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  • 11
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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
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  • 12
    Online Resource
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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
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  • 13
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    Regulation of the epigenetic signature in leukemia by Ikaros (800.5)
    Wiley ; 2014
    In:  The FASEB Journal Vol. 28, No. S1 ( 2014-04)
    Details
    In: The FASEB Journal, Wiley, Vol. 28, No. S1 ( 2014-04)
    Type of Medium: Online Resource
    ISSN: 0892-6638 , 1530-6860
    URL: Issue
    URL: Article
    DOI: 10.1096/fsb2.v28.S1
    DOI: 10.1096/fasebj.28.1_supplement.800.5
    Language: English
    Publisher: Wiley
    Publication Date: 2014
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    SSG: 12
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  • 14
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    High efficacy of Azacitidine plus HAG in acute myeloid leukemia: an open-label, single-arm, multi-center, phase 2 study
    Springer Science and Business Media LLC ; 2022
    In:  Blood Cancer Journal Vol. 12, No. 10 ( 2022-10-28)
    Details
    In: Blood Cancer Journal, Springer Science and Business Media LLC, Vol. 12, No. 10 ( 2022-10-28)
    Type of Medium: Online Resource
    ISSN: 2044-5385
    URL: Article
    DOI: 10.1038/s41408-022-00740-3
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 15
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    Characterization of the DNA binding of Ikaros protein using three dimensional modeling and rapid prototyping technology
    Wiley ; 2010
    In:  The FASEB Journal Vol. 24, No. S1 ( 2010-04)
    Details
    In: The FASEB Journal, Wiley, Vol. 24, No. S1 ( 2010-04)
    Type of Medium: Online Resource
    ISSN: 0892-6638 , 1530-6860
    URL: Issue
    URL: Article
    DOI: 10.1096/fsb2.v24.S1
    DOI: 10.1096/fasebj.24.1_supplement.lb60
    Language: English
    Publisher: Wiley
    Publication Date: 2010
    detail.hit.zdb_id: 1468876-1
    SSG: 12
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  • 16
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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
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  • 17
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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
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 18
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    Abstract 2537: Regulation of LMO2 oncogene expression in high-risk B-cell acute lymphoblastic leukemia
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2537-2537
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2537-2537
    Abstract: LIM domain only protein 2 (LMO2) is an oncogene that is overexpressed in a subset of B-cell acute lymphoblastic leukemia (B-ALL). The mechanisms that regulate LMO2 expression in B-ALL are still unknown. Here, we show that transcription of LMO2 in B-ALL is regulated by Ikaros, a tumor suppressor protein, which is encoded by the IKZF1 gene, and whose deletion is associated with development of high-risk B-ALL. The use of global chromatin immunoprecipitation coupled with the next-generation sequencing (ChIP-seq) studies in primary human B-ALL cells and in cell lines revealed a strong Ikaros occupancy at the promoter of the LMO2 gene. Ikaros binding to the LMO2 promoter was confirmed by quantitative chromatin immunoprecipitation (qChIP). We tested the role of Ikaros in regulating LMO2 transcription in B-ALL using gain-of-function and loss-of-function experiments. A luciferase reporter assay with the LMO2 promoter showed that Ikaros directly represses LMO2 transcription. Overexpression of Ikaros in B-ALL via retroviral transduction was associated with strongly reduced expression of LMO2. Furthermore, Ikaros knock-down with shRNA, resulted in increased transcription of LMO2 in B-ALL cells. These results suggest that Ikaros represses transcription of LMO2 in B-ALL. Since Ikaros' function in B-ALL is negatively regulated by pro-oncogenic Casein Kinase II (CK2), we tested whether CK2 inhibition affects Ikaros-mediated repression of LMO2. Both molecular inhibition with shRNA, and pharmacological inhibition of CK2 with a specific CK2 inhibitor, CX-4945, resulted in reduced expression of LMO2. Inhibition of CK2 was also associated with increased Ikaros occupancy at the LMO2 promoter. In high-risk B-ALL that have deletion of a single copy of the IKZF1 gene, Ikaros does not bind to the LMO2 promoter. Treatment of primary B-ALL cells that have IKZF1 haploinsufficiency restores Ikaros binding to the LMO2 promoter and results in reduced LMO2 expression. In conclusion, our data demonstrate that Ikaros and CK2 regulate transcription and overall expression of the LMO2 oncogene in B-ALL. Our results identify a novel mechanism of therapeutic action of CK2 inhibitors in high-risk B-ALL—repression of LMO2 expression via restoration of Ikaros' tumor suppressor function. Citation Format: Yali Ding, Jonathon L. Payne, Shriya Kane, Elanora Dovat, Mario Soliman, Chunhua Song, Sinisa Dovat. Regulation of LMO2 oncogene expression in high-risk B-cell acute lymphoblastic leukemia [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 2537.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-2537
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 19
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    Ikaros regulation of the BCL6/BACH2 axis and its clinical relevance in acute lymphoblastic leukemia
    Impact Journals, LLC ; 2017
    In:  Oncotarget Vol. 8, No. 5 ( 2017-01-31), p. 8022-8034
    Details
    In: Oncotarget, Impact Journals, LLC, Vol. 8, No. 5 ( 2017-01-31), p. 8022-8034
    Type of Medium: Online Resource
    ISSN: 1949-2553
    URL: Issue
    URL: Article
    DOI: 10.18632/oncotarget.v8i5
    DOI: 10.18632/oncotarget.14038
    Language: English
    Publisher: Impact Journals, LLC
    Publication Date: 2017
    detail.hit.zdb_id: 2560162-3
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