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タイトル: | KAT7 is a genetic vulnerability of acute myeloid leukemias driven by MLL rearrangements |
著者: | Au, Yan Zi Gu, Muxin De Braekeleer, Etienne Gozdecka, Malgorzata Aspris, Demetrios Tarumoto, Yusuke https://orcid.org/0000-0001-6652-9618 (unconfirmed) Cooper, Jonathan Yu, Jason Ong, Swee Hoe Chen, Xi Tzelepis, Konstantinos Huntly, Brian J. P. Vassiliou, George Yusa, Kosuke https://orcid.org/0000-0002-3442-021X (unconfirmed) |
著者名の別形: | 樽本, 雄介 遊佐, 宏介 |
キーワード: | Cancer epigenetics Cancer stem cells |
発行日: | Apr-2020 |
出版者: | Springer Nature |
誌名: | Leukemia |
巻: | 35 |
号: | 4 |
開始ページ: | 1012 |
終了ページ: | 1022 |
抄録: | Histone acetyltransferases (HATs) catalyze the transfer of an acetyl group from acetyl-CoA to lysine residues of histones and play a central role in transcriptional regulation in diverse biological processes. Dysregulation of HAT activity can lead to human diseases including developmental disorders and cancer. Through genome-wide CRISPR-Cas9 screens, we identified several HATs of the MYST family as fitness genes for acute myeloid leukemia (AML). Here we investigate the essentiality of lysine acetyltransferase KAT7 in AMLs driven by the MLL-X gene fusions. We found that KAT7 loss leads to a rapid and complete loss of both H3K14ac and H4K12ac marks, in association with reduced proliferation, increased apoptosis, and differentiation of AML cells. Acetyltransferase activity of KAT7 is essential for the proliferation of these cells. Mechanistically, our data propose that acetylated histones provide a platform for the recruitment of MLL-fusion-associated adaptor proteins such as BRD4 and AF4 to gene promoters. Upon KAT7 loss, these factors together with RNA polymerase II rapidly dissociate from several MLL-fusion target genes that are essential for AML cell proliferation, including MEIS1, PBX3, and SENP6. Our findings reveal that KAT7 is a plausible therapeutic target for this poor prognosis AML subtype. |
著作権等: | © The Author(s) 2020. This article is published with 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/. |
URI: | http://hdl.handle.net/2433/261905 |
DOI(出版社版): | 10.1038/s41375-020-1001-z |
PubMed ID: | 32764680 |
出現コレクション: | 学術雑誌掲載論文等 |
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