Oncotarget

Research Papers:

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

Abhishek A. Singh, Francesca Petraglia, Angela Nebbioso, Guoqiang Yi, Mariarosaria Conte, Sergio Valente, Amit Mandoli, Lucia Scisciola, Rik Lindeboom, Hinri Kerstens, Eva M. Janssen-Megens, Farzin Pourfarzad, Ehsan Habibi, Kim Berentsen, Bowon Kim, Colin Logie, Simon Heath, Albertus T.J. Wierenga, Laura Clarke, Paul Flicek, Joop H. Jansen, Taco Kuijpers, Marie Laure Yaspo, Veronique Della Valle, Olivier Bernard, Ivo Gut, Edo Vellenga, Hendrik G. Stunnenberg, Antonello Mai, Lucia Altucci and Joost H.A. Martens _

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Oncotarget. 2018; 9:25647-25660. https://doi.org/10.18632/oncotarget.25429

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Abstract

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

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.


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