Journal article
Epigenetic Activation of Plasmacytoid DCs Drives IFNAR-Dependent Therapeutic Differentiation of AML
JM Salmon, I Todorovski, KL Stanley, C Bruedigam, CJ Kearney, LG Martelotto, F Rossello, T Semple, GM Arnau, M Zethoven, M Bots, S Bjelosevic, LA Cluse, PJ Fraser, V Litalien, E Vidacs, K McArthur, AY Matthews, E Gressier, NA De Weerd Show all
Cancer Discovery | AMER ASSOC CANCER RESEARCH | Published : 2022
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 increase..
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Awarded by Cancer Council Victoria
Funding Acknowledgements
We thank staff from the Animal Facility, Genotyping Core, Flow Cytometry Facility, Molecular Genomics Core, Victorian Center for Functional Genomics, Centre for Advanced Histology and Microscopy and Bioinformatics Consulting Core of the Peter MacCallum Cancer Centre, and members of the Johnstone laboratory for useful discussions. We acknowledge Nicole Messina and Dan Andrews for providing reagents and advice and support from the Peter MacCallum Cancer Centre Foundation and Australian Cancer Research Foundation. We also thank the Monash Histology Platform and Gareth Gregory for processing and assessing, respectively, the histology sections from the PDX models. Research reported in this publication was supported by Cure Cancer Australia under award number 1051444, awarded to J.M. Salmon and R.W. Johnstone. I. Todorovski was supported by an Australian Research Training Program (RTP) Scholarship during this study; S.J. Vervoort was supported by a Rubicon Fellowship from the Netherlands Organization for Scientific Research (NWO; 019.161LW.017), a National Health and Medical Research Council (NHMRC) EL1 Fellowship (GNT1178339), and a Peter MacCallum Cancer Foundation Grant; S.J. Hogg was supported by a Postdoctoral Fellowship from Cancer Council Victoria (CCV); L.G. Martelotto and Single Cell Innovation Lab were supported by The Lorenzo and Pamela Galli Research Fund Trust; L.M. Kats was supported by a Victorian Cancer Agency Fellowship (MCRF15003); S. Scheu was supported by the German Research Foundation (DFG; 270650915/GRK2158 and SCHE692/6-1) and the Manchot Graduate School "Molecules of Infection III"; D.D. De Carvalho is funded by the Canadian Institute of Health Research (201512MSH360794-228629, FDN 148430, and PJT 165986) and the Canada Research Chairs; B.T. Kile is funded by a Project Grant from NHMRC (Grant No. 1113577) and an NHMRC Principal Research Fellowship (No. 1063008); P.M. Dominguez was supported by a Postdoctoral Fellowship Grant from the Lymphoma Research Foundation and is funded by an Ideas Grant from the NHMRC (GNT2011217); and R.W. Johnstone is funded by a Project Grant from CCV, a Project Grant and Program Grant (grant 454569) from the NHMRC, an NHMRC Senior Principal Research Fellowship, and a Grant from The Kids' Cancer Project (to R.W. Johnstone and S.J. Vervoort).