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ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism
Recurring chromosomal translocation t(10;17)(p15;q21) present in a subset of human acute myeloid leukemia (AML) patients creates an aberrant fusion gene termed ZMYND11-MBTD1 (ZM); however, its function remains undetermined. Here, we show that ZM confers primary murine hematopoietic stem/progenitor c...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886901/ https://www.ncbi.nlm.nih.gov/pubmed/33594072 http://dx.doi.org/10.1038/s41467-021-21357-3 |
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author | Li, Jie Galbo, Phillip M. Gong, Weida Storey, Aaron J. Tsai, Yi-Hsuan Yu, Xufen Ahn, Jeong Hyun Guo, Yiran Mackintosh, Samuel G. Edmondson, Ricky D. Byrum, Stephanie D. Farrar, Jason E. He, Shenghui Cai, Ling Jin, Jian Tackett, Alan J. Zheng, Deyou Wang, Gang Greg |
author_facet | Li, Jie Galbo, Phillip M. Gong, Weida Storey, Aaron J. Tsai, Yi-Hsuan Yu, Xufen Ahn, Jeong Hyun Guo, Yiran Mackintosh, Samuel G. Edmondson, Ricky D. Byrum, Stephanie D. Farrar, Jason E. He, Shenghui Cai, Ling Jin, Jian Tackett, Alan J. Zheng, Deyou Wang, Gang Greg |
author_sort | Li, Jie |
collection | PubMed |
description | Recurring chromosomal translocation t(10;17)(p15;q21) present in a subset of human acute myeloid leukemia (AML) patients creates an aberrant fusion gene termed ZMYND11-MBTD1 (ZM); however, its function remains undetermined. Here, we show that ZM confers primary murine hematopoietic stem/progenitor cells indefinite self-renewal capability ex vivo and causes AML in vivo. Genomics profilings reveal that ZM directly binds to and maintains high expression of pro-leukemic genes including Hoxa, Meis1, Myb, Myc and Sox4. Mechanistically, ZM recruits the NuA4/Tip60 histone acetyltransferase complex to cis-regulatory elements, sustaining an active chromatin state enriched in histone acetylation and devoid of repressive histone marks. Systematic mutagenesis of ZM demonstrates essential requirements of Tip60 interaction and an H3K36me3-binding PWWP (Pro-Trp-Trp-Pro) domain for oncogenesis. Inhibitor of histone acetylation-‘reading’ bromodomain proteins, which act downstream of ZM, is efficacious in treating ZM-induced AML. Collectively, this study demonstrates AML-causing effects of ZM, examines its gene-regulatory roles, and reports an attractive mechanism-guided therapeutic strategy. |
format | Online Article Text |
id | pubmed-7886901 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-78869012021-03-03 ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism Li, Jie Galbo, Phillip M. Gong, Weida Storey, Aaron J. Tsai, Yi-Hsuan Yu, Xufen Ahn, Jeong Hyun Guo, Yiran Mackintosh, Samuel G. Edmondson, Ricky D. Byrum, Stephanie D. Farrar, Jason E. He, Shenghui Cai, Ling Jin, Jian Tackett, Alan J. Zheng, Deyou Wang, Gang Greg Nat Commun Article Recurring chromosomal translocation t(10;17)(p15;q21) present in a subset of human acute myeloid leukemia (AML) patients creates an aberrant fusion gene termed ZMYND11-MBTD1 (ZM); however, its function remains undetermined. Here, we show that ZM confers primary murine hematopoietic stem/progenitor cells indefinite self-renewal capability ex vivo and causes AML in vivo. Genomics profilings reveal that ZM directly binds to and maintains high expression of pro-leukemic genes including Hoxa, Meis1, Myb, Myc and Sox4. Mechanistically, ZM recruits the NuA4/Tip60 histone acetyltransferase complex to cis-regulatory elements, sustaining an active chromatin state enriched in histone acetylation and devoid of repressive histone marks. Systematic mutagenesis of ZM demonstrates essential requirements of Tip60 interaction and an H3K36me3-binding PWWP (Pro-Trp-Trp-Pro) domain for oncogenesis. Inhibitor of histone acetylation-‘reading’ bromodomain proteins, which act downstream of ZM, is efficacious in treating ZM-induced AML. Collectively, this study demonstrates AML-causing effects of ZM, examines its gene-regulatory roles, and reports an attractive mechanism-guided therapeutic strategy. Nature Publishing Group UK 2021-02-16 /pmc/articles/PMC7886901/ /pubmed/33594072 http://dx.doi.org/10.1038/s41467-021-21357-3 Text en © The Author(s) 2021 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/. |
spellingShingle | Article Li, Jie Galbo, Phillip M. Gong, Weida Storey, Aaron J. Tsai, Yi-Hsuan Yu, Xufen Ahn, Jeong Hyun Guo, Yiran Mackintosh, Samuel G. Edmondson, Ricky D. Byrum, Stephanie D. Farrar, Jason E. He, Shenghui Cai, Ling Jin, Jian Tackett, Alan J. Zheng, Deyou Wang, Gang Greg ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism |
title | ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism |
title_full | ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism |
title_fullStr | ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism |
title_full_unstemmed | ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism |
title_short | ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism |
title_sort | zmynd11-mbtd1 induces leukemogenesis through hijacking nua4/tip60 acetyltransferase complex and a pwwp-mediated chromatin association mechanism |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886901/ https://www.ncbi.nlm.nih.gov/pubmed/33594072 http://dx.doi.org/10.1038/s41467-021-21357-3 |
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