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  • American Association for Cancer Research (AACR)  (57)
  • 1
    Online Resource
    Online Resource
    Abstract 3512: Ikaros regulation of the BCL6/BACH2 axis and its clinical relevance in acute lymphoblastic leukemia
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 3512-3512
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 3512-3512
    Abstract: B-Cell CLL/Lymphoma 6 (BCL6) is a proto-oncogene that is highly expressed in acute lymphoblastic leukemia (ALL). BTB and CNC Homology 1 Basic Leucine Zipper Transcription Factor 2 (BACH2) is a suppressor of transcription. The BACH2-BCL6 balance controls selection at the pre-B cell receptor checkpoint by regulating p53 expression. However, the underlying mechanism and the clinical relevance of the BCL6/BACH2 axis are unknown. Here, we found that Ikaros, a tumor suppressor encoded by IKZF1, directly binds to both the BCL6 and BACH2 promoters where it suppresses BCL6 and promotes BACH2 expression in B-cell ALL (B-ALL) cells. Casein kinase 2 (CK2) inhibitors increase Ikaros function thereby inhibiting BCL6 and promoting BACH2 expression in an Ikaros-dependent manner. We also found that the expression of BCL6 is higher while BACH2 expression is lower in patients with B-ALL than normal bone marrow control. High BCL6 and low BACH2 expression is associated with high leukemic cell proliferation, unfavorable clinical and laboratory features, and inferior outcomes. Moreover, IKZF1 deletion is associated with high BCL6 and low BACH2 expression in B-ALL patients. CK2 inhibitors increase Ikaros binding to the promoter of BCL6 and BACH2 and suppress BCL6 while promoting BACH2 expression in the primary B-ALL cells. Our data indicates that Ikaros regulates expression of the BCL6/BACH2 axis in B-ALL. High BCL6 and low BACH2 expression are associated with Ikaros dysregulation and have a potential effect on the development of B-ALL. Citation Format: Chunhua Song, Zheng Ge, Jianyong Li, Baoan Chen, Elanora Dovat, Katarina Dovat, Jonathon Payne, Sinisa Dovat. Ikaros regulation of the BCL6/BACH2 axis and its clinical relevance in acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3512. doi:10.1158/1538-7445.AM2017-3512
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-3512
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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  • 2
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    Online Resource
    Abstract 1047: Dual targeting of CK2 and MTOR as a novel therapeutic approach for high-risk B-cell acute lymphoblastic leukemia
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1047-1047
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1047-1047
    Abstract: Genomic defect and Casein Kinase II-mediated hyper-phosphorylation of Ikaros tumor suppressor cause the loss of function of Ikaros, and Ikaros dysfunction is characteristics of high-risk B-cell acute lymphoblastic leukemia (HR B-ALL) with poor prognosis. The increased activation of the PI3K/AKT/mTOR pathway is also observed in HR B-ALL and identifies mTOR as an attractive therapeutic target in HR B-ALL. Here, we report that Ikaros represses MTOR transcription and Ikaros' ability to repress MTOR in leukemia is impaired by oncogenic CK2 kinase. Treatment with the CK2 inhibitor, CX-4945, enhances Ikaros activity as a repressor of MTOR, resulting in reduced expression of MTOR in HR B-ALL. Thus, we designed a novel therapeutic approach that implements dual targeting of mTOR: direct inhibition of the mTOR protein (with rapamycin), in combination with Ikaros-mediated transcriptional repression of the MTOR gene (using the CK2 inhibitor, CX-4945). Combination treatment with rapamycin and CX-4945 shows synergistic therapeutic effects in vitro and in patient-derived xenografts from HR B-ALL. These data suggest that such therapy has the potential to reduce the death rate in HR B-ALL. The dual targeting of oncogene transcription, combined with inhibition of the corresponding oncoprotein provides a paradigm for a novel precision medicine approach for treating hematological malignancies. Citation Format: Chunhua Song, Zheng Ge, Yali Ding, Bihua Tan, Elanora Dovat, Yiping Yang, Chandrika Gowda, Sinisa Dovat. Dual targeting of CK2 and MTOR as a novel therapeutic approach for high-risk B-cell acute lymphoblastic leukemia [abstract] . In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1047.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-1047
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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  • 3
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    Abstract 1984: The Ikaros tumor suppressor regulates transcription of genes involved in cell signaling in human leukemia.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 1984-1984
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 1984-1984
    Abstract: The IKZF1 gene encodes Ikaros, a DNA binding zinc finger protein that is essential for normal hematopoietic differentiation. Deletion or mutation of Ikaros has been associated with a both T and B-cell acute lymphoblastic leukemia (ALL), as well as acute and chronic myelogenous leukemias (AML and CML). Deletion of an Ikaros allele has also been identified as a poor prognostic marker in childhood B-ALL. Thus, Ikaros is established as a major tumor suppressor in hematopoietic malignancies. The Ikaros protein can activate or repress target gene expression via chromatin remodeling. The specific mechanisms by which Ikaros exerts its tumor suppressor activities are unknown. We have defined genome-wide occupancy of Ikaros in human leukemia using ChIP-SEQ and identified a large number of potential Ikaros target genes. The quantitative Chromatin Immunoprecipitation assay (qChIP) was used to identify genes whose expression is directly regulated by Ikaros. Using this technique we show that Ikaros binds to the promoter region of a gene that is part of a pro-oncogenic pathway, as well as a tumor suppressor gene. Both genes are essential components of cell signaling pathways. The promoter regions of the two novel target genes were cloned into luciferase reporter constructs and used to transiently transfect HEK 293T cells that were co-transfected with Ikaros or empty vector (as a control). Luciferase reporter assays demonstrate that Ikaros suppresses transcription of the gene that is involved in oncogenic transformation, while it positively regulates transcription of the tumor suppressor gene. In summary, we have identified two novel Ikaros target genes. Our results suggest that Ikaros exerts its tumor suppression function by regulating the expression of target genes involved in pro-oncogenic and tumor suppressor signaling in leukemia cells. These data identify mechanisms of the tumor suppressor activity of Ikaros in leukemia. Citation Format: Jonathon L. Payne, Justin Sloane, Rebekka M. Bamert, Elanora Dovat, Hui Li, Marie Bulathsinghala, Chandrika Gowda, Chunhua Song, Sinisa Dovat. The Ikaros tumor suppressor regulates transcription of genes involved in cell signaling in human leukemia. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1984. doi:10.1158/1538-7445.AM2013-1984
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-1984
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 4
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    Abstract 5540: Transcriptional control of signaling pathways in T-cell lymphoblastic leukemia by Ikaros tumor suppressor
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 5540-5540
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 5540-5540
    Abstract: Cellular proliferation in T-cell acute lymphoblastic leukemia is regulated by multiple signaling pathways. The Phosphoinositide 3-kinase (PI3K)/AKT pathway is frequently dysregulated in T-ALL. Targeting the PI3K pathway has shown promise as a novel therapeutic approach for T-ALL. However, regulation of the PI3K pathway is still not well understood. Here, we report that PI3K activity in T-ALL can be controlled by transcriptional regulation of key members of this pathway, PIK3CD and PIKFYVE. DNA binding analysis of primary T-ALL using qChIP revealed that the tumor suppressor protein, Ikaros, binds the promoter regions of PIK3CD and PIKFYVE. Since Ikaros acts as a regulator of transcription, we tested whether Ikaros binding to PIK3CD and PIKFYVE affects their expression. Overexpression of Ikaros results in reduced transcription of PIK3CD and PIKFYVE in T-ALL. Targeting Ikaros with a specific shRNA, resulted in increased transcription of PIK3CD and PIKFYVE in T-ALL. Together, these results demonstrate that Ikaros functions as a transcriptional repressor of both PIK3CD and PIKFYVE, and suggest that Ikaros can regulate the PI3K pathway in T-ALL. It has been previously shown that Ikaros function in B-cell acute lymphoblastic leukemia is regulated by oncogenic Casein Kinase II (CK2). We tested whether Ikaros ability to repress transcription of PIK3CD and PIKFYVE is regulated by CK2. Inhibition of CK2 by a specific pharmacological inhibitor, CX-4945, resulted in increased Ikaros binding to the promoters of PIK3CD and PIKFYVE, as well as in transcriptional repression of both of these genes. These results suggest that Ikaros function as a repressor of PIK3CD and PIKFYVE transcription is impaired by CK2 in T-ALL. CK2 inhibition restores Ikaros-mediated transcriptional repression of PIK3CD and PIKFYVE, which results in downregulation of the PI3K pathway. In conclusion, the presented data demonstrate that the PI3K signaling pathway is regulated by transcriptional repression of PIK3CD and PIKFYVE by Ikaros in T-ALL. Results reveal interplay between two signaling pathways in T-ALL, CK2 and PI3K, where CK2 positively regulates the PI3K pathway by inhibiting Ikaros function. These data reveal novel mechanisms that regulate cellular proliferation in T-ALL. Citation Format: Tommy Hu, Mario Soliman, Malika Kapadia, Elanora Dovat, Jonathan Payne, Chunhua Song, Sinisa Dovat. Transcriptional control of signaling pathways in T-cell lymphoblastic leukemia by Ikaros tumor suppressor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5540. doi:10.1158/1538-7445.AM2017-5540
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-5540
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 5
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    Abstract 409: Regulation of chromatin remodeling in leukemia by Ikzf1 and Casein Kinase II
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 409-409
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 409-409
    Abstract: Ikzf1 (Ikaros) encodes a zinc finger protein that binds DNA and regulates gene expression via chromatin remodeling. The loss of Ikaros activity due to genetic or functional inactivation results in leukemia with a poor prognosis. The goal of our project is to determine the mechanism by which Ikaros regulates chromatin remodeling in human leukemia. Previous studies showed that Ikaros function in leukemia is controlled through its direct phosphorylation by Casein Kinase II (CK2). Treatment of leukemia cells with CK2 inhibitors results in enhanced Ikaros activity, which leads to cessation of cell growth. We have studied the mechanism by which inhibition of CK2 regulates Ikaros-induced epigenetic changes in leukemia. The human Nalm6 pre-B cell leukemia was treated with CK2 inhibitor, and the epigenetic signature of the histone modifications H3K9ac and H3K9me3 were determined using chromatin immunoprecipitation coupled with next generation sequencing (ChIP-SEQ). H3K9ac histone modification is associated with positive regulation of gene expression, while H3K9me3 is associated with the formation of heterochromatin and repression. The enrichment of particular histone modifications was confirmed by quantitative chromatin immunoprecipitation (qChIP). The results demonstrated that the inhibition of CK2 activity in leukemia results in a marked alteration in the epigenetic signature of both H3K9ac and H3K9me3 compared to untreated cells. This is associated with altered Ikaros binding to its target genes following CK2 inhibition. Current bioinformatics analysis is directed toward establishing a link between epigenetic modifications and Ikaros binding in leukemia. These results suggest that CK2 and Ikaros regulate gene transcription via epigenetic modifications and chromatin remodeling in leukemia. Citation Format: Jonathon L. Payne, Carlos M. Casiano, Kimberly J. Payne, Justin Sloane, Elanora Dovat, Chunhua Song, Sinisa Dovat. Regulation of chromatin remodeling in leukemia by Ikzf1 and Casein Kinase II. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 409. doi:10.1158/1538-7445.AM2014-409
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-409
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 6
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    Abstract 4463: Epigenetic regulation of gene expression in high-risk B-cell acute lymphoblastic leukemia by Casein Kinase II
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 4463-4463
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 4463-4463
    Abstract: Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood. Although advances in the treatment of ALL have resulted in a high cure rate for this disease, high-risk ALL is characterized by both resistance to conventional chemotherapy and a poor prognosis. The pathogenesis of high-risk ALL is still not understood. Casein Kinase II (CK2) is an oncogenic kinase that is overexpressed in both B-cell ALL (B-ALL) and T-cell ALL (T-ALL) and is associated with poor outcome. Inhibition of CK2 results in a strong therapeutic effect in a preclinical model of leukemia. However, the mechanism by which CK2 promotes oncogenesis in leukemia is unknown. Here, we studied how CK2 regulates expression of histone demethylase KDM5B in ALL. The KDM5B gene encodes a histone demethylase that regulates levels of histone modification H3K4me3 in leukemia. Molecular inhibition of CK2 using shRNA that targets the CK2 catalytic subunit resulted in transcriptional repression of KDM5B in ALL as evidenced by qRT-PCR. A similar effect was observed when leukemia cells were treated with the CK2 inhibitor CX-4945. Inhibition of CK2 resulted in reduced expression of KDM5B with an increase in the global cellular level of H3K4me3 as evidenced by Western blot. The use of quantitative chromatin immunoprecipitation (qChIP) showed that CK2 inhibition enhances DNA binding of the Ikaros tumor suppressor to the promoter of the KDM5B gene. Ikaros is a DNA-binding protein that regulates transcription of its target genes via chromatin remodeling. Loss of Ikaros function results in high-risk ALL. Serial qChIP analysis demonstrated that the increased Ikaros binding to the KDM5B promoter following CK2 inhibition is associated with an alteration of the epigenetic signature at the DNA region that surrounds the Ikaros binding site. Specifically, enhanced Ikaros binding results in increased occupancy of the H3K27me3 histone modification, along with a reduced occupancy of the H3K9ac histone modification at the KDM5B promoter. These results are consistent with the formation of heterochromatin and transcriptional repression. We tested the effect of CK2 inhibitors on Ikaros-mediated repression of KDM5B in primary, high-risk B-ALL cells that have a deletion of one Ikaros allele. Results showed that CK2 inhibition in high-risk B-ALL restores Ikaros binding to KDM5B promoter and represses KDM5B transcription. These data suggest that the inhibition of CK2 controls expression of KDM5B and the global H3K4me3 level in ALL by regulating the function of Ikaros as a transcriptional repressor of KDM5B. This presented data demonstrates the role of the CK2-Ikaros signaling axis in the regulation of both gene expression and the global epigenetic signature in ALL, and provide a mechanistic insight into the role of CK2 in the pathogenesis of ALL. Citation Format: Morgann Loaec, Jonathon Payne, Elanora Dovat, Chunhua Song, Kimberly J. Payne, Sinisa Dovat. Epigenetic regulation of gene expression in high-risk B-cell acute lymphoblastic leukemia by Casein Kinase II. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4463.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-4463
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 7
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    Abstract 3504: Regulation of cell cycle progression by Ikaros in leukemia
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 3504-3504
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 3504-3504
    Abstract: Control of cell cycle progression is achieved by the coordinated function of a large set of genes that are highly conserved in eukaryotic organisms. Malignant cells have impaired regulation of cell cycle progression which results in uncontrolled cellular proliferation. Thus, understanding the regulation of cell cycle progression in malignant cells is essential to advance our knowledge of the process of malignant transformation and for designing novel treatments. Ikaros is a zinc finger protein that acts as a tumor suppressor in leukemia. The loss of Ikaros activity due to deletion or mutation has been associated with the development of high-risk B-cell acute lymphoblastic leukemia (B-ALL), as well as with T-cell ALL and acute myelogenous leukemia (AML). Ikaros binds DNA and regulates transcription of its target genes via chromatin remodeling. The mechanism of Ikaros tumor suppressor activity is largely unknown. Here, we present evidence that Ikaros regulates cell cycle progression in leukemia. Using quantitative Chromatin Immunoprecipitation assay (qChIP), we demonstrate that Ikaros binds in vivo to promoter regions of several genes that regulate cell cycle progression in B-ALL cell lines and in primary cells from patients with B-ALL. To study how Ikaros regulates transcription of these genes, luciferase reporter assays were performed. The promoter regions of three Ikaros target genes were cloned into luciferase reporter constructs. Each of these constructs has been co-transfected with Ikaros or an empty vector (as a negative control) into HEK 293T cells. Results showed that Ikaros represses transcription of the three genes that promote cell cycle progression. Overexpression of Ikaros in leukemia cells by retroviral transduction results in reduced transcription of the cell cycle promoting genes, as evidenced by quantitative real-time PCR (qRT-PCR), as well as cell cycle arrest. These data suggest that Ikaros regulates cell cycle progression in leukemia by direct repression of the transcription of the genes that promote cell cycle progression, and identifies one mechanism of Ikaros function as a tumor suppressor in leukemia. Citation Format: Elanora Dovat, Jonathon Payne, Carlos M. Casiano, Justin Sloane, Chandrika Gowda, Kimberly J. Payne, Sinisa Dovat, Chunhua Song. Regulation of cell cycle progression by Ikaros in leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3504. doi:10.1158/1538-7445.AM2014-3504
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-3504
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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  • 8
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    Abstract 286: Synergistic efficacy of CK2 inhibitor with common chemotherapy drugs by restoring Ikaros function in high-risk ALL
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 286-286
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 286-286
    Abstract: Objective: IKZF1 gene-coding protein, Ikaros functions as a leukemia suppressor. Casein Kinase II activity is overexpressed in acute lymphoblastic leukemia (ALL) and CK2-mediated-dysfunction of Ikaros is one of the key reason for high-risk ALL and CK2 inhibitor -CX4945 treatment shows high therapeutic efficacy on high-risk ALL. The anti-apoptotic factors are highly expressed in leukemia and the commonly-used 1st-line chemotherapy drugs exerts the anti-tumor effect by suppression of anti-apoptosis signaling. Ikaros binding peaks was identified in the promoter of anti-apoptotic genes by ChIP-seq, suggesting Ikaros regulation on their expression. These observations also suggest the synergistic effect of restoring Ikaros function with common chemotherapy durgs in ALL. Methods: The ChIP-seq and qChIP assays were performed to determine the enrichment of Ikaros and H3K4me3 in promotor of the genes. Lentiviral Ikaros or IKZF1 shRNA were used for functional analysis. WST-1 cell proliferation assay, Annexin-V staining plus flow cytometry and Patients-derived xenograft mouse (PDX) model were used for observing the anti-tumor effect in vitro and in vivo, respectively. Results: ChIP-seq and qChIP assays identified Ikaros binding peaks in the promoter of anti-apoptotic genes in cell-lines and patients’ samples. Ikaros overexpression suppresses but IKZF1 knockdown promotes the gene expression. CX-4945 suppresses the expression of the genes by decreasing the H3k27me3 enrichment in an Ikaros and HDAC1-dependent manner in B-ALL cells. The anti-apoptotic gene is significantly up-regulated in ALL patients. CX-4945+chemoterhapy drugs significantly induces the cell proliferation arrest and apoptosis compared to single drugs in vitro and also show the synergistic effect analyzed by CalcuSyn software. CX-4945+chemotherapy drugs significantly reduced the total leukemia cells and % leukemic cells in the three high-risk B-ALL Patient Derived Xenograft (PDX) mice model compared to that of single drugs, which indicated that their synergistic therapeutic efficacy on leukemia development. Conclusion: Ikaros suppressed anti-apoptotic gene expression through histone modification in ALL. CK2 inhibitor, CX-4945 by restoring Ikaros function have synergistic efficacy with common chemotherapy drugs on high-risk B-ALL. Citation Format: chunhua song, Zheng Ge, Chandrika Gowda, Yali Ding, Jonathon Payne, Bihua Tan, Nathalia M. Cury, Elanora Dovat, Zhijun Zhao, Xiaoguang Lyu, Mary McGrath, Dhimant Desai, Soumya lyer, Pavan K. DhanyamRaju, Kimberly J. Payne, Sinisa Dovat. Synergistic efficacy of CK2 inhibitor with common chemotherapy drugs by restoring Ikaros function in high-risk ALL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 286.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-286
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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  • 9
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    Abstract 5542: Regulation of cell cycle control in T-cell acute lymphoblastic leukemia by Ikaros and Casein Kinase II
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 5542-5542
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 5542-5542
    Abstract: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that represents a therapeutic challenge. Next-generation sequencing revealed that a subset of T-ALL harbors inactivating mutations or deletion of one allele of the IKZF1 tumor suppressor. These data suggest that IKZF1 acts as a tumor suppressor in T-ALL. The IKZF1 gene encodes the Ikaros protein that functions as a regulator of transcription and a tumor suppressor in B cell acute lymphoblastic leukemia. However, the molecular mechanism of Ikaros tumor suppressor function in T-ALL is unclear. Using quantitative chromatin immunoprecipitation (qChIP), we determined that Ikaros binds to the promoter regions of the CDC2 and CDC7 cell cycle genes in primary T-ALL cells in vivo. Gain-of function experiments showed that Ikaros overexpression in T-ALL results in reduced expression of CDC2 and CDC7, as evidenced by quantitative RT-PCR (qRT-PCR) and Western blot. The knock-down of Ikaros with shRNA in T-ALL cells resulted in increased transcription of CDC2 and CDC7 as indicated by qRT-PCR. These data suggest that Ikaros can regulate cell cycle progression in T-ALL by repressing transcription of the CDC2 and CDC7 genes. Next, we studied the mechanisms that regulate Ikaros’ ability to repress CDC2 and CDC7 in T-ALL. Ikaros function as a transcriptional repressor is regulated by Casein Kinase II (CK2). CK2 is overexpressed in hematopoietic malignancies and increased expression of CK2 results in T-ALL in murine models. We tested the effect of CK2 inhibition on Ikaros’ ability to regulate transcription of CDC2 and CDC7 in human T-ALL. Molecular inhibition of CK2 with shRNA against the CK2 catalytic subunit resulted in reduced transcription of CDC2 and CDC7, as evidenced by qRT-PCR. This was associated with increased DNA-binding of Ikaros to promoters of CDC2 and CDC7, as shown by qChIP. These data suggest that CK2 impairs Ikaros’ ability to transcriptionally repress CDC2 and CDC7 and to regulate cell cycle progression in T-ALL. Inhibition of CK2 enhances transcriptional repression of CDC2 and CDC7 by Ikaros, resulting in improved control of cell cycle progression in T-ALL. In conclusion, our results show that control of cell cycle progression in T-ALL occurs trough Ikaros-mediated transcriptional regulation of CDC2 and CDC7. Overexpession of CK2 impairs Ikaros ability to repress CDC2 and CDC7 expression, which contributes to deregulation of cell cycle control in T-ALL. Results suggest a potential mechanism of therapeutic action of CK2 inhibitors for the treatment of T-ALL. Note: This abstract was not presented at the meeting. Citation Format: Mario A. Soliman, Tommy Hu, Malika Kapadia, Elanora Dovat, Yali Ding, Chunhua Song, Jonathon L. Payne, Sinisa Dovat. Regulation of cell cycle control in T-cell acute lymphoblastic leukemia by Ikaros and Casein Kinase II [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5542. doi:10.1158/1538-7445.AM2017-5542
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-5542
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2036785-5
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    Abstract 2527: Regulation of mitotic progression in T-cell acute lymphoblastic leukemia by the Ikaros tumor suppressor
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2527-2527
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2527-2527
    Abstract: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that represents a therapeutic challenge. Next-generation sequencing revealed that a subset of high-risk T-ALL which is associated with poor prognosis harbor inactivating mutations or deletion of one allele of the IKZF1 tumor suppressor. The IKZF1 gene encodes the Ikaros protein that functions as a regulator of transcription and a tumor suppressor. However, the molecular mechanism of Ikaros' tumor suppressor function in T-ALL is unclear. The use of quantitative chromatin immunoprecipitation (qChIP) determined that Ikaros binds to the promoter regions of Anaphase Promoting Complex Subunit 1 (ANAPC1) and Anaphase Promoting Complex Subunit 7 (ANAPC7) cell cycle genes in T-ALL primary cells in vivo. ANAPC1 and ANAPC7 genes encode proteins whose function is essential for progression through mitosis, as well as through the G1 phase of the cell cycle. Ikaros overexpression in T-ALL via retroviral transduction, results in reduced expression of ANAPC1and ANAPC7, as evidenced by quantitative RT-PCR (qRT-PCR) and Western blot. The luciferase reporter assay further confirmed Ikaros' function as a transcriptional repressor of ANAPC1 and ANAPC7. The knock-down of Ikaros with shRNA in T-ALL resulted in increased transcription of ANAPC1 and ANAPC7, as evidenced by qRT-PCR. These data suggest that Ikaros can regulate mitotic progression in T-ALL by repressing transcription of ANAPC1 and ANAPC7 genes. Next, we studied the mechanisms that regulate Ikaros' ability to repress ANAPC1 and ANAPC7 in T-ALL. Ikaros' function as a transcriptional repressor is regulated by Casein Kinase II (CK2). CK2 is overexpressed in hematopoietic malignancies and increased expression of CK2 results in T-ALL in murine models. We tested the effect of CK2 inhibition on Ikaros' ability to regulate transcription of ANAPC1 and ANAPC7 in human T-ALL. Molecular inhibition of CK2 with shRNA against the CK2 catalytic subunit resulted in reduced transcription of ANAPC1 and ANAPC7, as evidenced by qRT-PCR. This was associated with increased DNA-binding of Ikaros to the promoters of ANAPC1 and ANAPC7, as evidenced by qChIP. These data suggest that CK2 impairs Ikaros' ability to transcriptionally repress ANAPC1 and ANAPC7 and to regulate mitotic progression in T-ALL. Inhibition of CK2 enhances transcriptional repression of ANAPC1 and ANAPC7 by Ikaros, resulting in the cell cycle arrest of T-ALL. In conclusion, our results show that mitotic progression in T-ALL is controlled by transcriptional regulation of ANAPC1 and ANAPC7 by Ikaros. Overexpression of CK2 impairs Ikaros' ability to repress ANAPC1 and ANAPC7 expression, which contributes to deregulation of the control of mitotic progression in T-ALL. Results suggest the novel therapeutic mechanism of CK2 inhibitors for treatment of T-ALL. Citation Format: Jonathon L. Payne, Elanora Dovat, Mario Soliman, Chunhua Song, Sinisa Dovat. Regulation of mitotic progression in T-cell acute lymphoblastic leukemia by the Ikaros tumor suppressor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2527.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-2527
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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