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 FlicekJoop H. Jansen, Taco Kuijpers, Marie Laure Yaspo, Veronique Della Valle, Olivier Bernard, Ivo Gut, Edo Vellenga, Hendrik G. Stunnenberg, Antonello Mai, Lucia Altucci, Joost H.A. Martens

Research output: Contribution to journalArticle

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 highrisk 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.

Original languageEnglish
Pages (from-to)25647-25660
Number of pages14
JournalOncotarget
Volume9
Issue number39
DOIs
Publication statusPublished - May 22 2018

Keywords

  • Acute promyelocytic leukemia (APL)
  • Epi-drugs
  • Epigenome
  • High-risk APL
  • PML-RARA

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Singh, A. A., Petraglia, F., Nebbioso, A., Yi, G., Conte, M., Valente, S., Mandoli, A., Scisciola, L., Lindeboom, R., Kerstens, H., Janssen-Megens, E. M., Pourfarzad, F., Habibi, E., Berentsen, K., Kim, B., Logie, C., Heath, S., Wierenga, A. T. J., Clarke, L., ... Martens, J. H. A. (2018). Multi-omics profiling reveals a distinctive epigenome signature for high-risk acute promyelocytic leukemia. Oncotarget, 9(39), 25647-25660. https://doi.org/10.18632/oncotarget.25429