivo and to determine the role of Ikaros in chromatin remodeling in B-ALL. Results reveal that Ikaros binds to the promoter regions of a large number of genes that are critical for cell cycle progression. These include CDC2, CDC16, CDC25A, ANAPC1, and ANAPC7. Overexpression of Ikaros in leukemia cells resulted in transcriptional repression of Ikaros target genes. Results from luciferase reporter assays performed using the respective promoters of Ikaros target genes support a role for Ikaros as a transcriptional repressor of these genes. Downregulation of Ikaros by siRNA resulted in increased expression of Ikaros target genes that control cell cycle progression. These results suggest that Ikaros functions as a negative regulator of cell cycle progression by repressing transcription of cell cycle-promoting genes. Next, we studied how Ikaros binding affects the epigenetic signature at promoters of Ikaros target genes. Global epigenetic mapping showed that Ikaros binding at the promoter region of cell cycle-promoting genes is associated with the formation of one of two types of repressive epigenetic marks – either H3K27me3 or H3K9me3. While these epigenetic marks were mutually exclusive, they were both associated with the loss of H3K9 acetylation and transcriptional repression. Serial qChIP assays spanning promoters of the Ikaros target genes revealed that the presence of H3K27me3 is associated with Ikaros and HDAC1 binding, while the H3K9me3 modification is associated with Ikaros binding and the absence of HDAC1. ChIP-SEQ analysis of HDAC1 global genomic binding demonstrated that over 80% of H3K27me3 modifications at promoter regions are associated with HDAC1 binding at surrounding sites. The treatment of leukemia cells with the histone deacetylase inhibitor – trichostatin (TSA) resulted in a severe reduction of global levels of H3K27me3, as evidenced by Wesern blot. These data suggest that HDAC1 activity in leukemia is essential for the formation of repressive chromatin that is characterized by the presence of H3K27me3. Our data suggest that Ikaros binding at the promoters of its target genes can result in the formation of repressive chromatin by two distinct mechanisms: 1) direct Ikaros binding resulting in increased H3K9me3 or 2) Ikaros recruitment of HDAC1 with increased H3K27me3 modifications. These data suggest distinct mechanisms for the regulation of chromatin remodeling and target gene expression by Ikaros alone, and Ikaros in complex with HDAC1. In conclusion, the presented data suggest that HDAC1 has a key role in regulating cell cycle progression and proliferation in B-ALL. Our results identify novel, Ikaros-mediated mechanisms of epigenetic regulation that contribute to tumor suppression in leukemia. Supported by National Institutes of Health R01 HL095120, and the Four Diamonds Fund Endowment. Disclosures No relevant conflicts of interest to declare.

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9

Foscolou, Alexandra, Christina Chrysohoou, Kyriakos Dimitriadis, Konstantina Masoura, Georgia Vogiatzi, Viktor Gkotzamanis, George Lazaros, Costas Tsioufis y Christodoulos Stefanadis. "The Association of Healthy Aging with Multimorbidity: IKARIA Study". Nutrients 13, n.º 4 (20 de abril de 2021): 1386. http://dx.doi.org/10.3390/nu13041386.

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The aim of this study was to evaluate several sociodemographic, lifestyle, and clinical characteristics of the IKARIA study participants and to find healthy aging trajectories of multimorbidity of Ikarian islanders. During 2009, 1410 people (aged 30+) from Ikaria Island, Greece, were voluntarily enrolled in the IKARIA study. Multimorbidity was defined as the combination of at least two of the following chronic diseases: hypertension; hypercholesterolemia; diabetes; obesity; cancer; CVD; osteoporosis; thyroid, renal, and chronic obstructive pulmonary disease. A healthy aging index (HAI) ranging from 0 to 100 was constructed using 4 attributes, i.e., depression symptomatology, cognitive function, mobility, and socializing. The prevalence of multimorbidity was 51% among men and 65.5% among women, while the average number of comorbidities was 1.7 ± 1.4 for men and 2.2 ± 1.4 for women. The most prevalent chronic diseases among men with multimorbidity were hypertension, hypercholesterolemia, and obesity while among women they were hypertension, hypercholesterolemia, and thyroid disease. Multimorbidity was correlated with HAI (Spearman’s rho = −0.127, p < 0.001) and for every 10-unit increase in HAI, participants had 20% lower odds of being multimorbid. Multimorbidity in relation to HAI revealed a different trend across aging among men and women, coinciding only in the seventh decade of life. Aging is usually accompanied by chronic diseases, but multimorbidity seems to also be common among younger adults. However, healthy aging is a lifelong process that may lead to limited co-morbidities across the lifespan.

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10

Nahar, Rahul, Parham Ramezani-Rad, Sinisa Dovat, Maike Buchner, Thomas G. Graeber y Markus Muschen. "Mechanisms of Ikaros-Mediated Tumor Suppression". Blood 118, n.º 21 (18 de noviembre de 2011): 408. http://dx.doi.org/10.1182/blood.v118.21.408.408.

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Abstract Abstract 408 Background: The Ikaros (IKZF1) tumor suppressor is deleted in >80% of the cases of Ph+ ALL. While Ikaros cooperates with pre-B cell receptor signaling to induce cell cycle exit in Ph+ ALL (Trageser et al., J Exp Med, 2009), the mechanism of Ikaros-mediated tumor suppression is poorly understood. Here we report on a series of genetic experiments that show that Ikaros (i) interferes with key survival pathways downstream of the BCR-ABL1 kinase, (ii) inhibits leukemia cell proliferation through interaction with the pre-B cell receptor signaling pathway and (iii) activates the tumor suppressors p53, p21 and p27. Results: To elucidate the mechanism of Ikaros-dependent tumor suppression in BCR-ABL1-driven B cell lineage leukemia, we studied regulation of critical phosphorylation events downstream of the BCR-ABL1 kinase as a central mediators of survival and proliferation. Reconstitution of Ikaros expression in BCR-ABL1-transformed pre-B ALL cells resulted in rapid and global dephosphorylation comparable to the effect of Imatinib. A detailed analysis showed that Ikaros-induced dephosphorylation events affect activation of Stat5 (Y694), AKT (S473), ERK1/2 (T202 and Y204) and SRC (Y416). Interestingly, both Imatinib-treatment and reconstitution of pre-B cell receptor signaling using retroviral vectors for expression of the m heavy chain or the BLNK adapter molecule have the same effects as reconstitution of Ikaros. In fact, a comprehensive gene expression analysis demonstrated that Ikaros reconstitution resulted in similar gene expression changes as reconstitution of pre-B cell receptor signaling (m heavy chain or BLNK), reconstitution of PAX5, Cre-mediated deletion of Stat5 or Myc, or treatment with Imatinib. The signature of common gene expression changes shared between reconstitution of Ikaros, Pax5, m heavy chain, BLNK and inducible deletion of Stat5 or Myc and Imatinib-treatment involves known tumor suppressors including SPIB, BTG1, and BTG2. These findings suggest that reconstitution of tumor suppressive transcription factor (Ikaros, Pax5) converges with pre-B cell receptor-mediated tumor suppression. To better understand how pre-B cell receptor signaling and Ikaros intersect, we combined reconstitution of Ikaros with genetic deletion of either the (more proximal) SYK kinase or the (more distal) BLNK adapter molecule. While inducible Cre-mediated deletion of Syk had no effect on Ikaros-mediated tumor suppression, deletion of the BLNK adapter compromised the ability of Ikaros to function as tumor suppressor. These findings were confirmed in an in vivo transplantation experiment. While mice transplanted with Ikaros+ BLNK+ leukemia cells survived indefinitely, mice transplanted with Ikaros- BLNK+, Ikaros+ BLNK- or Ikaros- BLNK- leukemia cells died after 24 to 31 days post transplantation. While these findings provide genetic evidence for collaboration between the Ikaros and pre-B cell receptor tumor suppressor pathways, Ikaros and pre-B cell receptor signaling differ with respect to activation of classical tumor suppressor pathways. While reconstitution of pre-B cell receptor signaling failed to activate Arf, p53 or p27, protein levels of all these molecules were strongly upregulated by Ikaros. In agreement with these findings, reconstitution of pre-B cell receptor signaling had the same tumor suppressive effect in wildtype leukemia cells as in Arf−/−, p53−/− as well as p27−/− leukemia cells. Conversely, deletion of Arf and p53 significantly diminished the ability of Ikaros to function as tumor suppressor. Conclusion: Ikaros deletion represents a near-obligatory lesion in the pathogenesis of Ph+ ALL. Here we provide genetic evidence for three novel pathways of Ikaros-mediated tumor suppression. Like PAX5, Ikaros reconstitution results in multiple dephosphorylation events (Stat5, AKT, ERK1/2 and SRC are affected). In collaboration with the pre-B cell receptor and its downstream adapter molecule BLNK, Ikaros suppressed MYC and inhibits cell cycle progression. Induction of the Arf/p53 pathway represents a distinct function of Ikaros, which is not shared with the pre-B cell receptor signaling pathway. Disclosures: No relevant conflicts of interest to declare.

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11

Gowda, Chandrika S., Chunhua Song, Yali Ding, Malika Kapadia y Sinisa Dovat. "Protein signaling and regulation of gene transcription in leukemia: role of the Casein Kinase II-Ikaros axis". Journal of Investigative Medicine 64, n.º 3 (9 de febrero de 2016): 735–39. http://dx.doi.org/10.1136/jim-2016-000075.

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Protein signaling and regulation of gene expression are the two major mechanisms that regulate cellular proliferation in leukemia. Discerning the function of these processes is essential for understanding the pathogenesis of leukemia and for developing the targeted therapies. Here, we provide an overview of one of the mechanisms that regulates gene transcription in leukemia. This mechanism involves the direct interaction between Casein Kinase II (CK2) and the Ikaros transcription factor. Ikaros (IKZF1) functions as a master regulator of hematopoiesis and a tumor suppressor in acute lymphoblastic leukemia (ALL). Impaired Ikaros function results in the development of high-risk leukemia. Ikaros binds to the upstream regulatory elements of its target genes and regulates their transcription via chromatin remodeling. In vivo, Ikaros is a target for CK2, a pro-oncogenic kinase. CK2 directly phosphorylates Ikaros at multiple amino acids. Functional experiments showed that CK2-mediated phosphorylation of Ikaros, regulates Ikaros’ DNA binding affinity, subcellular localization and protein stability. Recent studies revealed that phosphorylation of Ikaros by CK2 regulates Ikaros binding and repression of the terminal deoxytransferase (TdT) gene in normal thymocytes and in T-cell ALL. Available data suggest that the oncogenic activity of CK2 in leukemia involves functional inactivation of Ikaros and provide a rationale for CK2 inhibitors as a potential treatment for ALL.

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12

Dovat, Sinsa, Chunhua Song, Zafer Gurel, Kimberly J. Payne y Marcela Popescu. "Regulation of Ikaros Function by CK2 Kinase During Lymphocyte Differentiation and Leukemia". Blood 116, n.º 21 (19 de noviembre de 2010): 4196. http://dx.doi.org/10.1182/blood.v116.21.4196.4196.

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Abstract Abstract 4196 Ikaros encodes a DNA-binding zinc finger protein that functions as a master regulator of lymphocyte differentiation and acts as a tumor suppressor in leukemia. The loss of Ikaros activity has been associated with both B and T cell leukemia and deletion of Ikaros has been associated with poor outcome in childhood ALL. Ikaros function depends on its ability to localize to pericentromeric heterochromatin (PC-HC). Ikaros protein binds to the upstream regulatory elements of target genes, aids in their recruitment to PC-HC, and regulates their transcription. Ikaros protein interacts with histone deacetylation complex and represses transcription of its target genes via chromatin remodeling. We have previously reported that Ikaros' activity and protein stability is regulated by pro-oncogenic CK2 kinase (Popescu et al. J Biol Chem 2009 284:13869). Here we studied the effect of CK2-mediated phosphorylation on Ikaros function in primary thymocytes. Using Ikaros phosphomimetic and phosphoresistant mutants of CK2 phosphorylation sites we demonstrate that Ikaros proteins with phosphomimetic mutations at CK2 phosphorylation sites 1) have decreased DNA-binding affinity for the promoter of the terminal deoxynucleotidetransferase (TdT) gene, and other Ikaros target genes involved in lymphocyte differentiation; 2) lose the ability to associate with Sin3a, a component of the NuRD histone deacetylase complex, as indicated by co-immunoprecipitation assays and 3) fail to repress genes involved in thymocyte differentiation as indicated by luciferase reporter assay. The introduction of phosphoresistant mutations at five N-terminal CK2 phosphorylation sites on the Ikaros protein restored Ikaros' association with Sin3a, as well as wild-type levels of repressor activity. Treatment of primary thymocytes with specific inhibitors of CK2 kinase (TBB or DMAT) resulted in increased Ikaros' DNA-binding affinity to the promoter regions of its target genes as measured by quantitative chromatin immunoprecipitation, similar to the results with phosphoresistant mutants. We tested the effect of CK2 kinase inhibition on Ikaros' activity in human leukemia cells. Inhibition of CK2 kinase with TBB led to increased Ikaros' DNA-binding affinity and increased repression of Ikaros target genes. Increased Ikaros activity following inhibition of CK2 kinase was associated with increased sensitivity of human leukemia cells to Doxorubicin or radiation. In summary, these results demonstrate that CK2 kinase regulates thymocyte differentiation by controlling Ikaros' association with chromatin remodeling complexes and its ability to repress the transcription of developmentally regulated genes. Results suggest that CK2 kinase exerts its pro-oncogenic activity in human leukemia cells by inhibiting Ikaros' function as a tumor suppressor. Inhibition of CK2 kinase restores Ikaros function in thymocyte differentiation, along with its tumor suppressor activity and led to increased sensitivity of human leukemia cells to chemotherapy and/or radiation treatment. Thus, inhibition of the CK2 kinase pathway is a promising therapeutic target for human leukemia. Disclosures: No relevant conflicts of interest to declare.

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13

Malinge, Sebastien, Clarisse Thiollier, Timothy M. Chlon, Louis C. Dore, Lauren Diebold, Susan Winandy, Thomas Mercher y John Crispino. "Ikaros Is a GATA Switch Target Gene That Restrains Megakaryopoiesis In Part by Blocking Notch Signaling." Blood 116, n.º 21 (19 de noviembre de 2010): 1602. http://dx.doi.org/10.1182/blood.v116.21.1602.1602.

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Abstract Abstract 1602 The hematopoietic transcription factor Ikaros regulates the development of lymphoid cells. In particular, Ikaros has been shown to suppress expression of Notch target genes in developing thymocytes. In addition, Ikaros-deficient animals fail to develop B cells and instead display a T cell lymphoproliferative disorder. Furthermore, alterations in Ikaros gene expression are associated with human lymphoid neoplasms and loss of Ikaros is associated with progression of myeloproliferative neoplasms to acute myeloid leukemia. However, the role of Ikaros in normal and malignant myelopoiesis is not well characterized. Therefore, we first analyzed myeloid development in Ikaros deficient mice and observed extramedullary hematopoiesis in the spleen and a striking thrombocytosis in the peripheral blood of 8–9 week-old Ikaros-null mice (2×106 platelets/μl, compared to 0.5×106 platelets/μl in wild-type littermates). Flow cytometry, histology and colony forming assays revealed that the bone marrow and spleen of young Ikaros-null mice harbored a substantial increase in the numbers of megakaryocytes and myeloid cells. We next investigated how Ikaros activity is reduced during terminal differentiation. Previous reports have shown that GATA1-deficient and GATA1s mutant megakaryocytes, which are associated with Down syndrome acute megakaryoblastic leukemia (DS-AMKL), express aberrantly high levels of Ikaros, suggesting that Ikaros is a target of GATA-1 repression during terminal megakaryocyte differentiation. By chromatin immunoprecipitation assays, we found multiple sites in the Ikaros locus that are bound by GATA-2 in proliferating progenitors and by GATA-1 in maturing megakaryocytes. Furthermore, we discovered that GATA-1s fails to occupy these conserved Ikaros loci. Together these results strongly suggest that GATA-1, but not GATA-1s, displaces GATA-2 from the Ikaros gene during differentiation and that this GATA switch leads to repression of Ikaros, in turn allowing for terminal maturation of megakaryocytes. Since Notch participates in specification of the megakaryocyte lineage, we then asked whether Ikaros inhibited megakaryopoiesis by interfering with Notch signaling. Retroviral transduction of full-length Ikaros in murine common myeloid progenitors, but not in LSK cells, reduced megakaryocyte development upon Notch stimulation in OP9-DL1 stromal co-cultures. Ectopic expression of Ikaros in the 6133 cell line, which models the t(1;22) subtype of AMKL and shows aberrant Notch target genes activation by the OTT-MAL fusion oncogene, inhibited proliferation and induced apoptosis. Genome wide expression profiling in transduced 6133 cells confirmed that Ikaros alters expression of several genes involved in the Notch and growth factor signaling pathways. These results indicate that Ikaros restricts megakaryocyte development and inhibits proliferation of OTT-MAL-transformed AMKL cells at least in part by suppressing Notch signaling. Together, our results suggest that a functional antagonism between the Notch pathway and Ikaros controls normal megakaryocyte development and that this axis is deregulated in AMKL, contributing to aberrant expansion of immature megakaryoblasts. Disclosures: No relevant conflicts of interest to declare.

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14

Gounari, Fotini y Barbara L. Kee. "Fingerprinting Ikaros". Nature Immunology 14, n.º 10 (18 de septiembre de 2013): 1034–35. http://dx.doi.org/10.1038/ni.2709.

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15

Seng, Amara, Julie L. Mitchell y Thomas M. Yankee. "Expression and splicing of Ikaros family members in murine and human thymocytes". Journal of Immunology 198, n.º 1_Supplement (1 de mayo de 2017): 60.11. http://dx.doi.org/10.4049/jimmunol.198.supp.60.11.

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Abstract The Ikaros family of transcription factors consists of five highly homologous zinc-finger proteins: Ikaros, Helios, Eos, Aiolos and Pegasus. These family members can homodimerize or heterodimerize in any combination which can alter transcriptional activity. Ikaros family member function can further vary with alternative splicing that affects DNA-binding. Previous studies have demonstrated that abolishing the function of the entire Ikaros family blocks lymphocyte development. Whereas eliminating the function of one Ikaros family member results in relatively minor defects. These data indicate that multiple Ikaros family members play a role in lymphocyte development. The goal of this study was to fully characterize expression and splicing of Ikaros family members in murine and human T cell development from the CD4−CD8− double negative (DN) developmental stage to the CD4+CD8+ double positive (DP) stage. In both mice and humans, Aiolos and Ikaros mRNA levels increase during the progression of T cell development from the DN to DP stages. However, the corresponding increase in Aiolos and Ikaros protein levels was only observed in mice. Additionally, extensive alternative splicing of Ikaros and Aiolos was observed in mice, but only Ikaros was extensively spliced in humans. Helios mRNA and protein levels decreased during murine T cell development, but increased in human T cell development. These data indicate that differences in human and murine T cell development may be regulated by differences in Ikaros family member expression and splicing.

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Dovat, Sinisa, Chunhua Song, Xiaokang Pan, Yali Ding, Chandrika S. Gowda, Marie S. Bulathsinghala, Mansi Sachdev, Haijun Wang y Kimberly J. Payne. "Epigenetic Control Of Cell Cycle-Promoting Genes By Ikaros and Casein Kinase II In B-Cell Acute Lymphoblastic Leukemia". Blood 122, n.º 21 (15 de noviembre de 2013): 3734. http://dx.doi.org/10.1182/blood.v122.21.3734.3734.

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Abstract IKZF1 (Ikaros) encodes a kruppel-like zinc finger protein that is essential for normal hematopoiesis and acts as a tumor suppressor in acute lymphoblastic leukemia (ALL). The deletion and/or mutation of Ikaros is associated with the development of human T-cell and B-cell acute lymphoblastic leukemia (B-ALL) with poor outcome. In vivo, Ikaros binds DNA and regulates gene expression by chromatin remodeling. Since there is a paucity of known genes that are regulated by Ikaros, the molecular mechanisms through which Ikaros exerts its tumor suppressor function remain unknown. Here we describe studies that identify the targets and mechanisms of Ikaros-mediated epigenetic regulation in human B-ALL. We used chromatin immunoprecipitation coupled with next generation sequencing (ChIP-seq) to identify target genes that are bound by Ikaros in vivo in human B-ALL, and to define epigenetic patterns associated with Ikaros binding. ChIP-seq revealed a large set of Ikaros target genes that contain a characteristic Ikaros binding motif. The largest group of genes that are direct Ikaros targets included genes that are essential for cell cycle progression. These included CDC2, CDC7, CDK2 and CDK6 genes whose deregulation is associated with malignant transformation. The strong binding of ikaros to the promoters of cell cycle-promoting genes was confirmed by quantitative immunoprecipitation in primary leukemia cells. To establish whether Ikaros directly regulates transcription of the cell cycle-promoting genes, their expression was measured in B-ALL cells that were transduced with either a retroviral vector that contains Ikaros, or a control vector. Target gene expression was monitored by qRT-PCR. Ikaros strongly repressed transcription of the cell cycle-promoting genes, which resulted in cell cycle arrest. Global epigenetic profiling using ChIP-seq suggested that Ikaros represses cell cycle-promoting genes by inducing epigenetic changes that are consistent with repressive chromatin. High-resolution epigenetic profiling of the upstream regulatory elements of the cell cycle-promoting genes targeted by Ikaros showed that increased Ikaros expression results in the formation of heterochromatin, which is characterized by the presence of the H3K9me3 histone modification and associated transcriptional repression. Functional analysis revealed that phosphorylation of Ikaros by the oncogenic protein. Casein kinase II (CK2), impairs its function as a transcriptional repressor of the cell cycle-regulating genes. Inhibition of CK2 by specific inhibitors enhances Ikaros-mediated repression of the cell cycle-regulating genes resulting in cessation of cellular proliferation and cell cycle arrest in vitro and in vivo in a B-cell ALL preclinical model. This was associated with increased Ikaros binding and the formation of heterochromatin at upstream regulatory elements of the cell cycle-promoting genes. Our results provide evidence that Ikaros functions as a repressor of cell cycle-promoting genes in B-ALL by directly binding their promoters and inducing the formation of heterochromatin with characteristic H3K9me3 histone modifications Ikaros repressor function is negatively regulated by CK2 kinase in B-cell ALL. Inhibition of CK2 enhances Ikaros mediated-repression of cell cycle-promoting genes resulting in an anti-leukemia effect in a preclinical model of B-cell ALL. Presented data identified the mechanism of action of CK2 inhibitors and demonstrated their efficacy in B-cell ALL preclinical model. Results support the use of CK2 inhibitors in Phase I clinical trial. Supported by National Institutes of Health R01 HL095120 and a St. Baldrick’s Foundation Career Development Award (to S.D.). Disclosures: No relevant conflicts of interest to declare.

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17

Gómez-del Arco, Pablo, Joseph Koipally y Katia Georgopoulos. "Ikaros SUMOylation: Switching Out of Repression". Molecular and Cellular Biology 25, n.º 7 (1 de abril de 2005): 2688–97. http://dx.doi.org/10.1128/mcb.25.7.2688-2697.2005.

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ABSTRACT Ikaros plays a key role in lymphocyte development and homeostasis by both potentiating and repressing gene expression. Here we show that Ikaros interacts with components of the SUMO pathway and is SUMOylated in vivo. Two SUMOylation sites are identified on Ikaros whose simultaneous modification results in a loss of Ikaros' repression function. Ikaros SUMOylation disrupts its participation in both histone deacetylase (HDAC)-dependent and HDAC-independent repression but does not influence its nuclear localization into pericentromeric heterochromatin. These studies reveal a new dynamic way by which Ikaros-mediated gene repression is controlled by SUMOylation.

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18

Dovat, Sinisa, Chunhua Song y Kimberly Payne. "Ikaros directly upregulates transcription of B lineage-specific genes in human B cell leukemia (P4412)". Journal of Immunology 190, n.º 1_Supplement (1 de mayo de 2013): 52.26. http://dx.doi.org/10.4049/jimmunol.190.supp.52.26.

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Abstract Ikaros encodes a DNA-binding protein that functions as a master regulator of hematopoiesis and a tumor suppressor in pre-B acute lymphoblastic leukemia (B-ALL). Loss of Ikaros function is associated with impaired hematopoiesis and high-risk B-ALL in humans. The mechanism of Ikaros tumor suppressor activity is unknown. Using quantitative chromatin immunoprecipitation (qChIP) we demonstrate that Ikaros binds to the promoters of genes required for B cell differentiation in primary leukemia cells. Luciferase reporter assays demonstrated that Ikaros activates transcription of these B lineage-specific genes. Increased expression of Ikaros via retroviral transduction in B-ALL cells resulted in increased transcription of these critical B cell differentiation genes, as well as increased binding of Ikaros to their promoters. The inhibition of Casein Kinase II (CK2) resulted in dephosphorylation of Ikaros and enhanced Ikaros-mediated transcriptional activation of the B lineage-specific genes in B-ALL. Treatment of the pre-B ALL cell line, Nalm6, with a CK2 inhibitor, resulted in increased Ikaros binding to the promoters of B lineage genes, increased transcription of B cell differentiation genes, and cell cycle arrest. Results suggest that Ikaros functions as a positive regulator of B cell differentiation by directly upregulating the transcription of B lineage-specific genes in B-ALL. The presented data suggest that CK2 has a critical role in B cell differentiation and in leukemogenesis.

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Lemarié, Maud, Stefania Bottardi, Lionel Mavoungou, Helen Pak y Eric Milot. "IKAROS is required for the measured response of NOTCH target genes upon external NOTCH signaling". PLOS Genetics 17, n.º 3 (26 de marzo de 2021): e1009478. http://dx.doi.org/10.1371/journal.pgen.1009478.

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The tumor suppressor IKAROS binds and represses multiple NOTCH target genes. For their induction upon NOTCH signaling, IKAROS is removed and replaced by NOTCH Intracellular Domain (NICD)-associated proteins. However, IKAROS remains associated to other NOTCH activated genes upon signaling and induction. Whether IKAROS could participate to the induction of this second group of NOTCH activated genes is unknown. We analyzed the combined effect of IKAROS abrogation and NOTCH signaling on the expression of NOTCH activated genes in erythroid cells. In IKAROS-deleted cells, we observed that many of these genes were either overexpressed or no longer responsive to NOTCH signaling. IKAROS is then required for the organization of bivalent chromatin and poised transcription of NOTCH activated genes belonging to either of the aforementioned groups. Furthermore, we show that IKAROS-dependent poised organization of the NOTCH target Cdkn1a is also required for its adequate induction upon genotoxic insults. These results highlight the critical role played by IKAROS in establishing bivalent chromatin and transcriptional poised state at target genes for their activation by NOTCH or other stress signals.

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20

Kathrein, Katie L., Rachelle Lorenz, Angela Minniti Innes, Erin Griffiths y Susan Winandy. "Ikaros Induces Quiescence and T-Cell Differentiation in a Leukemia Cell Line". Molecular and Cellular Biology 25, n.º 5 (1 de marzo de 2005): 1645–54. http://dx.doi.org/10.1128/mcb.25.5.1645-1654.2005.

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ABSTRACT Ikaros is a hematopoietic cell-specific zinc finger DNA binding protein that plays an important role in lymphocyte development. Genetic disruption of Ikaros results in T-cell transformation. Ikaros null mice develop leukemia with 100% penetrance. It has been hypothesized that Ikaros controls gene expression through its association with chromatin remodeling complexes. The development of leukemia in Ikaros null mice suggests that Ikaros has the characteristics of a tumor suppressor gene. In this report, we show that the introduction of Ikaros into an established mouse Ikaros null T leukemia cell line leads to growth arrest at the G0/G1 stage of the cell cycle. This arrest is associated with up-regulation of the cell cycle-dependent kinase inhibitor p27kip1, the induction of expression of T-cell differentiation markers, and a global and specific increase in histone H3 acetylation status. These studies provide strong evidence that Ikaros possesses the properties of a bona fide tumor suppressor gene for the T-cell lineage and offer insight into the mechanism of Ikaros's tumor suppressive activity.

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21

Heizmann, Beate, Stéphanie Le Gras, Célestine Simand, Patricia Marchal, Susan Chan y Philippe Kastner. "Ikaros antagonizes DNA binding by STAT5 in pre-B cells". PLOS ONE 15, n.º 11 (12 de noviembre de 2020): e0242211. http://dx.doi.org/10.1371/journal.pone.0242211.

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The IKZF1 gene, which encodes the Ikaros transcription factor, is frequently deleted or mutated in patients with B-cell precursor acute lymphoblastic leukemias that express oncogenes, like BCR-ABL, which activate the JAK-STAT5 pathway. Ikaros functionally antagonizes the transcriptional programs downstream of IL-7/STAT5 during B cell development, as well as STAT5 activity in leukemic cells. However, the mechanisms by which Ikaros interferes with STAT5 function is unknown. We studied the genomic distribution of Ikaros and STAT5 on chromatin in a murine pre-B cell line, and found that both proteins colocalize on >60% of STAT5 target regions. Strikingly, Ikaros activity leads to widespread loss of STAT5 binding at most of its genomic targets within two hours of Ikaros induction, suggesting a direct mechanism. Ikaros did not alter the level of total or phosphorylated STAT5 proteins, nor did it associate with STAT5. Using sequences from the Cish, Socs2 and Bcl6 genes that Ikaros and STAT5 target, we show that both proteins bind overlapping sequences at GGAA motifs. Our results demonstrate that Ikaros antagonizes STAT5 DNA binding, in part by competing for common target sequences. Our study has implications for understanding the functions of Ikaros and STAT5 in B cell development and transformation.

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22

Dovat, Sinisa, Chunhua Song, Zafer Gurel, Kimberly Payne y Marcela Popescu. "Regulation of chromatin remodeling during thymocyte differentiation (88.5)". Journal of Immunology 184, n.º 1_Supplement (1 de abril de 2010): 88.5. http://dx.doi.org/10.4049/jimmunol.184.supp.88.5.

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Abstract The Ikaros gene encodes a DNA-binding protein that functions as a master regulator of lymphoid development. Ikaros protein interacts with histone deacetylation complex and represses transcription of its target genes via chromatin remodeling. We have previously reported that Ikaros’ activity and protein stability is regulated by CK2 kinase (Popescu et al. J Biol Chem 2009 284:13869). We studied the effect of CK2-mediated phosphorylation on Ikaros function in primary thymocytes. Ikaros proteins with phosphomimetic mutations at CK2 phosphorylation sites 1) lose the ability to associate with Sin3a, a component of the NuRD histone deacetylase, as indicated by co-immunoprecipitation assays and 2) fail to repress genes involved in thymocyte differentiation as indicated by luciferase reporter assay. The introduction of phosphoresistant mutations at five N-terminal CK2 phosphorylation sites on the Ikaros protein restored Ikaros’ association with Sin3a, as well as wild-type levels of repressor activity. The treatment of primary thymocytes with CK2 kinase inhibitors resulted in increased levels of Ikaros protein and increased Ikaros’ DNA-binding affinity to the promoter regions of its target genes, as measured by quantitative chromatin immunoprecipitation. These results demonstrate that CK2 kinase regulates thymocyte differentiation by controlling Ikaros’ association with chromatin remodeling complexes and its ability to repress the transcription of developmentally regulated genes.

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Umetsu, Sarah E. y Susan Winandy. "Ikaros regulates IL-10 expression in CD4+ T cells (38.27)". Journal of Immunology 182, n.º 1_Supplement (1 de abril de 2009): 38.27. http://dx.doi.org/10.4049/jimmunol.182.supp.38.27.

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Abstract IL-10 is a regulatory cytokine critical for controlling inflammatory responses. However, little is known about the molecular mechanisms controlling Il10 gene expression, although GATA-3 is known to be involved in Il10 expression by Th2 cells. Here we show that Ikaros, a zinc finger DNA-binding protein, plays an important role in the regulation of IL-10 in T cells. Upon initial stimulation by T cell receptor, cells deficient in Ikaros (Ikaros null) express significantly lower levels of IL-10 compared to wild type T cells. In addition, under Th2 skewing conditions, which induce high levels of IL-10 production by wild type cells, Ikaros null T cells are unable to properly differentiate and produce only low levels of IL-10. The use of a retroviral vector system to express a dominant negative isoform of Ikaros in wild type Th2 cells represses IL-10 production but does not significantly alter the levels of transcription factors Gata3 and Tbet. Further, expression of Ikaros in Ikaros null T cells restores IL-10 expression. We found that Ikaros binds to conserved regulatory regions of the Il10 gene locus in Th2 cells, supporting a direct role for Ikaros in Il10 expression. In addition, we have evidence to suggest a coordinate role for Ikaros and Gata3 in the regulation of Il10. A direct interaction of these proteins is being examined. Thus, we suggest of novel role of Ikaros in regulating Il10 gene expression.

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Schjerven, Hilde, Etapong Fonabei Ayongaba, Jami McLaughlin, Donghui Cheng, Linn Margrethe Eggesbø, Ida Lindeman, Eugene Park et al. "Analysis of Ikaros tumor suppressor function in BCR-ABL1+ pre-B ALL reveals conserved target genes and biological pathways". Journal of Immunology 196, n.º 1_Supplement (1 de mayo de 2016): 122.6. http://dx.doi.org/10.4049/jimmunol.196.supp.122.6.

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Abstract Inactivation of the transcriptional factor Ikaros (IKZF1) correlates with poor prognosis in progenitor B-cell acute lymphoblastic leukemia (pre-B ALL), and is a hallmark of the BCR-ABL1+ subgroup of pre-B ALL. Ikaros is a critical regulator of hematopoietic development and required for B-cell development, however the mechanisms by which Ikaros functions as a tumor suppressor in pre-B ALL remain poorly understood. We analyzed recently developed mouse models of BCR-ABL1+ pre-B ALL containing targeted deletions of Ikaros DNA-binding zinc finger domains together with a new model of inducible expression of WT Ikaros in IKZF1-mutant human BCR-ABL1+ pre-B ALL. We found that both the mouse and human Ikaros-mutated leukemic cells displayed a less mature cell surface phenotype and failed to downregulate the developmentally restricted cell surface receptors c-kit and CD34, respectively. In addition, Ctnnd1, a gene that is also expressed in earlier hematopoietic progenitor cells and normally downregulated as cells differentiate down the B-cell lineage, was found to be a conserved Ikaros target gene, with increased expression in Ikaros-mutated leukemic cells. RNA sequencing defined the Ikaros target genes in both mouse and human Ikaros-mutated pre-B ALL cells and revealed additional conserved target genes and biological functions. Loss of Ikaros tumor suppression was associated with deregulated adhesion pathways and stem-cell signatures. Furthermore, our results presented herein suggest that Ikaros mediates tumor suppressor function, at least in part, by enforcing proper developmental-stage specific expression of multiple genes involved in a network of cadherin-dependent, Rho-regulated Wnt/b-catenin pathways.

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Alkhatib, Alabbas, Markus Werner, Eva Hug, Sebastian Herzog, Cathrin Eschbach, Hemin Faraidun, Fabian Köhler, Thomas Wossning y Hassan Jumaa. "FoxO1 induces Ikaros splicing to promote immunoglobulin gene recombination". Journal of Experimental Medicine 209, n.º 2 (30 de enero de 2012): 395–406. http://dx.doi.org/10.1084/jem.20110216.

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Somatic rearrangement of immunoglobulin (Ig) genes is a key step during B cell development. Using pro–B cells lacking the phosphatase Pten (phosphatase and tensin homolog), which negatively regulates phosphoinositide-3-kinase (PI3K) signaling, we show that PI3K signaling inhibits Ig gene rearrangement by suppressing the expression of the transcription factor Ikaros. Further analysis revealed that the transcription factor FoxO1 is crucial for Ikaros expression and that PI3K-mediated down-regulation of FoxO1 suppresses Ikaros expression. Interestingly, FoxO1 did not influence Ikaros transcription; instead, FoxO1 is essential for proper Ikaros mRNA splicing, as FoxO1-deficient cells contain aberrantly processed Ikaros transcripts. Moreover, FoxO1-induced Ikaros expression was sufficient only for proximal VH to DJH gene rearrangement. Simultaneous expression of the transcription factor Pax5 was needed for the activation of distal VH genes; however, Pax5 did not induce any Ig gene rearrangement in the absence of Ikaros. Together, our results suggest that ordered Ig gene rearrangement is regulated by distinct activities of Ikaros, which mediates proximal VH to DJH gene rearrangement downstream of FoxO1 and cooperates with Pax5 to activate the rearrangement of distal VH genes.

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Park, Bongkyun y Suhkneung Pyo. "The role of Ikaros in adipocyte differentiation of MDI-stimulated 3T3-L1 cells (P3111)". Journal of Immunology 190, n.º 1_Supplement (1 de mayo de 2013): 43.17. http://dx.doi.org/10.4049/jimmunol.190.supp.43.17.

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Abstract Adipogenesis is a tightly regulated cellular differentiation process, in which the preadipocytes are transformed into differentiated adipocyte cells. Ikaros has been known as a cell cycle regulator on lymphoid and myeloid cell differentiation. However, the precise role of Ikaros in adipogenesis is still unclear. We investigated the role of Ikaros in vitro in adipocyte differentiation of preadipocyte cell line, 3T3-L1. Western blot analysis showed that Ikaros expression was significantly increased by 2 days in MDI-treated 3T3-L1 cells, whereas the expression of c-Myc was markedly decreased after 2 days. Oil red O staining revealed that inhibition of Ikaros by siRNA suppressed lipid droplet accumulation. In addition, knockdown of Ikaros resulted in re-entry of cell cycle progression from G1 phase as well as inhibition of p21 and p27 expression, cell cycle arrest proteins. In contrast, c-Myc expression was increased. Immunoprecipitation analysis demonstrated that the interaction of Ikaros and c-Myc was significantly enhanced in MDI-treated 3T3-L1 cells, suggesting that the interaction between Ikaros and c-Myc is required for adipogenesis. Taken together, our data suggest that Ikaros may play a critical role in adipocyte differentiation by negatively regulating c-Myc expression.

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Ding, Yali, Chunhua Song, Chandrika S. Gowda, Malika Kapadia, Kimberly Payne y Sinisa Dovat. "Transcriptional Repression of the LMO2 Oncogene By Ikaros in T-Cell Acute Lymphoblastic Leukemia". Blood 128, n.º 22 (2 de diciembre de 2016): 439. http://dx.doi.org/10.1182/blood.v128.22.439.439.

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Abstract LIM domain only protein 2 (LMO2) is a regulator of hematopoiesis and an oncogene that is overexpressed in a subset of T-cell acute lymphoblastic leukemia (T-ALL). Overexpression of LMO2 in T-ALL is associated with a poor prognosis. The mechanisms that regulate LMO2 expression in T-ALL are still unknown. Here, we present evidence that expression of LMO2 in T-ALL is regulated at the transcriptional level by Ikaros, a tumor suppressor protein whose deletion is associated with the development T-ALL. Global chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-seq) studies in primary human acute lymphoblastic leukemia cells and in cell lines demonstrated Ikaros occupancy of the LMO2 promoter. Ikaros binding at the LMO2 promoter was confirmed by quantitative chromatin immunoprecipitation (qChIP) in primary T-ALL and B-ALL cells. The role of Ikaros in the regulation of LMO2 transcription in T-ALL was tested using gain-of-function and loss-of-function experiments. Ikaros knock-down with siRNA resulted in increased transcription of LMO2 in T-ALL. Overexpression of Ikaros in human T-ALL was associated with strongly reduced transcription of LMO2. In mice, T-ALL cells that are derived from Ikaros-knockout mice express high levels of LMO2. Transduction of these cells with Ikaros-containing retrovirus, results in a sharp reduction of LMO2 expression. Since Ikaros function in T-ALL is negatively regulated by the pro-oncogenic Casein Kinase II (CK2), we tested whether CK2 inhibition can enhance Ikaros-mediated transcriptional repression of LMO2. Molecular inhibition of CK2 using shRNA, as well as pharmacological inhibition with a specific CK2 inhibitor, resulted in reduced expression of LMO2 in primary human T-ALL. Inhibition of CK2 was associated with increased Ikaros binding at the LMO2 promoter. Ikaros knock-down restored high expression of LMO2 in T-ALL cells that were treated with CK2 inhibitors. These data show that Ikaros is a major regulator of LMO2 transcription in T-ALL and that CK2 inhibition requires Ikaros activity to repress LMO2 transcription. Increased Ikaros binding was associated with reduced histone H3K9ac and H3K4me3 marks at the LMO2 promoter suggesting that Ikaros regulates LMO2 transcription via chromatin remodeling. In conclusion, these results provide evidence that expression of the LMO2 oncogene is regulated by Ikaros and CK2 in T-ALL. Targeting CK2 with specific inhibitors has been used as a therapeutic strategy in a preclinical model of T-ALL. The presented data reveal a novel mechanism of therapeutic action for CK2 inhibitors - repression of LMO2 expression via Ikaros. These results provide a rationale for the use of CK2 inhibitors in T-ALL with LMO2 overexpression. Disclosures No relevant conflicts of interest to declare.

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Dovat, Sinsa, Kimberly J. Payne y Chunhua Song. "Protein Phosphatase 1 Regulates the Tumor Suppressor Function of Ikaros and Radiation Resistance in Acute Lymphoblastic Leukemia". Blood 118, n.º 21 (18 de noviembre de 2011): 2465. http://dx.doi.org/10.1182/blood.v118.21.2465.2465.

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Abstract Abstract 2465 The Ikaros gene encodes a DNA-binding zinc finger protein that acts as a master regulator of hematopoiesis and a tumor suppressor in acute lymphoblastic leukemia (ALL). Ikaros exerts its tumor suppressor activity by binding to the upstream regulatory regions of its target genes resulting in chromatin remodeling and transcriptional repression of the target gene. We have previously reported that Ikaros is a substrate for Protein Phosphatase 1 (PP1), and that PP1 regulates the DNA-binding affinity of Ikaros and its subcellular localization to pericentromeric heterochromatin. PP1 has been postulated to possess tumor suppressor activity, although the mechanisms were unknown. We hypothesize that PP1 positively regulates the tumor suppressor function of Ikaros in ALL. In this report, we studied the role of PP1 in regulating Ikaros function as a transcriptional regulator of its target genes in acute lymphoblastic leukemia (ALL), and in controlling the sensitivity of leukemia cells to radiation. An Ikaros construct with a mutated PP1 interaction site (IK 465/7A) was tested for: 1) association with histone deacetylase (HDAC) chromatin remodeling complex by co-immunoprecipitation; 2) in vivo DNA-binding to promoter regions of known Ikaros target genes by quantitative chromatin immunoprecipitation (qChIP); and 3) direct transcriptional repression of Ikaros target genes, by transient luciferase reporter assay. Our results demonstrate that the loss of interaction with PP1 results in hyperphosphorylation of Ikaros protein resulting in an inability of Ikaros to interact with the HDAC chromatin remodeling complex. The loss of PP1 interaction impaired Ikaros' ability to function as transcriptional repressor due to poor DNA-binding affinity toward the promoters of Ikaros target genes. The introduction of phosphoresistant (alanine) mutations at CK2 kinase phosphorylation sites on the Ikaros protein (IK 465/7A+A11 mutant) restored Ikaros' ability to bind the histone deacetylase complex (including HDAC1 and HDAC2 proteins), as well as its transcriptional repressor function and DNA-binding affinity toward promoters of its target genes. These data strongly suggest that dephosphorylation of Ikaros by PP1 is essential for its function in chromatin remodeling and regulation of gene expression. To study the role of PP1 in ALL, we treated primary ALL cells with specific inhibitors of PP1 and studied the impact PP1 inhibition on ALL cells. Our data demonstrate that the inhibition of PP1 activity results in decreased sensitivity of ALL cells to radiation treatment, and that these changes correlate with a decrease in Ikaros' DNA-binding affinity (as evidenced by qChIP), and a loss of Ikaros function as a direct regulator of target gene transcription. These studies identified PP1 as an important signal transduction pathway that controls the proliferation of ALL cells. Our results suggest that PP1-mediated dephosphorylation and CK2 kinase-mediated phosphorylation are two opposing signaling pathways that regulate Ikaros function as a tumor suppressor in ALL, as well as the resistance of leukemia cells to radiation treatment. Disclosures: No relevant conflicts of interest to declare.

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Schjerven, Hilde, Linn Eggesbo, Ida Lindeman y Markus Muschen. "Ikaros tumor suppressor function in pre-B ALL: potential role of Ikaros target gene Ctnnd1 (IRM10P.621)". Journal of Immunology 194, n.º 1_Supplement (1 de mayo de 2015): 131.19. http://dx.doi.org/10.4049/jimmunol.194.supp.131.19.

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Abstract Ikaros is a zinc finger transcription factor required for B-cell development and proper hematopoiesis, and an important tumor suppressor in developing lymphocytes. To understand the mechanism of Ikaros tumor suppressor function and potentially develop new and improved targeted therapies, it is important to elucidate the downstream target genes involved. With this aim, we combine mouse models of pre-B ALL and in vitro culture of human patient-derived pre-B ALL cells. A mouse model with targeted deletion of the fourth DNA-binding zinc finger of Ikaros resulted in loss of tumor suppressor function, with a limited set of deregulated genes useful to narrow down the list of putative relevant Ikaros target genes (Schjerven et al., 2013). To specifically address the role of Ikaros as a tumor suppressor in human pre-B ALL, we developed TET-regulated Ikaros expression in human pre-B ALL cells. This enables us to test specific Ikaros target genes from the mouse model, and allows for genome-wide expression analysis by RNA-seq to elucidate all genes downstream of Ikaros in human pre-B ALL cells. To help distinguish direct from indirect target genes, we have mapped the genome-wide binding sites of Ikaros in these human pre-B ALL cells by ChIP-Seq. This approach has identified the Ikaros target gene Ctnnd1. Ongoing experiments explore the potential role of Ctnnd1 and test the current hypothesis that Ikaros-mediated repression of Ctnnd1 limits CyclinD levels and leukemic growth in pre-B ALL.

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Gowda, Chandrika S., Chunhua Song, Sunil Muthusami, Yali Ding, Mansi Sachdev, Kimberly Payne y Sinisa Dovat. "Restoring Ikaros Function in Leukemia : Casein Kinase II ( CK2) Inhibition Restores Ikaros Tumor Supressor Function and Shows Theraputic Efficacy in Preclinical Models of High Risk Pediatric Leukemia". Blood 124, n.º 21 (6 de diciembre de 2014): 3712. http://dx.doi.org/10.1182/blood.v124.21.3712.3712.

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Abstract One common feature of high-risk pediatric B-cell acute lymphoblastic leukemia (B-ALL) is impaired function of the Ikaros (IKZF1) tumor suppressor gene. Ikaros encodes a DNA-binding, zinc finger protein that regulates expression of its target genes. Using chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-SEQ) we determined that Ikaros targets multiple genes that regulate cell cycle progression. Functional studies provided evidence that Ikaros acts as a transcriptional repressor of several key cell cycle-promoting genes. We hypothesize that Ikaros’ ability to regulate transcription is reduced in leukemia and that restoration of Ikaros function as transcriptional repressor of cell cycle-promoting genes will have a strong anti-leukemia effect. We have previously shown that Casein Kinase II (CK2) directly phosphorylates Ikaros in vivo and that this phosphorylation impairs Ikaros function. Here, we show that the activity of Casein Kinase II (CK2) is more than 5-fold increased in primary B-ALL cells as compared to normal bone marrow in kinase assays. We tested whether CK2 inhibition can enhance the binding of Ikaros to cell cycle-promoting genes and enhance Ikaros transcriptional repressor activity. Treatment of leukemia cell lines, as well as primary B-ALL cells, with different CK2 inhibitors resulted in enhanced Ikaros binding to its target genes, as evidenced by quantitative chromatin immunoprecipitation (qChIP). This was associated with transcriptional repression of the Ikaros target genes that function as cell cycle promoters, as evidenced by quantitative real-time PCR (qRT-PCR), and by cell cycle arrest in treated cells. CK2 inhibition had a particularly pronounced effect on Ikaros activity in cells of primary high-risk B-ALL, which carry a deletion of one Ikaros allele. When these cells were untreated Ikaros was unable to bind promoters of its target genes. CK2 inhibition restored Ikaros binding to promoters of the cell cycle-promoting genes resulting in their repression. These results suggest that CK2 inhibition has an anti-proliferative effect on leukemia cells and that these effects occur via enhanced Ikaros tumor suppressor activity as a transcriptional repressor of cell cycle-promoting genes. We tested whether CK2 inhibition can produce an anti-leukemia effect in vivo using two preclinical human-mouse xenograft models of B-ALL: Nalm6 xenografts and primary patient-derived xenografts produced from high-risk leukemia cells that have a deletion of one Ikaros allele. Our results demonstrate that CK2 inhibition results in a potent anti-leukemia therapeutic effect in both xenograft models as evidenced by a reduction of leukemia burden in bone marrow and in spleen of treated mice, along with their prolonged survival as compared to controls. In summary, our results demonstrate the therapeutic efficacy of a novel therapeutic approach for high-risk leukemia – restoration of Ikaros tumor suppressor activity via inhibition of CK2. These results provide a rationale for the use of CK2 inhibitors in clinical trial for high-risk leukemia, including cases with deletion of one Ikaros allele. Supported by the National Institutes of Health R01 HL095120, and the Four Diamonds Fund Endowment. Disclosures No relevant conflicts of interest to declare.

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Ezzat, Shereen, Shunjiang Yu y Sylvia L. Asa. "The Zinc Finger Ikaros Transcription Factor Regulates Pituitary Growth Hormone and Prolactin Gene Expression through Distinct Effects on Chromatin Accessibility". Molecular Endocrinology 19, n.º 4 (1 de abril de 2005): 1004–11. http://dx.doi.org/10.1210/me.2004-0432.

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Abstract The Ikaros transcription factors perform critical functions in the control of lymphohematopoiesis and immune regulation. Family members contain multiple zinc fingers that mediate DNA binding but have also been implicated as part of a complex chromatin-remodeling network. We show here that Ikaros is expressed in pituitary mammosomatotrophs where it regulates the GH and prolactin (PRL) genes. Ikaros was detected by Northern and Western blotting in GH4 pituitary mammosomatotroph cells. Wild-type Ikaros (Ik1) inhibits GH mRNA and protein expression but stimulates PRL mRNA and protein levels. Ikaros does not bind directly to the proximal GH promoter but abrogates the effect of the histone deacetylation inhibitor trichostatin A on this region. Ikaros selectively deacetylates histone 3 residues on the proximal transfected or endogenous GH promoter and limits access of the Pit1 activator. In contrast, Ikaros acetylates histone 3 on the proximal PRL promoter and facilitates Pit1 binding to this region in the same cells. These data provide evidence for Ikaros-mediated histone acetylation and chromatin remodeling in the selective regulation of pituitary GH and PRL hormone gene expression.

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Gowda, Chandrika, Chunhua Song, Sadie Steffens, Yali Ding, Bo Zhang, Feng Yue, Soumya Iyer et al. "CK2 Inhibitor CX4945 Shows Strong In Vivo Anti Leukemia Effect in AML Via Augmented Ikaros-Mediated Regulation of Global Epigenetic Landscape". Blood 134, Supplement_1 (13 de noviembre de 2019): 2522. http://dx.doi.org/10.1182/blood-2019-131200.

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Over-expression of Casein Kinase II (CK2) pro-oncogenic kinase in Acute Myelogenous Leukemia (AML) is associated with poor prognosis. Inhibition of CK2 by siRNAs or with the specific inhibitor, CX-4945, shows strong cytotoxic effects. CK2 is a ubiquitous, constitutively active serine/ threonine kinase which has been implicated in leukemia progression via multiple mechanisms. One of the well-established mechanism is CK2 mediated phosphorylation and impairment of tumor suppressor function of Ikaros transcription factor. Impaired function of Ikaros has been associated with the development of leukemia including AML. In B-cell lymphoblastic leukemia, CK2 inhibition has been shown to exert a therapeutic effect via restoration and/or enhancement of the tumor suppressor activity of the Ikaros protein. The mechanism of therapeutic action of CK2 inhibition in AML is largely unknown and in vivo efficacy CK2 inhibitors in AML has never been established. Here we report anti-leukemia effect of CX-4945 in preclinical models of AML and demonstrate mechanism of action of CK2 inhibitor via restoration of Ikaros driven global regulation of epigenetic landscape. In order to study the effect of CK2 inhibition on Ikaros function in AML, we used U937 - a human myelomonocytic leukemia cell line with high baseline CK2 expression. U937 cells were treated with specific CK2 inhibitor, CX4945 for 72 hours. CK2 activity and Ikaros phosphorylation was measured using CK2 kinase assay and in vivo labeling - radio immunoblot assay. Results showed significant decrease in CK2 activity and Ikaros phosphorylation with no change in overall expression of the Ikaros protein. Expression analysis using RNA sequencing showed that treatment with CX-4945 caused significant upregulation of genes controlling immunity, and inflammation; and downregulation of genes involved in nucleic acid metabolism, RNA processing, and translation. Analysis of global genome-wide Ikaros occupancy using Chromatin Immunoprecipitation followed by next generation sequencing (ChIP-seq) of CX4945 treated U937 cells demonstrated that CX-4945 treatment significantly increased the number of Ikaros binding sites as well as increased peak strength while minimally re-distributing Ikaros' global genomic occupancy. While increased binding to the Promoter, Gene Body, and Gene Desert elements in CX-4945-treated cells was similar, the increase in Ikaros' DNA binding to enhancers was particularly pronounced. Further analysis showed that enhanced Ikaros DNA binding following treatment with CX-4945, directly induces formation of de novo enhancers. In order to test whether enhanced DNA binding of Ikaros is accompanied by augmented Ikaros function in the global epigenetic regulation of gene expression. We determined and compared chromatin accessibility of U937 cells before and after treatment with CX-4945, using ATAC-seq. Results indicate that Ikaros-induced de novo open chromatin at distal regulatory regions controls genes involved in the negative regulation of biological processes and cellular metabolism. Overall, these data demonstrate that, augmented Ikaros DNA-binding following CK2 inhibition resulted in 1) Ikaros' pioneering activity, 2) Ikaros' ability to induce the de novo formation of enhancers and super-enhancers, and 3) Ikaros' ability to induce the de novo formation of active enhancers and to activate poised enhancers. Together, these data uncover novel Ikaros functions in regulating the epigenetic landscape and identifies CK2 as a critical regulator of Ikaros activity. Next, we treated AML xenograft model of luciferase labelled U937 cells with CX4945 via oral gavage at dose 200mg/kg/day for 3 weeks and demonstrated significantly lower leukemia burden in treated group as measured by decreased bio-luminescence imaging. In summary, these results demonstrate for the first time that CK2 inhibitor, CX-4945 has strong anti-leukemia effect in AML preclinical models. One of the mechanisms by which CX4945 exert a therapeutic effect in AML involves enhancing Ikaros' function as regulator of global epigenomic landscape. These results provide strong mechanistic basis to develop novel targeted combination therapies using CK2 inhibitors for treatment of AML. Further studies evaluating combination therapies using patient derived xenograft (PDX) models of AML are underway. Disclosures Payne: Elf Zone, Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

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Dovat, Sinsa, Chunhua Song, Kimberly J. Payne y Chandrika S. Gowda. "Targeting of Casein Kinase II (CK2) Enhances Ikaros-Mediated Control of the Cell Cycle Progression in Pre-Clinical Model of Pre-B-ALL." Blood 120, n.º 21 (16 de noviembre de 2012): 2431. http://dx.doi.org/10.1182/blood.v120.21.2431.2431.

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Abstract Abstract 2431 The Ikaros (IKZF1) gene encodes a DNA-binding zinc finger protein that functions as a tumor suppressor in leukemia. Defects in the Ikaros gene that lead to its decreased activity are associated with the development of B-cell precursor acute lymphoblastic leukemia (pre-B-ALL). However, the mechanisms by which Ikaros exerts its tumor suppressor activity, as well as the mechanisms that control the tumor suppressor function of Ikaros are poorly understood. Here, we report the identification of two novel Ikaros target genes, as well as a signal transduction pathway that regulates the Ikaros-mediated transcriptional control of these genes in pre-B ALL. We also present evidence that targeting the signal transduction pathway which regulates Ikaros transcriptional control is a potent therapeutic tool for treating pre-B ALL. Analysis of the promoter sequences of the CDC7 and the CDK6 genes revealed multiple evolutionarily-conserved Ikaros consensus binding sites. Using qChIP (quantitative chromatin immunoprecipitation assay) we found that Ikaros binds in vivo to the promoters of the CDC7 and CDK6 genes in the human Nalm6 pre-B ALL cell line, and in primary human pre-B ALL cells. This led to the hypothesis that Ikaros regulates transcription of CDC7 and CDK6 - genes whose expression is essential for cell cycle progression and cellular proliferation. The effect of Ikaros on CDC7 and CDK6 expression was studied using a transient co-transfection assay. Luciferase reporter plasmids containing the CDC7 or CDK6 promoter regions were co-transfected with or without Ikaros into 293T cells. Co-transfection of Ikaros led to decreased luciferase activity, suggesting that Ikaros acts as a repressor of the CDC7 and CDK6 upstream regulatory elements. Increased expression of Ikaros via retroviral transduction in Nalm6 cells resulted in decreased transcription of CDC7 and CDK6. Decreased transcription of these genes was associated with increased binding of Ikaros to their promoter regions as measured by qChIP. These results suggest that Ikaros negatively regulates transcription of CDC7 and CDK6, and thus negatively regulates cell cycle progression in pre-B cell leukemia. We have shown previously that phosphorylation of Ikaros by casein kinase II (CK2) inhibits Ikaros' ability to bind DNA and to regulate transcription of its target genes. CK2 activity is elevated in human leukemia. We tested whether the inhibition of CK2 affects the transcription of CDC7 and CDK6 in pre-B ALL in vitro and in vivo. In vitro treatment of Nalm6 pre-B ALL with TBB, a specific CK2 inhibitor, decreased transcription of CDC7 and CDK6 and was associated with increased binding of Ikaros to the promoters of these genes. Using an in vivo preclinical model of pre-B ALL we tested whether targeting of CK2 would affect transcription of CDC7 and CDK6. In vivo treatment of a human-mouse xenograft model of pre-B ALL with a CK2 inhibitor resulted in decreased transcription of CDC7 and CDK6 and strongly increased Ikaros binding to the promoters of these genes. The in vivo targeting of CK2 provided a strong anti-leukemia effect that resulted in the prolonged survival of treated mice as compared to controls. In summary, our results suggest that Ikaros exerts its tumor suppressor activity in pre-B ALL by repressing transcription of cell cycle-promoting genes. Targeting CK2 in vivo enhances Ikaros-mediated repression of cell cycle progression resulting in an anti-leukemia effect. These data demonstrate the efficacy of CK2 targeting as a treatment for pre-B ALL in a preclinical model. These results provide a mechanistic rationale and support for the use of CK2 inhibitors as a targeted treatment of pre-B ALL in early-stage clinical trials. Supported by National Institutes of Health R01 HL095120 and a St. Baldrick's Foundation Career Development Award (to S.D.). Disclosures: No relevant conflicts of interest to declare.

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Dovat, Sinisa, Zafer Gurel, Kimberly J. Payne y Marcela Popescu. "Dephosphorylation of Ikaros by a specific phosphatase regulates its function in chromatin remodeling (136.9)". Journal of Immunology 182, n.º 1_Supplement (1 de abril de 2009): 136.9. http://dx.doi.org/10.4049/jimmunol.182.supp.136.9.

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Abstract Ikaros encodes a zinc finger protein essential for lymphoid development. Ikaros localizes to pericentromeric heterochromatin (PC-HC) where it recruits target genes, resulting in their activation or repression via chromatin remodeling. Ikaros' function is controlled by post-translational modification. Our previous studies show that phosphorylation of Ikaros by CK2 kinase controls its PC-HC localization, and its ability to bind the upstream regulatory region (URE) and regulate expression of TdT during thymocyte differentiation. Here, we demonstrate, by co-immunoprecipitation, that Ikaros interacts in vivo with a specific phosphatase for which it is a substrate. Mutational analysis identified specific residues essential for Ikaros-phosphatase interaction. Mutant Ikaros protein with disrupted phosphatase interaction undergoes CK-2-mediated hyperphosphorylation that inhibits its ability to bind the TdT URE, and its PC-HC localization. Alanine mutations at the CK2-phosphorylated residues restore both Ikaros' DNA-binding ability and PC-HC localization, regardless of its ability to interact with the phosphatase. We propose a model whereby the regulation of TdT expression by Ikaros is controlled by CK2 kinase and interaction with a specific phosphatase and that the balance of these two signal transduction pathways is essential for normal T cell differentiation. Supported by NIH K22CA111392 (SD)

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35

Zhao, Wei, Tong-bing Chen y Hui Wang. "Ikaros is heterogeneously expressed in lung adenocarcinoma and is involved in its progression". Journal of International Medical Research 48, n.º 8 (agosto de 2020): 030006052094586. http://dx.doi.org/10.1177/0300060520945860.

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Objective The aim of the present study was to assess the expression of the Ikaros transcription factor (IKZF1) in lung adenocarcinoma and investigate whether expression levels of Ikaros are correlated with lung adenocarcinoma progression. Methods We conducted a retrospective study of 325 cases of resected stage I pulmonary adenocarcinoma, in which histological subtyping was performed according to the 2015 World Health Organization classification. We performed immunohistochemical examinations to assess expression of Ikaros in pulmonary adenocarcinomas and evaluated the correlation between Ikaros expression and cancer progression. Results Immunohistochemical staining was heterogeneous, with the majority of well-differentiated and moderately differentiated lung adenocarcinomas being weakly positive and the majority of the poorly differentiated lung adenocarcinomas exhibiting strong positive staining. Higher expression of Ikaros was associated with tumor recurrence or metastasis. Conclusions Ikaros is heterogeneously expressed in different subtypes of lung adenocarcinoma; higher expression of Ikaros was found to be associated with cancer progression.

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Jena, Nilamani, Ila Joshi, Toshimi Yoshida, Xiaoqing Qi, Jiangwen Zhang, Katia Georgopoulos y Richard A. Van Etten. "Ikaros Mutation Confers Integrin-Dependent Survival Of Pre-B Cells and Progression To Acute Lymphoblastic Leukemia". Blood 122, n.º 21 (15 de noviembre de 2013): 1259. http://dx.doi.org/10.1182/blood.v122.21.1259.1259.

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Abstract Deletion of the IKAROS DNA-binding domain generates dominant-negative isoforms that interfere with the transcriptional activity of the IKAROS family and correlate with poor prognosis in human precursor B cell acute lymphoblastic leukemias (B-ALL). In this study, we defined the role of the Ikaros family during pre-B cell differentiation, the stage from which human B-ALLs arise, by conditionally inactivating IKAROS DNA binding in the immediate precursors of pre-B cells in mice. We demonstrate a novel niche-dependent phase in early pre-B cell differentiation that supports self-renewal and proliferative expansion. Expression of dominant-negative IKAROS arrests cells in this state by augmenting integrin and MAPK signaling and attenuating pre-B cell receptor signaling and differentiation. Up-regulated genes in Ikaros mutant pre-B cells were highly enriched in pathways involved in focal adhesion and remodeling of the actin cytoskeleton. The mutant pre-B cells had increased β1 integrin-mediated adhesion and elevated levels of activated focal adhesion kinase (FAK), whereas treatment with a small molecule FAK inhibitor greatly reduced pre-B cell stromal adhesion and selectively induced apoptosis in Ikaros mutant but not WT pre-B cells. Transplantation of polyclonal Ikaros mutant pre-B cells into recipient mice resulted in long-latency oligoclonal pre-B-ALL, demonstrating that loss of IKAROS contributes to multistep B-leukemogenesis. The highly proliferative and aberrantly self-renewing phenotype of Ikaros-deficient pre-B cells illuminates mechanisms underlying human IKAROS mutant B-ALL and suggests new therapeutic strategies for treatment of this aggressive leukemia. Disclosures: Van Etten: Bristol Myers Squibb: Consultancy; Deciphera Pharmaceuticals: Consultancy; TEVA Pharmaceuticals: Consultancy, Research Funding.

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Schjerven, Hilde, Etapong F. Ayongaba, Ali Aghajanirefah, Jami McLaughlin, Donghui Cheng, Huimin Geng, Joseph R. Boyd et al. "Genetic analysis of Ikaros target genes and tumor suppressor function in BCR-ABL1+ pre–B ALL". Journal of Experimental Medicine 214, n.º 3 (11 de febrero de 2017): 793–814. http://dx.doi.org/10.1084/jem.20160049.

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Inactivation of the tumor suppressor gene encoding the transcriptional regulator Ikaros (IKZF1) is a hallmark of BCR-ABL1+ precursor B cell acute lymphoblastic leukemia (pre–B ALL). However, the mechanisms by which Ikaros functions as a tumor suppressor in pre–B ALL remain poorly understood. Here, we analyzed a mouse model of BCR-ABL1+ pre–B ALL together with a new model of inducible expression of wild-type Ikaros in IKZF1 mutant human BCR-ABL1+ pre–B ALL. We performed integrated genome-wide chromatin and expression analyses and identified Ikaros target genes in mouse and human BCR-ABL1+ pre–B ALL, revealing novel conserved gene pathways associated with Ikaros tumor suppressor function. Notably, genetic depletion of different Ikaros targets, including CTNND1 and the early hematopoietic cell surface marker CD34, resulted in reduced leukemic growth. Our results suggest that Ikaros mediates tumor suppressor function by enforcing proper developmental stage–specific expression of multiple genes through chromatin compaction at its target genes.

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Molnár, A., P. Wu, D. A. Largespada, A. Vortkamp, S. Scherer, N. G. Copeland, N. A. Jenkins, G. Bruns y K. Georgopoulos. "The Ikaros gene encodes a family of lymphocyte-restricted zinc finger DNA binding proteins, highly conserved in human and mouse." Journal of Immunology 156, n.º 2 (15 de enero de 1996): 585–92. http://dx.doi.org/10.4049/jimmunol.156.2.585.

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Abstract The Ikaros gene is an essential regulator in the development and homeostasis of the mouse lymphopoietic system. To study the role of the Ikaros gene in the human lymphopoietic system, we cloned and characterized human Ikaros cDNAs. In the human, as in the mouse, differential splicing of Ikaros primary transcripts generates a family of lymphoid-restricted zinc finger DNA binding proteins, highly conserved in sequence composition and relative expression to the mouse homologues. Expression of Ikaros isoforms is highly restricted to the lymphopoietic system and is particularly enriched in maturing thymocytes. The Ikaros gene maps at a syntenic locus located on the short arm of human chromosome 7 and on mouse chromosome 11 next to the epidermal growth factor receptor (Egfr). The high degree of conservation of the Ikaros gene at the genetic and expression levels strongly suggests that it plays a fundamental role in the ontogeny of the lymphopoietic system across species.

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Thomas, Rajan, Neelanjana Chunder, Chunxia Chen, Justin Taylor, Edward Pearce y Andrew Wells. "Ikaros silences the ifnγ gene during T cell anergy and T helper polarization (88.14)". Journal of Immunology 184, n.º 1_Supplement (1 de abril de 2010): 88.14. http://dx.doi.org/10.4049/jimmunol.184.supp.88.14.

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Abstract Ikaros is a zinc finger transcription factor required for lymphocyte development, but recent studies indicate that this factor also regulates peripheral T cell function. Our previous studies showed that Ikaros is a major repressor of il2 gene expression during the induction of T cell anergy, and in the present study, we have examined the role of Ikaros in ifnγ gene expression in CD4+ T cells. We find that Ikaros binds to the endogenous ifnγ and tbx21 loci, an event associated with increased DNA methylation at the ifnγ gene. Loss of Ikaros function in vitro resulted in increased IFNγ production by anergic T cells and Th2 cells, and was reinforced in Th2 cells by dysregulated expression of Tbet. Loss of Ikaros function in vivo led to an inappropriate Th1 response to the Th2 parasite S. mansoni, and also led to increased ifnγ gene expression and fatal intestinal immunopathology in a DSS model of colitis. Our results show that Ikaros is an important transcriptional repressor of Tbet and IFNγ expression, and further establish a role for Ikaros in T cell tolerance and T helper polarization.

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Ma, Shibin, Simanta Pathak, Malay Mandal, Long Trinh, Marcus R. Clark y Runqing Lu. "Ikaros and Aiolos Inhibit Pre-B-Cell Proliferation by Directly Suppressing c-Myc Expression". Molecular and Cellular Biology 30, n.º 17 (21 de junio de 2010): 4149–58. http://dx.doi.org/10.1128/mcb.00224-10.

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ABSTRACT Pre-B-cell expansion is driven by signals from the interleukin-7 receptor and the pre-B-cell receptor and is dependent on cyclin D3 and c-Myc. We have shown previously that interferon regulatory factors 4 and 8 induce the expression of Ikaros and Aiolos to suppress pre-B-cell proliferation. However, the molecular mechanisms through which Ikaros and Aiolos exert their growth inhibitory effect remain to be determined. Here, we provide evidence that Aiolos and Ikaros bind to the c-Myc promoter in vivo and directly suppress c-Myc expression in pre-B cells. We further show that downregulation of c-Myc is critical for the growth-inhibitory effect of Ikaros and Aiolos. Ikaros and Aiolos also induce expression of p27 and downregulate cyclin D3 in pre-B cells, and the growth-inhibitory effect of Ikaros and Aiolos is compromised in the absence of p27. A time course analysis further reveals that downregulation of c-Myc by Ikaros and Aiolos precedes p27 induction and cyclin D3 downregulation. Moreover, downregulation of c-Myc by Ikaros and Aiolos is necessary for the induction of p27 and downregulation of cyclin D3. Collectively, our studies identify a pre-B-cell receptor signaling induced inhibitory network, orchestrated by Ikaros and Aiolos, which functions to terminate pre-B-cell expansion.

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Brugmann, William y Susan Winandy. "Ikaros null mice demonstrate defects in dendritic cell development. (36.17)". Journal of Immunology 184, n.º 1_Supplement (1 de abril de 2010): 36.17. http://dx.doi.org/10.4049/jimmunol.184.supp.36.17.

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Abstract Ikaros is a transcription factor that is expressed almost exclusively in cells of the hematopoietic lineage. Ikaros null mice lack several hematopoietic cell lineages including some dendritic cell (DC) subsets. Additionally, several Ikaros null bone marrow (BM) progenitor populations have a decreased expression of the receptor tyrosine kinase, Flt3. DCs can be generated in vitro by culture of BM with either GM-CSF or Flt3L (the ligand for Flt3). Our studies find that loss of Ikaros leads to a specific defect in the ability of BM precursors to generate DCs in response to culture with Flt3L but not in response to culture with GM-CSF. Those DCs that do develop from the culture of Ikaros null BM with Flt3L have an activated phenotype with higher expression of MHC class II and the costimulatory molecules CD40, CD80 and CD86 than their wild type counterparts. An examination of gene expression in Ikaros null BM progenitors cultured with Flt3L shows an inappropriately low expression of Irf4, Irf8 and Spib, genes encoding transcription factors known to be important for DC development. Studies are currently underway to determine whether enforced expression of Ikaros, Flt3 or one of the above-mentioned transcription factors can rescue DC development upon culture of Ikaros null BM with Flt3L. These studies will provide a potential molecular mechanism for the impaired development of DCs in Ikaros null mice.

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Dovat, Sinisa, Zhanjun Li, Kimberly Payne y Chunhua Song. "Regulation of gene expression during thymocyte differentiation by Protein Phosphatase 1 (64.16)". Journal of Immunology 186, n.º 1_Supplement (1 de abril de 2011): 64.16. http://dx.doi.org/10.4049/jimmunol.186.supp.64.16.

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Abstract The goal of our research is to define signal transduction pathways that regulate thymocyte differentiation. We have previously reported that Protein Phosphatase 1 (PP1) directly dephosphorylates and regulates the activity of the Ikaros protein - a master regulator of lymphocyte differentiation (Popescu et al. J Biol Chem 2009 284:13869). We extended our studies to determine whether PP1-mediated dephoshorylation of Ikaros controls Ikaros’ function in regulating the expression of the terminal deoxynucleotidyl transferase (TdT) gene during thymocyte differentiation. An Ikaros mutant that is unable to interact with PP1 (IK 465/7A), and that is subsequently hyperphosphorylated, was compared to the wild type Ikaros for DNA-binding affinity toward the TdT promoter and for ability to repress transcription of the TdT gene using a luciferase reporter assay. Chromatin immunoprecipitation assays showed that the loss of PP1-mediated dephosphorylation of Ikaros leads to decreased Ikaros DNA-binding affinity for the D’ regulatory element of the TdT promoter in vivo. The IK 465/7A mutant also failed to repress transcription of TdT in the luciferase reporter assay, suggesting that Ikaros’ interaction with PP1 and subsequent dephosphorylation is essential for its function as repressor of TdT transcription. Results suggest that the PP1 signal transduction pathway regulates thymocyte differentiation by controlling the function of Ikaros and transcriptional repression of the TdT gene.

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Thomas, Rajan M., Liqing Wang, Chunxia Chen, Wayne W. Hancock y Andrew D. Wells. "Foxp3 cooperates with Ikaros to control the suppressive function of regulatory T cells". Journal of Immunology 202, n.º 1_Supplement (1 de mayo de 2019): 69.23. http://dx.doi.org/10.4049/jimmunol.202.supp.69.23.

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Abstract Ikaros (encoded by Ikzf1) is a lymphocyte-specific transcription factor that controls a wide spectrum of T cell functions, including T helper differentiation, cytokine production, and tolerance in response to antigenic stimuli. Using heterozygous and dominant-negative mouse models, we have shown previously that Ikaros controls IL-2 production by conventional T cells, T helper differentiation, CD8+ effector differentiation, and anergy induction. While the role of Ikaros in many T cell subsets has been established, its role in Treg-mediated peripheral tolerance has not been examined. To examine the Treg-specific role of Ikaros, we generated Ikzf1-fl/fl-Foxp3-YFP-Cre+ mouse with conditional deletion of Ikaros in Tregs. Ikzf1-fl/fl-Foxp3-YFP-Cre+ mouse exhibited enlarged secondary lymphoid tissues, with increased frequencies of effector memory Tconv and Treg. We show that Ikaros expression by Tregs is required for immune tolerance in an allogenic cardiac transplant model. While CD28- and CD40L-blockade induced long-term cardiac allograft tolerance in control recipients, Ikzf1-fl/fl-Foxp3-YFP-Cre+ recipients rejected the allografts in a short duration (p<0.01). We show that Ikaros forms a complex with Foxp3, which is required for Foxp3 to bind to and repress inflammatory cytokine genes. Ikaros is also required for normal iTreg development in vitro, as TGF-B/IL-2-induced iTreg development is impaired in conventional CD4+ T cells with reduced Ikaros activity. These studies suggest that Ikaros interacts with Foxp3 and directs Foxp3 to exert its suppressive function in Tregs.

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Schjerven, Hilde, Princess Rodriguez, Danielle Hagen, Marit Rasmussen, Etapong F. Ayongaba y Seth Frietze. "Ikaros regulates B-cell tolerance". Journal of Immunology 200, n.º 1_Supplement (1 de mayo de 2018): 40.14. http://dx.doi.org/10.4049/jimmunol.200.supp.40.14.

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Abstract B-cell development and activation are tightly regulated at multiple steps to ensure a protective immune response, and at the same time avoiding harmful self-reactivity and autoimmunity. Ikaros is a transcription factor that is critical for B-cell development, as demonstrated by the complete lack of B-cells in Ikaros-null mice. Furthermore, Ikaros is shown to play important roles also at later stages of B-cell development, but the precise roles of Ikaros at different stages of B-cell development is still not fully understood. In recent years, Ikaros (encoded by the IKZF1 gene) has been linked to autoimmune disease in humans through both genome-wide association studies (GWAS) as well as recent reports of germline IKZF1 mutations in patients with autoimmune disease. However, the mechanisms underlying altered Ikaros function and the development of autoimmunity are not known. We previously developed Ikaros-mutant mouse models with targeted deletions of the exons encoding the DNA-binding zinc finger 1 (ZnF1) or ZnF4, and found that both mutants have B cells, but display selective partial defects at different stages of B-cell development. We recently found that the Ikzf1-ZnF4-mutant strain displays very high levels of serum Anti-Nuclear Antibodies (ANA) at young age, a hallmark of autoimmune disease. This indicates that Ikaros (and specifically exon 6 encoding ZnF4) is required to regulate B-cell tolerance, and we hypothesize that Ikaros regulates this, at least in part, by establishing a chromatin structure that sets restrictions on B-cell responses to limit autoreactive B cells. We are using our Ikaros-mutant mice to further study the role of Ikaros in B-cell development and tolerance, and will present our results to-date at the meeting.

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Reyes-Hernández, José L., Aslak Kappel Hansen y Alexey Solodovnikov. "Ikaros navarretei (Coleoptera, Staphylinidae, Staphylininae), a new apterous rove beetle species from high elevations in Colombia". Alpine Entomology 6 (11 de mayo de 2022): 13–18. http://dx.doi.org/10.3897/alpento.6.80349.

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A new species of the xanthopygine genus Ikaros Chatzimanolis & Brunke, 2021 is described from Colombia: Ikaros navarreteisp. nov. Illustrations and a key are provided to identify the four known species of Ikaros.

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Schjerven, Hilde, Etapong F. Ayongaba, Princess Rodriguez y Seth Frietze. "Ikaros regulates epigenetic and transcriptional programs in progenitor B cell leukemia". Journal of Immunology 200, n.º 1_Supplement (1 de mayo de 2018): 103.26. http://dx.doi.org/10.4049/jimmunol.200.supp.103.26.

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Abstract Hematopoietic cell development is tightly controlled by a network of transcriptional and epigenetic regulators, many of which are mutated or have altered expression in hematological malignancies. Ikaros is a transcription factor that is critical for the proper development of several hematopoietic lineages, and essential for the B-cell lineage. It is recognized as a critical tumor suppressor in precursor B-cell lineage acute lymphoblastic leukemia (pre-B ALL), and is emerging to play roles also in other hematopoietic malignancies. In pre-B ALL, Ikaros mutations are particularly prevalent in the Ph+ (BCR-ABL1+) and ‘Ph-like’ subgroups of leukemia, and Ikaros mutations correlate with poor prognosis. To study the mechanisms of Ikaros tumor suppressor function, we developed a mouse model and a human model system with selective perturbation of Ikaros in Ph+ pre-B ALL cells. This has revealed conserved deregulated genes and pathways, and underscored the role of Ikaros in regulating progenitor-restricted gene programs. Furthermore, our recent studies have highlighted the role of Ikaros in regulation of chromatin structure, and revealed a novel role in epigenetic regulation. It is challenging to therapeutically target mutations in a tumor suppressor factor. It is therefore important to understand the mechanism of action and downstream targets to elucidate targetable vulnerabilities of the Ikaros-mutant leukemic cells. Investigating the tumor suppressor role of Ikaros in developing B cells also sheds light on its role in normal B cell development. We are using our newly established models of Ikaros-mutated pre-B ALL to study the underlying molecular mechanisms and downstream targets, and will present our results to-date at the meeting.

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Witkowski, Matthew T., Yifang Hu, Kathryn G. Roberts, Judith M. Boer, Mark D. McKenzie, Grace J. Liu, Oliver D. Le Grice et al. "Conserved IKAROS-regulated genes associated with B-progenitor acute lymphoblastic leukemia outcome". Journal of Experimental Medicine 214, n.º 3 (11 de febrero de 2017): 773–91. http://dx.doi.org/10.1084/jem.20160048.

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Genetic alterations disrupting the transcription factor IKZF1 (encoding IKAROS) are associated with poor outcome in B lineage acute lymphoblastic leukemia (B-ALL) and occur in >70% of the high-risk BCR-ABL1+ (Ph+) and Ph-like disease subtypes. To examine IKAROS function in this context, we have developed novel mouse models allowing reversible RNAi-based control of Ikaros expression in established B-ALL in vivo. Notably, leukemias driven by combined BCR-ABL1 expression and Ikaros suppression rapidly regress when endogenous Ikaros is restored, causing sustained disease remission or ablation. Comparison of transcriptional profiles accompanying dynamic Ikaros perturbation in murine B-ALL in vivo with two independent human B-ALL cohorts identified nine evolutionarily conserved IKAROS-repressed genes. Notably, high expression of six of these genes is associated with inferior event–free survival in both patient cohorts. Among them are EMP1, which was recently implicated in B-ALL proliferation and prednisolone resistance, and the novel target CTNND1, encoding P120-catenin. We demonstrate that elevated Ctnnd1 expression contributes to maintenance of murine B-ALL cells with compromised Ikaros function. These results suggest that IKZF1 alterations in B-ALL leads to induction of multiple genes associated with proliferation and treatment resistance, identifying potential new therapeutic targets for high-risk disease.

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48

Nichogiannopoulou, Aliki, Maryanne Trevisan, Steve Neben, Christoph Friedrich y Katia Georgopoulos. "Defects in Hemopoietic Stem Cell Activity in Ikaros Mutant Mice". Journal of Experimental Medicine 190, n.º 9 (1 de noviembre de 1999): 1201–14. http://dx.doi.org/10.1084/jem.190.9.1201.

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Here we provide evidence that the Ikaros family of DNA binding factors is critical for the activity of hemopoietic stem cells (HSCs) in the mouse. Mice homozygous for an Ikaros null mutation display a >30-fold reduction in long-term repopulation units, whereas mice homozygous for an Ikaros dominant negative mutation have no measurable activity. The defect in HSC activity is also illustrated by the ability of wild-type marrow to repopulate unconditioned Ikaros mutants. A progressive reduction in multipotent CFU-S14 (colony-forming unit-spleen) progenitors and the earliest erythroid-restricted precursors (BFU-E [burst-forming unit-erythroid]) is also detected in the Ikaros mutant strains consistent with the reduction in HSCs. Nonetheless, the more mature clonogenic erythroid and myeloid precursors are less affected, indicating either the action of a compensatory mechanism to provide more progeny or a negative role of Ikaros at later stages of erythromyeloid differentiation. In Ikaros mutant mice, a decrease in expression of the tyrosine kinase receptors flk-2 and c-kit is observed in the lineage-depleted c-kit+Sca-1+ population that is normally enriched for HSCs and may in part contribute to the early hemopoietic phenotypes manifested in the absence of Ikaros.

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49

Dhanyamraju, Pavan Kumar, Soumya Iyer, Gayle Smink, Yevgeniya Bamme, Preeti Bhadauria, Jonathon L. Payne, Elanora Dovat, Morgann Klink y Yali Ding. "Transcriptional Regulation of Genes by Ikaros Tumor Suppressor in Acute Lymphoblastic Leukemia". International Journal of Molecular Sciences 21, n.º 4 (18 de febrero de 2020): 1377. http://dx.doi.org/10.3390/ijms21041377.

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Regulation of oncogenic gene expression by transcription factors that function as tumor suppressors is one of the major mechanisms that regulate leukemogenesis. Understanding this complex process is essential for explaining the pathogenesis of leukemia as well as developing targeted therapies. Here, we provide an overview of the role of Ikaros tumor suppressor and its role in regulation of gene transcription in acute leukemia. Ikaros (IKZF1) is a DNA-binding protein that functions as a master regulator of hematopoiesis and the immune system, as well as a tumor suppressor in acute lymphoblastic leukemia (ALL). Genetic alteration or functional inactivation of Ikaros results in the development of high-risk leukemia. Ikaros binds to the specific consensus binding motif at upstream regulatory elements of its target genes, recruits chromatin-remodeling complexes and activates or represses transcription via chromatin remodeling. Over the last twenty years, a large number of Ikaros target genes have been identified, and the role of Ikaros in the regulation of their expression provided insight into the mechanisms of Ikaros tumor suppressor function in leukemia. Here we summarize the role of Ikaros in the regulation of the expression of the genes whose function is critical for cellular proliferation, development, and progression of acute lymphoblastic leukemia.

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50

Ge, Zheng, Xing Guo, Jianyong Li, Melanie Hartman, Yuka Imamura Kawasawa, Sinisa Dovat y Chunhua Song. "Clinical Significance of High C-MYC and Low MYCBP2 Expression and Their Association with Ikaros Dysfunction in Adult Acute Lymphoblastic Leukemia". Blood 126, n.º 23 (3 de diciembre de 2015): 3713. http://dx.doi.org/10.1182/blood.v126.23.3713.3713.

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Abstract Objective: The Myc proteins are transcription factors with essential roles in cell growth and proliferation through their ability to regulate gene expression. MYC binding protein 2(MYCBP2) is probable E3 ubiquitin-protein ligase and its function in leukemia is undetermined. IKZF1 encodes a kruppel-like zinc finger protein Ikaros that is essential for normal hematopoiesis and acts as a tumor suppressor in acute lymphoblastic leukemia(ALL). IKZF1 deletion is associated with the development of ALL and poor clinical outcome. This study aimed to explore the expression of c-MYC and MYCBP2 and their correlation with clinical features in adult ALL, as well as the mechanism by which Ikaros directly regulates c-MYC/MYCBP2 expression in ALL. Methods: Quantitative PCR (qPCR) was performed to explore the expression of c-MYC and MYCBP2 in 151 newly diagnosed adult patients with ALL. The correlations of c-MYC/MYCBP2 expression with clinical parameters and survival status were analyzed. In addition, luciferase assay, quantitative Chromatin Immunoprecipitation (qChIP) and Ikaros shRNA knockdown were performed to further explore the mechanism underlying regulation of c-MYC/MYCBP2 expression. Results: Expression of c-MYC is significantly higher and MYCBP2 is significantly lower in both B-ALL and T-ALL patients compared with that in normal controls. C-MYC expression is also negatively co-related with the MYCBP2 in ALL cohorts. The patients with c-MYC high and MYCBP2 low expression (c-MYChigh +MYCBP2low) showed higher median white blood cell counts (WBC) (101.5×109/L vs 29.4×109/L, P =0.007), incidence of splenomegaly and liver infiltration (75.0% vs 33.3%, P =0.004;75.0% vs19.4%, P =0.000), percentage of CD34(+) and CD33(+) cells (90.0% vs 61.3%, P =0.025; 80.0% vs 25.8%, P =0.000) and a lower percentage of complete remission (CR) rate (60.0% vs 92.0%,P =0.027) compared with that of patients with c-MYC low and MYCBP2 high expression (c-MYClow +MYCBP2high). Notably, our Ikaros ChIP-seq data showed strong Ikaros binding peaks in the promoter region of both c-MYC and MYCBP2. The qChIP assay showed that Ikaros significantly binds to c-MYC and MYCBP2 promoter regions in both Nalm6 B-ALL and Molt4 T-ALL cells. Moreover, expression of Ikaros suppressed c-MYC but increased MYCBP2 expression in both Nalm6 and CEM T-ALL cells. Conversely, Ikaros knockdown induced the increase of c-MYC but decrease of MYCBP2 in Nalm6 and CEM cells. Ikaros activator,Ck2 inhibitor TBB suppress c-MYC and increase MYCBP2 expression in a dose-dependent manner in Nalm6 and CEM cells. Ikaros knockdown with shRNA could block the TBB-induced suppression of c-MYC and increase of MYCBP2 expression. These data indicated that both c-MYC and MYCBP2 are direct Ikaros targets in ALL and Ikaros regulates their expression. Importantly, we also observed Ikaros binding to c-MYC and MYCBP2 promoters in primary B-All and T-ALL. The expression of c-MYC significantly increased and MYCBP2 decreased in patients with Ikaros deletion compared to that of Ikaros wild type. These data indicated Ikaros regulatory effect on c-MYC and MYCBP2 in ALL patients and Ikaros deletion is one of the reasons for expression change of c-MYC and MYCBP2 in the patients. Conclusion: We observed the expression of c-MYC significantly increased and MYCBP2 decreased in adult ALL patients. C-MYC high and MYCBP2 low expression is correlated with high-risk leukemia. Ikaros dysfunction is one of the reasons underlying c-MYC high and MYCBP2 low expression in the patients. Our data revealed the oncogenic effect of Ikaros/MYCBP2/c-MYC on oncogenesis in adult ALL, also suggested CK2 inhibitor exert its anti-leukemia effect through Ikaros-mediated regulation on c-MYC and MYCBP2 expression in leukemia. Disclosures No relevant conflicts of interest to declare.

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