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ASXL1 mutations are associated with distinct epigenomic alterations that lead to sensitivity to venetoclax and azacytidine
The BCL2-inhibitor, Venetoclax (VEN), has shown significant anti-leukemic efficacy in combination with the DNMT-inhibitor, Azacytidine (AZA). To explore the mechanisms underlying the selective sensitivity of mutant leukemia cells to VEN and AZA, we used cell-based isogenic models containing a common...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455571/ https://www.ncbi.nlm.nih.gov/pubmed/34548471 http://dx.doi.org/10.1038/s41408-021-00541-0 |
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author | Rahmani, Nora E. Ramachandra, Nandini Sahu, Srabani Gitego, Nadege Lopez, Andrea Pradhan, Kith Bhagat, Tushar D. Gordon-Mitchell, Shanisha Pena, Bianca Rivera Kazemi, Mohammad Rao, Keshav Giricz, Orsi Maqbool, Shahina Bano Olea, Raul Zhao, Yongmei Zhang, Jinghang Dolatshad, Hamid Tittrea, Vickram Tatwavedi, Dharamveer Singh, Shalini Lee, Juseong Sun, Tianyu Steidl, Ulrich Shastri, Aditi Inoue, Daichi Abdel-Wahab, Omar Pellagatti, Andrea Gavathiotis, Evripidis Boultwood, Jacqueline Verma, Amit |
author_facet | Rahmani, Nora E. Ramachandra, Nandini Sahu, Srabani Gitego, Nadege Lopez, Andrea Pradhan, Kith Bhagat, Tushar D. Gordon-Mitchell, Shanisha Pena, Bianca Rivera Kazemi, Mohammad Rao, Keshav Giricz, Orsi Maqbool, Shahina Bano Olea, Raul Zhao, Yongmei Zhang, Jinghang Dolatshad, Hamid Tittrea, Vickram Tatwavedi, Dharamveer Singh, Shalini Lee, Juseong Sun, Tianyu Steidl, Ulrich Shastri, Aditi Inoue, Daichi Abdel-Wahab, Omar Pellagatti, Andrea Gavathiotis, Evripidis Boultwood, Jacqueline Verma, Amit |
author_sort | Rahmani, Nora E. |
collection | PubMed |
description | The BCL2-inhibitor, Venetoclax (VEN), has shown significant anti-leukemic efficacy in combination with the DNMT-inhibitor, Azacytidine (AZA). To explore the mechanisms underlying the selective sensitivity of mutant leukemia cells to VEN and AZA, we used cell-based isogenic models containing a common leukemia-associated mutation in the epigenetic regulator ASXL1. KBM5 cells with CRISPR/Cas9-mediated correction of the ASXL1(G710X) mutation showed reduced leukemic growth, increased myeloid differentiation, and decreased HOXA and BCL2 gene expression in vitro compared to uncorrected KBM5 cells. Increased expression of the anti-apoptotic gene, BCL2, was also observed in bone marrow CD34+ cells from ASXL1 mutant MDS patients compared to CD34+ cells from wild-type MDS cases. ATAC-sequencing demonstrated open chromatin at the BCL2 promoter in the ASXL1 mutant KBM5 cells. BH3 profiling demonstrated increased dependence of mutant cells on BCL2. Upon treatment with VEN, mutant cells demonstrated increased growth inhibition. In addition, genome-wide methylome analysis of primary MDS samples and isogenic cell lines demonstrated increased gene-body methylation in ASXL1 mutant cells, with consequently increased sensitivity to AZA. These data mechanistically link the common leukemia-associated mutation ASXL1 to enhanced sensitivity to VEN and AZA via epigenetic upregulation of BCL2 expression and widespread alterations in DNA methylation. |
format | Online Article Text |
id | pubmed-8455571 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-84555712021-10-07 ASXL1 mutations are associated with distinct epigenomic alterations that lead to sensitivity to venetoclax and azacytidine Rahmani, Nora E. Ramachandra, Nandini Sahu, Srabani Gitego, Nadege Lopez, Andrea Pradhan, Kith Bhagat, Tushar D. Gordon-Mitchell, Shanisha Pena, Bianca Rivera Kazemi, Mohammad Rao, Keshav Giricz, Orsi Maqbool, Shahina Bano Olea, Raul Zhao, Yongmei Zhang, Jinghang Dolatshad, Hamid Tittrea, Vickram Tatwavedi, Dharamveer Singh, Shalini Lee, Juseong Sun, Tianyu Steidl, Ulrich Shastri, Aditi Inoue, Daichi Abdel-Wahab, Omar Pellagatti, Andrea Gavathiotis, Evripidis Boultwood, Jacqueline Verma, Amit Blood Cancer J Article The BCL2-inhibitor, Venetoclax (VEN), has shown significant anti-leukemic efficacy in combination with the DNMT-inhibitor, Azacytidine (AZA). To explore the mechanisms underlying the selective sensitivity of mutant leukemia cells to VEN and AZA, we used cell-based isogenic models containing a common leukemia-associated mutation in the epigenetic regulator ASXL1. KBM5 cells with CRISPR/Cas9-mediated correction of the ASXL1(G710X) mutation showed reduced leukemic growth, increased myeloid differentiation, and decreased HOXA and BCL2 gene expression in vitro compared to uncorrected KBM5 cells. Increased expression of the anti-apoptotic gene, BCL2, was also observed in bone marrow CD34+ cells from ASXL1 mutant MDS patients compared to CD34+ cells from wild-type MDS cases. ATAC-sequencing demonstrated open chromatin at the BCL2 promoter in the ASXL1 mutant KBM5 cells. BH3 profiling demonstrated increased dependence of mutant cells on BCL2. Upon treatment with VEN, mutant cells demonstrated increased growth inhibition. In addition, genome-wide methylome analysis of primary MDS samples and isogenic cell lines demonstrated increased gene-body methylation in ASXL1 mutant cells, with consequently increased sensitivity to AZA. These data mechanistically link the common leukemia-associated mutation ASXL1 to enhanced sensitivity to VEN and AZA via epigenetic upregulation of BCL2 expression and widespread alterations in DNA methylation. Nature Publishing Group UK 2021-09-21 /pmc/articles/PMC8455571/ /pubmed/34548471 http://dx.doi.org/10.1038/s41408-021-00541-0 Text en © The Author(s) 2021 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 Rahmani, Nora E. Ramachandra, Nandini Sahu, Srabani Gitego, Nadege Lopez, Andrea Pradhan, Kith Bhagat, Tushar D. Gordon-Mitchell, Shanisha Pena, Bianca Rivera Kazemi, Mohammad Rao, Keshav Giricz, Orsi Maqbool, Shahina Bano Olea, Raul Zhao, Yongmei Zhang, Jinghang Dolatshad, Hamid Tittrea, Vickram Tatwavedi, Dharamveer Singh, Shalini Lee, Juseong Sun, Tianyu Steidl, Ulrich Shastri, Aditi Inoue, Daichi Abdel-Wahab, Omar Pellagatti, Andrea Gavathiotis, Evripidis Boultwood, Jacqueline Verma, Amit ASXL1 mutations are associated with distinct epigenomic alterations that lead to sensitivity to venetoclax and azacytidine |
title | ASXL1 mutations are associated with distinct epigenomic alterations that lead to sensitivity to venetoclax and azacytidine |
title_full | ASXL1 mutations are associated with distinct epigenomic alterations that lead to sensitivity to venetoclax and azacytidine |
title_fullStr | ASXL1 mutations are associated with distinct epigenomic alterations that lead to sensitivity to venetoclax and azacytidine |
title_full_unstemmed | ASXL1 mutations are associated with distinct epigenomic alterations that lead to sensitivity to venetoclax and azacytidine |
title_short | ASXL1 mutations are associated with distinct epigenomic alterations that lead to sensitivity to venetoclax and azacytidine |
title_sort | asxl1 mutations are associated with distinct epigenomic alterations that lead to sensitivity to venetoclax and azacytidine |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455571/ https://www.ncbi.nlm.nih.gov/pubmed/34548471 http://dx.doi.org/10.1038/s41408-021-00541-0 |
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