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Acute Leukemias

Anti-leukemia activity of chaetocin via death receptor-dependent apoptosis and dual modulation of the histone methyl-transferase SUV39H1

Leukemia volume 26, pages 662–674 (2012)Cite this article

Abstract

Epigenetic deregulation is involved in acute myeloid leukemia (AML) pathogenesis and epigenetic targeting drugs are in clinical trial. Since the first results with histone-deacetylase inhibitors in AML are controversial, novel single and combined treatments need to be explored. It is tempting to combine chromatin-targeting drugs. SUV39H1, the main methyl-transferase for lysine 9 tri-methylation on histone H3, interacts with oncogenes involved in AML and acts as a transcriptional repressor for hematopoietic differentiation and immortalization. We report here that pharmacological inhibition of SUV39H1 by chaetocin induces apoptosis in leukemia cell lines in vitro and primary AML cells ex vivo, and that it interferes with leukemia growth in vivo. Chaetocin treatment upregulates reactive oxygen species (ROS) production as well as the transcription of death-receptor-related genes, in a ROS-dependent manner, leading to death receptor-dependent apoptosis. In addition to its direct inhibition by chaetocin, SUV39H1 is indirectly modulated by chaetocin-induced ROS. Accordingly, chaetocin potentiates other anti-AML drugs, in a ROS-dependent manner. The decryption of a dual mechanism of action against AML involving both direct and indirect SUV39H1 modulation represents an innovative read-out for the anticancer activity of chaetocin and for its synergy with other anti-AML drugs, suggesting new therapeutic combination strategies in AML.

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Acknowledgements

We thank Anne-Odile Hueber for providing the FADD-DN construct, Valérie Depraetere-Ferrier for critical reading and Yves Toiron and Nadège Delacourt for invaluable help for studies on synergism. CH was supported by a MRT fellowship, and CR and GS by fellowships from INCa and PT by the Foundation Monahan; AN was supported by EU (Contract No. 518417). This work was supported by funds from the INSERM, ANRS, INCA (Institut National de Recherche conre le Cancer), ARC (Association de Recherche contre le Cancer) and AIRC (Associazione Italiana per la ricerca contro il cancro, EU (APOSYS 200767 and LSHC-CT2005-518417).

Author contributions

HC performed and designed the research, analyzed data and wrote the manuscript. AN performed and designed the research, and analyzed data. RC, SG and AR performed the research and analyzed data. TP/NV/LA and YC designed the research, analyzed data and wrote the manuscript. LA and YC share senior authorship.

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Authors and Affiliations

  1. Inserm, U891, Centre de Recherche en Cancérologie de Marseille, Marseille, France

    H Chaib, T Prebet, R Castellano, S Garbit, A Restouin, N Vey & Y Collette

  2. Univ Méditerranée, Marseille, France

    H Chaib, T Prebet, R Castellano, S Garbit, A Restouin, N Vey & Y Collette

  3. Dipartimento di Patologia generale, Seconda Università degli Studi di Napoli, Napoli, Italy

    A Nebbioso & L Altucci

  4. Département d’Hématologie, Institut Paoli-Calmettes, Marseille, France

    T Prebet, R Castellano, A Restouin, N Vey & Y Collette

  5. IGB-CNR, Via Pietro Castellino, Napoli, Italy. E-mail: yves.collette@inserm.fr,

    L Altucci

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  1. H Chaib
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Correspondence to L Altucci.

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Chaib, H., Nebbioso, A., Prebet, T. et al. Anti-leukemia activity of chaetocin via death receptor-dependent apoptosis and dual modulation of the histone methyl-transferase SUV39H1. Leukemia 26, 662–674 (2012). https://doi.org/10.1038/leu.2011.271

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