High frequency of Ikaros isoform 6 expression in acute myelomonocytic and monocytic leukemias: implications for up-regulation of the antiapoptotic protein Bcl-XL in leukemogenesis

Yagi, T.; Hibi, Shigeyoshi; Takanashi, Mami; Kano, Gen; Tabata, Yasuhiro; Imamura, Toshihiko; Inaba, Tohru; Morimoto, Akira; Todo, Shinjiro; Imashuku, Shinsaku

doi:10.1182/blood.v99.4.1350

Cited by 73 publications

(78 citation statements)

References 20 publications

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“…Studies of mice with a disruption in the Ikaros gene demonstrate that Ikaros acts as a tumor suppressor (6). In humans, impaired Ikaros activity has been associated with the development of infant T-cell acute lymphoblastic leukemia (ALL) (7), adult B cell ALL (8), myelodysplastic syndrome (9), acute myeloid leukemia (10), and adult and juvenile chronic myelogenous leukemia (11). Recently, the deletion of Ikaros has been demonstrated in more than 30% of childhood leukemias, whereas a single copy or the complete absence of Ikaros was observed in more than 80% of patients with bcr-abl-positive acute lymphoblastic leukemia (12,13).…”

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confidence: 99%

Ikaros Stability and Pericentromeric Localization Are Regulated by Protein Phosphatase 1

Popescu

Gurel

Ronni

et al. 2009

Journal of Biological Chemistry

124

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Ikaros encodes a zinc finger protein that is involved in gene regulation and chromatin remodeling. The majority of Ikaros localizes at pericentromeric heterochromatin (PC-HC) where it regulates expression of target genes. Ikaros function is controlled by posttranslational modification. Phosphorylation of Ikaros by CK2 kinase determines its ability to bind DNA and exert cell cycle control as well as its subcellular localization. We report that Ikaros interacts with protein phosphatase 1 (PP1) via a conserved PP1 binding motif, RVXF, in the C-terminal end of the Ikaros protein. Point mutations of the RVXF motif abolish Ikaros-PP1 interaction and result in decreased DNA binding, an inability to localize to PC-HC, and rapid degradation of the Ikaros protein. The introduction of alanine mutations at CK2-phosphorylated residues increases the half-life of the PP1-nonbinding Ikaros mutant. This suggests that dephosphorylation of these sites by PP1 stabilizes the Ikaros protein and prevents its degradation. In the nucleus, Ikaros forms complexes with ubiquitin, providing evidence that Ikaros degradation involves the ubiquitin/proteasome pathway. In vivo, Ikaros can target PP1 to the nucleus, and a fraction of PP1 colocalizes with Ikaros at PC-HC. These data suggest a novel function for the Ikaros protein; that is, the targeting of PP1 to PC-HC and other chromatin structures. We propose a model whereby the function of Ikaros is controlled by the CK2 and PP1 pathways and that a balance between these two signal transduction pathways is essential for normal cellular function and for the prevention of malignant transformation.

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mentioning

confidence: 99%

Ikaros Stability and Pericentromeric Localization Are Regulated by Protein Phosphatase 1

Popescu

Gurel

Ronni

et al. 2009

Journal of Biological Chemistry

124

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“…4,6 We and others have found high levels of Ik6 expression in human leukaemias; these have ranged from B and T acute lymphoblastic leukaemias, [7][8][9][10][11] chronic myelogenous leukaemia 12 to acute myeloid leukaemias. 13 Ik6 overexpression has also been detected in human pituitary tumours. 14 Alternative pre-mRNA splicing has been found associated with cancer pathogenesis.…”

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confidence: 88%

“…[7][8][9][10][11][12][13] Moreover, ectopic expression of Ik6 in myeloid-and lymphoid cytokine-dependent cell lines has shown that Ik6 can delay cell death upon growth factor withdrawal. 9,13 In this study, we investigate the effect of Ik6 overexpression in murine haematopoietic progenitor cells using colony-forming assays and in an in vivo transplantation assay. We found that Ik6 can immortalise murine haematopoietic progenitor cells in myeloid conditions suggesting that Ik6 can confer a cell growth advantage to haematopoietic progenitor cells in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…17 Ik6 has been demonstrated to have a role in cell survival, since expression of Ik6 in cytokine-dependent cells efficiently delays cell death upon growth factor withdrawal. 9,13 Forced expression of Ik6 in human cord blood CD341 cells can impair B cell differentiation. 18 Since Ik6 overexpression is found in many leukaemias, it is possible that Ik6 per se may have an oncogenic action.…”

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confidence: 99%

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The Ikaros splice isoform, Ikaros 6, immortalizes murine haematopoietic progenitor cells

Ruiz

Williams

Brady

2008

Intl Journal of Cancer

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Alternative pre-mRNA splicing is emerging as a major control point in both the initiation and progression of tumourigenesis. Overexpression of the dominant negative Ikaros splice isoform, Ik6, is found in many human cancers particularly leukaemias. Ik6 has been demonstrated to have a role in cell survival in both myeloid-and lymphoid cytokine-dependent cell lines. To investigate the oncogenic potential of Ik6, we retrovirally transduced murine haematopoietic progenitor cells with Ik6 and have analysed the effects on proliferation and differentiation of these precursors using myeloid and lymphoid in vitro colony formation assays. We found that Ik6 can immortalize haematopoietic progenitor cells in myeloid conditions. Using an in vivo transplantation assay, we found that Ik6 favours reconstitution by haematopoietic precursors. These findings suggest that Ik6 may play an important role in the generation of the leukaemic phenotype.

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“…In humans, deletion of a single Ikaros allele is associated with the development of high-risk B-cell precursor acute lymphoblastic leukemia (B-ALL) 3 that is characterized by resistance to chemotherapy and poor prognosis (7)(8)(9). Alterations in the Ikaros have also been associated with T cell ALL (10,11) and myeloid leukemias (12)(13)(14)(15)(16). Ikaros regulates transcription of its target genes via chromatin remodeling (9).…”

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confidence: 99%

Transcriptional Regulation of JARID1B/KDM5B Histone Demethylase by Ikaros, Histone Deacetylase 1 (HDAC1), and Casein Kinase 2 (CK2) in B-cell Acute Lymphoblastic Leukemia

Wang

Song

Ding

et al. 2016

Journal of Biological Chemistry

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Impaired function of the Ikaros (IKZF1) protein is associated with the development of high-risk B-cell precursor acute lymphoblastic leukemia (B-ALL). The mechanisms of Ikaros tumorsuppressor activity in leukemia are unknown. Ikaros binds to the upstream regulatory elements of its target genes and regulates their transcription via chromatin remodeling. Here, we report that Ikaros represses transcription of the histone H3K4 demethylase, JARID1B (KDM5B). Transcriptional repression of JARID1B is associated with increased global levels of H3K4 trimethylation. Ikaros-mediated repression of JARID1B is dependent on the activity of the histone deacetylase, HDAC1, which binds to the upstream regulatory element of JARID1B in complex with Ikaros. In leukemia, JARID1B is overexpressed, and its inhibition results in cellular growth arrest. Ikaros-mediated repression of JARID1B in leukemia is impaired by pro-oncogenic casein kinase 2 (CK2). Inhibition of CK2 results in increased binding of the Ikaros-HDAC1 complex to the promoter of JARID1B, with increased formation of trimethylated histone H3 lysine 27 and decreased histone H3 Lys-9 acetylation. In cases of high-risk B-ALL that carry deletion of one Ikaros (IKZF1) allele, targeted inhibition of CK2 restores Ikaros binding to the JARID1B promoter and repression of JARID1B. In summary, the presented data suggest a mechanism through which Ikaros and HDAC1 regulate the epigenetic signature in leukemia: via regulation of JARID1B transcription. The presented data identify JARID1B as a novel therapeutic target in B-ALL and provide a rationale for the use of CK2 inhibitors in the treatment of high-risk B-ALL.IKZF1 encodes the Ikaros DNA-binding zinc finger protein (1-4). Ikaros is essential for normal hematopoiesis and acts as a tumor suppressor (5, 6). In humans, deletion of a single Ikaros allele is associated with the development of high-risk B-cell precursor acute lymphoblastic leukemia (B-ALL) 3 that is characterized by resistance to chemotherapy and poor prognosis (7-9). Alterations in the Ikaros have also been associated with T cell ALL (10, 11) and myeloid leukemias (12-16). Ikaros regulates transcription of its target genes via chromatin remodeling (9). Ikaros has been shown to directly bind histone deacetylases HDAC1 and HDAC2 and to associate with the chromatin remodeling complex NuRD through interaction with the Mi-2 protein (9, 17).Ikaros is hypothesized to recruit chromatin remodeling complexes to the regulatory elements of its target genes, resulting in chromatin modifications (primarily histone deacetylation) and transcriptional repression or activation of its target genes (18 -20). Mechanisms of Ikaros-mediated repression that are independent of histone deacetylase have also been described (18, 3 The abbreviations used are: B-ALL, B-cell precursor acute lymphoblastic leukemia; CK2, casein kinase 2; TSS, transcriptional start site; ALL, acute lymphoblastic leukemia; TBB, 4,5,6,7-tetrabromobenzotriazole; IK haploid , Ikaros haploinsufficiency; Ikaros-CTS, C terminus o...

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High frequency of Ikaros isoform 6 expression in acute myelomonocytic and monocytic leukemias: implications for up-regulation of the antiapoptotic protein Bcl-XL in leukemogenesis

Cited by 73 publications

References 20 publications

Ikaros Stability and Pericentromeric Localization Are Regulated by Protein Phosphatase 1

Ikaros Stability and Pericentromeric Localization Are Regulated by Protein Phosphatase 1

The Ikaros splice isoform, Ikaros 6, immortalizes murine haematopoietic progenitor cells

Transcriptional Regulation of JARID1B/KDM5B Histone Demethylase by Ikaros, Histone Deacetylase 1 (HDAC1), and Casein Kinase 2 (CK2) in B-cell Acute Lymphoblastic Leukemia

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