Ho, Matthew and Chen, Tianzeng and Liu, Jiye and Dowling, Paul and Hideshima, Teru and Zhang, Li and Morelli, Eugenio and Camci-Unal, Gulden and Wu, Xinchen and Tai, Yu-Tzu and Wen, Kenneth and Samur, Mehmet and Schlossman, Robert L. and Mazitschek, Ralph and Kavanagh, Emma L. and Lindsay, Sinead and Harada, Takeshi and McCann, Amanda and Anderson, Kenneth C. and O'Gorman, Peter and Bianchi, Giada (2020) Targeting histone deacetylase 3 (HDAC3) in the bone marrow microenvironment inhibits multiple myeloma proliferation by modulating exosomes and IL-6 trans-signaling. Leukemia, 34. pp. 196-209. ISSN 0887-6924

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Abstract

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.

Item Type:	Article
Additional Information:	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/. Cite as: Ho, M., Chen, T., Liu, J. et al. Targeting histone deacetylase 3 (HDAC3) in the bone marrow microenvironment inhibits multiple myeloma proliferation by modulating exosomes and IL-6 trans-signaling. Leukemia 34, 196–209 (2020). https://doi.org/10.1038/s41375-019-0493-x
Keywords:	Targeting; histone deacetylase 3; HDAC3; bone marrow; microenvironment; multiple myeloma proliferation; modulating exosomes; IL-6 trans-signaling;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	13580
Identification Number:	https://doi.org/10.1038/s41375-019-0493-x
Depositing User:	Paul Dowling
Date Deposited:	18 Nov 2020 16:40
Journal or Publication Title:	Leukemia
Publisher:	Springer Nature
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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