Abstract 1513: Epigenetic regulation of CD117 expression in B-cell acute lymphoblastic leukemia by Ikaros and histone deacetylase HDAC1
| العنوان: | Abstract 1513: Epigenetic regulation of CD117 expression in B-cell acute lymphoblastic leukemia by Ikaros and histone deacetylase HDAC1 |
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| المؤلفون: | Jonathon L. Payne, Chandrika Gowda, Shriya Kane, Kimberly J. Payne, Mario Soliman, Chunhua Song, Meixan Xiang, Sinisa Dovat |
| المصدر: | Cancer Research. 78:1513-1513 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Cancer Research, Myeloid leukemia, Biology, medicine.disease, Chromatin remodeling, HDAC1, Chromatin, Leukemia, Oncology, Cancer research, medicine, Transcriptional regulation, Histone deacetylase, Chromatin immunoprecipitation |
| الوصف: | The type III receptor tyrosine kinase, CD117, functions as a receptor for stem cell factor (SCF) and is encoded by the c-kit gene. During hematopoiesis, CD117 is normally expressed in hematopoietic stem cells, multipotent progenitors, common lymphoid progenitors, and early-stage thymocytes. Overexpression and/or activating mutations of c-kit have been demonstrated in acute myeloid leukemia (AML), early T-cell precursor acute lymphoblastic leukemia (ETP-ALL), and B-cell acute lymphoblastic leukemia (B-ALL). It has been suggested that increased expression of CD117 is associated with stem-like phenotype and worse clinical outcomes in AML and T-ALL. The regulation of expression of c-kit in leukemia is still largely unknown. Here we report that transcription of c-kit in B-ALL is regulated by the Ikaros tumor suppressor protein and histone deacetylase HDAC1. Global genome-wide binding studies using ChIP-seq, demonstrate the occupancy of both Ikaros and HDAC1 at the promoter of the c-kit gene in B-ALL cells. Ikaros and HDAC1 binding to the c-kit promoter was confirmed by quantitative chromatin immunoprecipitation (qChIP). Overexpression of Ikaros via retroviral transduction results in reduced transcription of c-kit in B-ALL cells. Consistent with this, Ikaros knock-down with shRNA results in increased transcription of c-kit in B-ALL. These data suggest that Ikaros represses transcription of c-kit. Ikaros overexpression was associated with increased HDAC1 occupancy while Ikaros knock-down resulted in reduced HDAC1 binding to the promoter of the c-kit gene. We tested whether Ikaros-mediated transcriptional repression of c-kit requires HDAC1 activity. Results showed that inhibition of HDAC1 activity with a pan-histone deacetylase inhibitor, trichostatin (TSA), or a specific HDAC1 inhibitor, MS-275, abolishes Ikaros' ability to repress c-kit transcription in luciferase reporter assays. Molecular inhibition of HDAC1 with shRNA confirmed that HDAC1 activity is essential for Ikaros-mediated transcriptional repression of c-kit. A serial qChIP assay spanning the c-kit promoter was used to analyze the epigenetic changes that are associated with Ikaros and HDAC1 binding at the c-kit promoter. Results showed that increased Ikaros and HDAC1 occupancy at the c-kit promoter in B-ALL cells results in enrichment for the markers of the repressive chromatin, H3K9me3 and H3K27me3, as well as reduced occupancy of H3K9ac, a marker of active chromatin. In conclusion, the presented results show that the expression of c-kit in B-ALL is regulated at the transcriptional level by Ikaros and HDAC1 via chromatin remodeling. These data provide a novel insight into the role of Ikaros in both tumor suppression and transcriptional regulation of gene expression in B-cell acute lymphoblastic leukemia. Citation Format: Shriya Kane, Jonathon L. Payne, Mario Soliman, Chandrika Gowda, Meixan Xiang, Chunhua Song, Kimberly J. Payne, Sinisa Dovat. Epigenetic regulation of CD117 expression in B-cell acute lymphoblastic leukemia by Ikaros and histone deacetylase HDAC1 [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 1513. |
| تدمد: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.am2018-1513 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::e55e711ec8425050e73e73a7bbc15009 https://doi.org/10.1158/1538-7445.am2018-1513 |
| رقم الانضمام: | edsair.doi...........e55e711ec8425050e73e73a7bbc15009 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15387445 00085472 |
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| DOI: | 10.1158/1538-7445.am2018-1513 |