PMID- 31142847 OWN - NLM STAT- MEDLINE DCOM- 20200701 LR - 20210731 IS - 1476-5551 (Electronic) IS - 0887-6924 (Print) IS - 0887-6924 (Linking) VI - 34 IP - 1 DP - 2020 Jan TI - Targeting histone deacetylase 3 (HDAC3) in the bone marrow microenvironment inhibits multiple myeloma proliferation by modulating exosomes and IL-6 trans-signaling. PG - 196-209 LID - 10.1038/s41375-019-0493-x [doi] AB - 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. FAU - Ho, Matthew AU - Ho M AD - 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. AD - UCD Conway Institute of Biomolecular and Biomedical Science, UCD School of Medicine, University College Dublin, Belfield (UCD), Dublin 4, Ireland. FAU - Chen, Tianzeng AU - Chen T AD - 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. FAU - Liu, Jiye AU - Liu J AD - 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. FAU - Dowling, Paul AU - Dowling P AD - Biology Department, National University of Ireland Maynooth, Co. Kildare, Kildare, Ireland. FAU - Hideshima, Teru AU - Hideshima T AD - 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. FAU - Zhang, Li AU - Zhang L AD - Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan, China. FAU - Morelli, Eugenio AU - Morelli E AUID- ORCID: 0000-0002-8850-0442 AD - 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. FAU - Camci-Unal, Gulden AU - Camci-Unal G AD - Department of Chemical Engineering, University of Massachusetts Lowell, One University Avenue, Lowell, MA, 01854, USA. FAU - Wu, Xinchen AU - Wu X AD - Department of Chemical Engineering, University of Massachusetts Lowell, One University Avenue, Lowell, MA, 01854, USA. AD - Biomedical Engineering and Biotechnology Program, University of Massachusetts Lowell, One University Avenue, Lowell, MA, 01854, USA. FAU - Tai, Yu-Tzu AU - Tai YT AD - 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. FAU - Wen, Kenneth AU - Wen K AD - 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. FAU - Samur, Mehmet AU - Samur M AD - 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. FAU - Schlossman, Robert L AU - Schlossman RL AD - 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. FAU - Mazitschek, Ralph AU - Mazitschek R AD - Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA. FAU - Kavanagh, Emma L AU - Kavanagh EL AD - UCD Conway Institute of Biomolecular and Biomedical Science, UCD School of Medicine, University College Dublin, Belfield (UCD), Dublin 4, Ireland. FAU - Lindsay, Sinead AU - Lindsay S AD - UCD Conway Institute of Biomolecular and Biomedical Science, UCD School of Medicine, University College Dublin, Belfield (UCD), Dublin 4, Ireland. FAU - Harada, Takeshi AU - Harada T AD - Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan. FAU - McCann, Amanda AU - McCann A AD - UCD Conway Institute of Biomolecular and Biomedical Science, UCD School of Medicine, University College Dublin, Belfield (UCD), Dublin 4, Ireland. FAU - Anderson, Kenneth C AU - Anderson KC AD - 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. FAU - O'Gorman, Peter AU - O'Gorman P AD - Haematology Department, Mater Misericordiae University Hospital, Dublin, Ireland. FAU - Bianchi, Giada AU - Bianchi G AD - 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. LA - eng GR - R01 CA178264/CA/NCI NIH HHS/United States GR - P01 CA155258/CA/NCI NIH HHS/United States GR - R01 CA050947/CA/NCI NIH HHS/United States GR - P50 CA100707/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20190529 PL - England TA - Leukemia JT - Leukemia JID - 8704895 RN - 0 (Interleukin-6) RN - EC 3.5.1.98 (Histone Deacetylases) RN - EC 3.5.1.98 (histone deacetylase 3) SB - IM MH - Animals MH - Bone Marrow/metabolism MH - Cell Proliferation/physiology MH - Endothelial Cells/enzymology MH - Exosomes/metabolism MH - Heterografts MH - Histone Deacetylases/*metabolism MH - Humans MH - Interleukin-6/metabolism MH - Mesenchymal Stem Cells/*enzymology MH - Mice MH - Multiple Myeloma/*enzymology/pathology MH - Signal Transduction/physiology MH - Tumor Microenvironment/*physiology PMC - PMC6883144 MID - NIHMS1527350 COIS- KCA serves on advisory boards to Celgene and Millennium, Bristol Myers Squibb, and Gilead. The remaining authors declare that they have no conflict of interest. EDAT- 2019/05/31 06:00 MHDA- 2020/07/02 06:00 PMCR- 2019/05/29 CRDT- 2019/05/31 06:00 PHST- 2018/12/08 00:00 [received] PHST- 2019/04/17 00:00 [accepted] PHST- 2019/05/31 06:00 [pubmed] PHST- 2020/07/02 06:00 [medline] PHST- 2019/05/31 06:00 [entrez] PHST- 2019/05/29 00:00 [pmc-release] AID - 10.1038/s41375-019-0493-x [pii] AID - 493 [pii] AID - 10.1038/s41375-019-0493-x [doi] PST - ppublish SO - Leukemia. 2020 Jan;34(1):196-209. doi: 10.1038/s41375-019-0493-x. Epub 2019 May 29.