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Leukemia. 2019 May 29. doi: 10.1038/s41375-019-0493-x. [Epub ahead of print]

Targeting histone deacetylase 3 (HDAC3) in the bone marrow microenvironment inhibits multiple myeloma proliferation by modulating exosomes and IL-6 trans-signaling.

Author information

1
LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA.
2
UCD Conway Institute of Biomolecular and Biomedical Science, UCD School of Medicine, University College Dublin, Belfield (UCD), Dublin 4, Ireland.
3
Biology Department, National University of Ireland Maynooth, Co. Kildare, Kildare, Ireland.
4
Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
5
Department of Chemical Engineering, University of Massachusetts Lowell, One University Avenue, Lowell, MA, 01854, USA.
6
Biomedical Engineering and Biotechnology Program, University of Massachusetts Lowell, One University Avenue, Lowell, MA, 01854, USA.
7
Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA.
8
Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan.
9
Haematology Department, Mater Misericordiae University Hospital, Dublin, Ireland.
10
LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA. Giada_bianchi@dfci.harvard.edu.

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.

PMID:
31142847
DOI:
10.1038/s41375-019-0493-x

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