Acute myeloid leukemia

The acetyltransferase GCN5 maintains ATRA-resistance in non-APL AML

Leukemia volume 33, pages2628–2639(2019)Cite this article

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  • A Correction to this article was published on 16 January 2020

Abstract

To date, only one subtype of acute myeloid leukemia (AML), acute promyelocytic leukemia (APL) can be effectively treated by differentiation therapy utilizing all-trans retinoic acid (ATRA). Non-APL AMLs are resistant to ATRA. Here we demonstrate that the acetyltransferase GCN5 contributes to ATRA resistance in non-APL AML via aberrant acetylation of histone 3 lysine 9 (H3K9ac) residues maintaining the expression of stemness and leukemia associated genes. We show that inhibition of GCN5 unlocks an ATRA-driven therapeutic response. This response is potentiated by coinhibition of the lysine demethylase LSD1, leading to differentiation in most non-APL AML. Induction of differentiation was not correlated to a specific AML subtype, cytogenetic, or mutational status. Our study shows a previously uncharacterized role of GCN5 in maintaining the immature state of leukemic blasts and identifies GCN5 as a therapeutic target in AML. The high efficacy of the combined epigenetic treatment with GCN5 and LSD1 inhibitors may enable the use of ATRA for differentiation therapy of non-APL AML. Furthermore, it supports a strategy of combined targeting of epigenetic factors to improve treatment, a concept potentially applicable for a broad range of malignancies.

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Data availability

Data discussed in this publication were deposited in NCBI’s Gene Expression Omnibus and are accessible through GEO Series accession number GSE124423.

Change history

  • 16 January 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Acknowledgements

We are grateful to Maren Godmann, Berit Jungnickel, and Christian Kosan for their advice during the project. We thank Ivonne Goerlich and Cornelia Luge for technical assistance in next-generation sequencing, Carl Crodel, Kai Sporkmann, and Tobias Rachow for their help collecting patients’ material and Carl Götze for his advice in stochastic analyses. MK and TS were supported by the German Research Council (SCHE1909/2–1). AB was supported by funding from the Foundation “Else Kröner-Fresenius-Stiftung”. FHH was supported by grants of the Thuringian state program ProExzellenz (RegenerAging—FSU-I-03/14) of the Thuringian Ministry for Research and in part by the German Research Council (DFG, HE6233/6–1).

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  1. Department of Hematology/Oncology, Clinic of Internal Medicine II, Jena University Hospital, Jena, Germany

    Melanie Kahl, Annamaria Brioli, Florian Perner, Ulf Schnetzke, Anna Hinze, Thomas Ernst, Florian H. Heidel, Sebastian Scholl, Andreas Hochhaus & Tino Schenk

  2. Institute of Molecular Cell Biology, Center for Molecular Biomedicine Jena (CMB), Jena University Hospital, Jena, Germany

    Melanie Kahl, Frank-Dietmar Böhmer & Tino Schenk

  3. Else-Kröner-Forschungskolleg, Jena, Germany

    Annamaria Brioli

  4. Leibniz-Institute on Aging, Fritz-Lipmann-Institute, Jena, Germany

    Martin Bens, Florian Perner, Anne Kresinsky, Marco Groth & Florian H. Heidel

  5. Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    Florian Perner

  6. Department of Medical Biology, Medical University-Plovdiv, Plovdiv, Bulgaria

    Yordan Sbirkov

  7. Department of Internal Medicine IV, Jena University Hospital, Jena, Germany

    Sven Stengel

  8. Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy

    Giorgia Simonetti & Giovanni Martinelli

  9. Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy

    Giovanni Martinelli

  10. School of Natural Sciences, University of Stirling, Stirling, UK

    Kevin Petrie

  11. Millitary Institute of Hygiene and Epidemiology, Warsaw, Poland

    Arthur Zelent

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Kahl, M., Brioli, A., Bens, M. et al. The acetyltransferase GCN5 maintains ATRA-resistance in non-APL AML. Leukemia 33, 2628–2639 (2019). https://doi.org/10.1038/s41375-019-0581-y

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