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ID 115638
著者
Ho, Matthew Harvard Medical School|University College Dublin
Chen, Tianzeng Harvard Medical School
Liu, Jiye Harvard Medical School
Dowling, Paul National University of Ireland Maynooth
Hideshima, Teru Harvard Medical School
Zhang, Li Sichuan University
Morelli, Eugenio Harvard Medical School
Camci-Unal, Gulden University of Massachusetts Lowell
Wu, Xinchen University of Massachusetts Lowell
Tai, Yu-Tzu Harvard Medical School
Wen, Kenneth Harvard Medical School
Samur, Mehmet Harvard Medical School
Schlossman, Robert L. Harvard Medical School
Mazitschek, Ralph Massachusetts General Hospital
Kavanagh, Emma L. University College Dublin
Lindsay, Sinéad University College Dublin
McCann, Amanda University College Dublin
Anderson, Kenneth C. Harvard Medical School
O’Gorman, Peter Mater Misericordiae University Hospital
Bianchi, Giada Harvard Medical School
資料タイプ
学術雑誌論文
抄録
Multiple myeloma (MM) is an incurable cancer that derives pro-survival/proliferative signals from the bone marrow (BM) niche. Novel agents targeting not only cancer cells, but also the BM-niche have shown the greatest activity in MM. Histone deacetylases (HDACs) are therapeutic targets in MM and we previously showed that HDAC3 inhibition decreases MM proliferation both alone and in co-culture with bone marrow stromal cells (BMSC). In this study, we investigate the effects of HDAC3 targeting in BMSCs. Using both BMSC lines as well as patient-derived BMSCs, we show that HDAC3 expression in BMSCs can be induced by co-culture with MM cells. Knock-out (KO), knock-down (KD), and pharmacologic inhibition of HDAC3 in BMSCs results in decreased MM cell proliferation; including in autologous cultures of patient MM cells with BMSCs. We identified both quantitative and qualitative changes in exosomes and exosomal miRNA, as well as inhibition of IL-6 trans-signaling, as molecular mechanisms mediating anti-MM activity. Furthermore, we show that HDAC3-KD in BM endothelial cells decreases neoangiogenesis, consistent with a broad effect of HDAC3 targeting in the BM-niche. Our results therefore support the clinical development of HDAC3 inhibitors based not only on their direct anti-MM effects, but also their modulation of the BM microenvironment.
掲載誌名
Leukemia
ISSN
08876924
14765551
cat書誌ID
AA10668706
AA12305962
出版者
Springer Nature
34
1
開始ページ
196
終了ページ
209
発行日
2019-05-29
権利情報
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/.
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出版社版DOI
出版社版URL
フルテキストファイル
言語
eng
著者版フラグ
出版社版
部局
病院