Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/135425
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Type: | Journal article |
Title: | Epigenetic activation of plasmacytoid DC drives IFNAR-dependent therapeutic differentiation of AML |
Author: | Salmon, J.M. Todorovski, I. Stanley, K.L. Bruedigam, C. Kearney, C.J. Martelotto, L.G. Rossello, F.J. Semple, T. Mir Arnau, G. Zethoven, M. Bots, M. Bjelosevic, S. Cluse, L.A. Fraser, P.J. Litalien, V. Vidacs, E. McArthur, K. Matthews, A.Y. Gressier, E. de Weerd, N.A. et al. |
Citation: | Cancer Discovery, 2022; 12(6):1560-1579 |
Publisher: | American Association for Cancer Research |
Issue Date: | 2022 |
ISSN: | 2159-8274 2159-8290 |
Statement of Responsibility: | Jessica M. Salmon, Izabela Todorovski, Kym L. Stanley, Claudia Bruedigam, Conor J. Kearney, Luciano G. Martelotto, Fernando Rossello, Timothy Semple, Gisela Mir Arnau, Magnus Zethoven, Michael Bots, Stefan Bjelosevic, Leonie A. Cluse, Peter J. Fraser, Veronique Litalien, Eva Vidacs, Kate McArthur, Antony Y. Matthews, Elise Gressier, Nicole A. de Weerd, Jens Lichte, Madison J. Kelly, Simon J. Hogg, Paul J. Hertzog, Lev M. Kats, Stephin J. Vervoort, Daniel D. De Carvalho, Stefanie Scheu, Sammy Bedoui, Benjamin T. Kile, Steven W. Lane, Andrew C. Perkins, Andrew H. Wei, Pilar M. Dominguez, and Ricky W. Johnstone |
Abstract: | Pharmacologic inhibition of epigenetic enzymes can have therapeutic benefit against hematologic malignancies. In addition to affecting tumor cell growth and proliferation, these epigenetic agents may induce antitumor immunity. Here, we discovered a novel immunoregulatory mechanism through inhibition of histone deacetylases (HDAC). In models of acute myeloid leukemia (AML), leukemia cell differentiation and therapeutic benefit mediated by the HDAC inhibitor (HDACi) panobinostat required activation of the type I interferon (IFN) pathway. Plasmacytoid dendritic cells (pDC) produced type I IFN after panobinostat treatment, through transcriptional activation of IFN genes concomitant with increased H3K27 acetylation at these loci. Depletion of pDCs abrogated panobinostat-mediated induction of type I IFN signaling in leukemia cells and impaired therapeutic efficacy, whereas combined treatment with panobinostat and IFNα improved outcomes in preclinical models. These discoveries offer a new therapeutic approach for AML and demonstrate that epigenetic rewiring of pDCs enhances antitumor immunity, opening the possibility of exploiting this approach for immunotherapies. |
Keywords: | Dendritic Cells Humans Histone Deacetylases Cell Differentiation Epigenesis, Genetic Leukemia, Myeloid, Acute Histone Deacetylase Inhibitors Panobinostat |
Rights: | ©2022 The Authors; Published by the American Association for Cancer Research. This open access article is distributed under Creative Commons Attribution- NonCommercial-NoDerivatives License 4.0 International (CC BY-NC-ND). |
DOI: | 10.1158/2159-8290.CD-20-1145 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/GNT1178339 http://purl.org/au-research/grants/nhmrc/1113577 http://purl.org/au-research/grants/nhmrc/1063008 http://purl.org/au-research/grants/nhmrc/GNT2011217 |
Published version: | http://dx.doi.org/10.1158/2159-8290.cd-20-1145 |
Appears in Collections: | Medical Sciences publications |
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hdl_135425.pdf | Published version | 9.13 MB | Adobe PDF | View/Open |
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