Multi-omics profiling reveals a distinctive epigenome signature for high-risk acute promyelocytic leukemia

Abstract

// Abhishek A. Singh 1, * , Francesca Petraglia 2, * , Angela Nebbioso 2 , Guoqiang Yi 1 , Mariarosaria Conte 3 , Sergio Valente 4 , Amit Mandoli 1 , Lucia Scisciola 2 , Rik Lindeboom 1 , Hinri Kerstens 1 , Eva M. Janssen-Megens 1 , Farzin Pourfarzad 5 , Ehsan Habibi 1 , Kim Berentsen 1 , Bowon Kim 1 , Colin Logie 1 , Simon Heath 6 , Albertus T.J. Wierenga 7 , Laura Clarke 8 , Paul Flicek 8 , Joop H. Jansen 9 , Taco Kuijpers 5 , Marie Laure Yaspo 10 , Veronique Della Valle 11 , Olivier Bernard 11 , Ivo Gut 6 , Edo Vellenga 7 , Hendrik G. Stunnenberg 1 , Antonello Mai 4, 12 , Lucia Altucci 2 and Joost H.A. Martens 1, 2 1 Department of Molecular Biology, Radboud University, Nijmegen, Netherlands 2 Dipartimento di Biochimica Biofisica e Patologia Generale, Università degli Studi della Campania Luigi Vanvitelli, Napoli, Italy 3 IRCCS SDN, Napoli Via E. Gianturco, Napoli, Italy 4 Dipartimento di Chimica e Tecnologie del Farmaco ‘Sapienza’ Università, Roma, Italy 5 Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands 6 Centro Nacional de Análisis Genómico, Barcelona, Spain 7 Department of Hematology, University of Groningen and University Medical Center Groningen, Groningen, Netherlands 8 European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom 9 Department of Laboratory Medicine, Radboud UMC, Nijmegen, Netherlands 10 Max Planck Institute for Molecular Genetics, Berlin, Germany 11 INSERM U1170, Universtité Paris-Saclay, Institut Gustave Roussy, Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC), Paris, France 12 Pasteur Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, Roma, Italy * These authors contributed equally to this work Correspondence to: Joost H.A. Martens, email: j.martens@ncmls.ru.nl Lucia Altucci, email: lucia.altucci@unicampania.it 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 ABSTRACT 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.