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Oncogenic gene expression and epigenetic remodeling of cis-regulatory elements in ASXL1-mutant chronic myelomonocytic leukemia
Myeloid neoplasms are clonal hematopoietic stem cell disorders driven by the sequential acquisition of recurrent genetic lesions. Truncating mutations in the chromatin remodeler ASXL1 (ASXL1(MT)) are associated with a high-risk disease phenotype with increased proliferation, epigenetic therapeutic r...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8931048/ https://www.ncbi.nlm.nih.gov/pubmed/35301312 http://dx.doi.org/10.1038/s41467-022-29142-6 |
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author | Binder, Moritz Carr, Ryan M. Lasho, Terra L. Finke, Christy M. Mangaonkar, Abhishek A. Pin, Christopher L. Berger, Kurt R. Mazzone, Amelia Potluri, Sandeep Ordog, Tamas Robertson, Keith D. Marks, David L. Fernandez-Zapico, Martin E. Gaspar-Maia, Alexandre Patnaik, Mrinal M. |
author_facet | Binder, Moritz Carr, Ryan M. Lasho, Terra L. Finke, Christy M. Mangaonkar, Abhishek A. Pin, Christopher L. Berger, Kurt R. Mazzone, Amelia Potluri, Sandeep Ordog, Tamas Robertson, Keith D. Marks, David L. Fernandez-Zapico, Martin E. Gaspar-Maia, Alexandre Patnaik, Mrinal M. |
author_sort | Binder, Moritz |
collection | PubMed |
description | Myeloid neoplasms are clonal hematopoietic stem cell disorders driven by the sequential acquisition of recurrent genetic lesions. Truncating mutations in the chromatin remodeler ASXL1 (ASXL1(MT)) are associated with a high-risk disease phenotype with increased proliferation, epigenetic therapeutic resistance, and poor survival outcomes. We performed a multi-omics interrogation to define gene expression and chromatin remodeling associated with ASXL1(MT) in chronic myelomonocytic leukemia (CMML). ASXL1(MT) are associated with a loss of repressive histone methylation and increase in permissive histone methylation and acetylation in promoter regions. ASXL1(MT) are further associated with de novo accessibility of distal enhancers binding ETS transcription factors, targeting important leukemogenic driver genes. Chromatin remodeling of promoters and enhancers is strongly associated with gene expression and heterogenous among overexpressed genes. These results provide a comprehensive map of the transcriptome and chromatin landscape of ASXL1(MT) CMML, forming an important framework for the development of novel therapeutic strategies targeting oncogenic cis interactions. |
format | Online Article Text |
id | pubmed-8931048 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-89310482022-04-01 Oncogenic gene expression and epigenetic remodeling of cis-regulatory elements in ASXL1-mutant chronic myelomonocytic leukemia Binder, Moritz Carr, Ryan M. Lasho, Terra L. Finke, Christy M. Mangaonkar, Abhishek A. Pin, Christopher L. Berger, Kurt R. Mazzone, Amelia Potluri, Sandeep Ordog, Tamas Robertson, Keith D. Marks, David L. Fernandez-Zapico, Martin E. Gaspar-Maia, Alexandre Patnaik, Mrinal M. Nat Commun Article Myeloid neoplasms are clonal hematopoietic stem cell disorders driven by the sequential acquisition of recurrent genetic lesions. Truncating mutations in the chromatin remodeler ASXL1 (ASXL1(MT)) are associated with a high-risk disease phenotype with increased proliferation, epigenetic therapeutic resistance, and poor survival outcomes. We performed a multi-omics interrogation to define gene expression and chromatin remodeling associated with ASXL1(MT) in chronic myelomonocytic leukemia (CMML). ASXL1(MT) are associated with a loss of repressive histone methylation and increase in permissive histone methylation and acetylation in promoter regions. ASXL1(MT) are further associated with de novo accessibility of distal enhancers binding ETS transcription factors, targeting important leukemogenic driver genes. Chromatin remodeling of promoters and enhancers is strongly associated with gene expression and heterogenous among overexpressed genes. These results provide a comprehensive map of the transcriptome and chromatin landscape of ASXL1(MT) CMML, forming an important framework for the development of novel therapeutic strategies targeting oncogenic cis interactions. Nature Publishing Group UK 2022-03-17 /pmc/articles/PMC8931048/ /pubmed/35301312 http://dx.doi.org/10.1038/s41467-022-29142-6 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Binder, Moritz Carr, Ryan M. Lasho, Terra L. Finke, Christy M. Mangaonkar, Abhishek A. Pin, Christopher L. Berger, Kurt R. Mazzone, Amelia Potluri, Sandeep Ordog, Tamas Robertson, Keith D. Marks, David L. Fernandez-Zapico, Martin E. Gaspar-Maia, Alexandre Patnaik, Mrinal M. Oncogenic gene expression and epigenetic remodeling of cis-regulatory elements in ASXL1-mutant chronic myelomonocytic leukemia |
title | Oncogenic gene expression and epigenetic remodeling of cis-regulatory elements in ASXL1-mutant chronic myelomonocytic leukemia |
title_full | Oncogenic gene expression and epigenetic remodeling of cis-regulatory elements in ASXL1-mutant chronic myelomonocytic leukemia |
title_fullStr | Oncogenic gene expression and epigenetic remodeling of cis-regulatory elements in ASXL1-mutant chronic myelomonocytic leukemia |
title_full_unstemmed | Oncogenic gene expression and epigenetic remodeling of cis-regulatory elements in ASXL1-mutant chronic myelomonocytic leukemia |
title_short | Oncogenic gene expression and epigenetic remodeling of cis-regulatory elements in ASXL1-mutant chronic myelomonocytic leukemia |
title_sort | oncogenic gene expression and epigenetic remodeling of cis-regulatory elements in asxl1-mutant chronic myelomonocytic leukemia |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8931048/ https://www.ncbi.nlm.nih.gov/pubmed/35301312 http://dx.doi.org/10.1038/s41467-022-29142-6 |
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