Multi-omics profiling reveals a distinctive epigenome signature for high-risk acute promyelocytic leukemia
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Abhishek A. Singh1,*, Francesca Petraglia2,*, Angela Nebbioso2, Guoqiang Yi1, Mariarosaria Conte3, Sergio Valente4, Amit Mandoli1, Lucia Scisciola2, Rik Lindeboom1, Hinri Kerstens1, Eva M. Janssen-Megens1, Farzin Pourfarzad5, Ehsan Habibi1, Kim Berentsen1, Bowon Kim1, Colin Logie1, Simon Heath6, Albertus T.J. Wierenga7, Laura Clarke8, Paul Flicek8, Joop H. Jansen9, Taco Kuijpers5, Marie Laure Yaspo10, Veronique Della Valle11, Olivier Bernard11, Ivo Gut6, Edo Vellenga7, Hendrik G. Stunnenberg1, Antonello Mai4,12, Lucia Altucci2 and Joost H.A. Martens1,2
1Department of Molecular Biology, Radboud University, Nijmegen, Netherlands
2Dipartimento di Biochimica Biofisica e Patologia Generale, Università degli Studi della Campania Luigi Vanvitelli, Napoli, Italy
3IRCCS SDN, Napoli Via E. Gianturco, Napoli, Italy
4Dipartimento di Chimica e Tecnologie del Farmaco ‘Sapienza’ Università, Roma, Italy
5Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
6Centro Nacional de Análisis Genómico, Barcelona, Spain
7Department of Hematology, University of Groningen and University Medical Center Groningen, Groningen, Netherlands
8European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom
9Department of Laboratory Medicine, Radboud UMC, Nijmegen, Netherlands
10Max Planck Institute for Molecular Genetics, Berlin, Germany
11INSERM U1170, Universtité Paris-Saclay, Institut Gustave Roussy, Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC), Paris, France
12Pasteur Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, Roma, Italy
*These authors contributed equally to this work
Joost H.A. Martens, email: [email protected]
Lucia Altucci, email: [email protected]
Keywords: epigenome; acute promyelocytic leukemia (APL); PML-RARA; high-risk APL; epi-drugs
Received: March 15, 2018 Accepted: May 01, 2018 Published: May 22, 2018
Epigenomic alterations have been associated with both pathogenesis and progression of cancer. Here, we analyzed the epigenome of two high-risk APL (hrAPL) patients and compared it to non-high-risk APL cases. Despite the lack of common genetic signatures, we found that human hrAPL blasts from patients with extremely poor prognosis display specific patterns of histone H3 acetylation, specifically hyperacetylation at a common set of enhancer regions. In addition, unique profiles of the repressive marks H3K27me3 and DNA methylation were exposed in high-risk APLs. Epigenetic comparison with low/intermediate-risk APLs and AMLs revealed hrAPL-specific patterns of histone acetylation and DNA methylation, suggesting these could be further developed into markers for clinical identification. The epigenetic drug MC2884, a newly generated general HAT/EZH2 inhibitor, induces apoptosis of high-risk APL blasts and reshapes their epigenomes by targeting both active and repressive marks. Together, our analysis uncovers distinctive epigenome signatures of hrAPL patients, and provides proof of concept for use of epigenome profiling coupled to epigenetic drugs to ‘personalize’ precision medicine.
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