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Acute Leukemias

Histone deacetylase inhibitors induce apoptosis in myeloid leukemia by suppressing autophagy

Leukemia volume 28, pages 577–588 (2014)Cite this article

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Abstract

Histone deacetylase (HDAC) inhibitors (HDACis) are well-characterized anti-cancer agents with promising results in clinical trials. However, mechanistically little is known regarding their selectivity in killing malignant cells while sparing normal cells. Gene expression-based chemical genomics identified HDACis as being particularly potent against Down syndrome-associated myeloid leukemia (DS-AMKL) blasts. Investigating the antileukemic function of HDACis revealed their transcriptional and post-translational regulation of key autophagic proteins, including ATG7. This leads to suppression of autophagy, a lysosomal degradation process that can protect cells against damaged or unnecessary organelles and protein aggregates. DS-AMKL cells exhibit low baseline autophagy due to mammalian target of rapamycin (mTOR) activation. Consequently, HDAC inhibition repressed autophagy below a critical threshold, which resulted in accumulation of mitochondria, production of reactive oxygen species, DNA damage and apoptosis. Those HDACi-mediated effects could be reverted upon autophagy activation or aggravated upon further pharmacological or genetic inhibition. Our findings were further extended to other major acute myeloid leukemia subgroups with low basal level autophagy. The constitutive suppression of autophagy due to mTOR activation represents an inherent difference between cancer and normal cells. Thus, via autophagy suppression, HDACis deprive cells of an essential pro-survival mechanism, which translates into an attractive strategy to specifically target cancer cells.

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Acknowledgements

We thank Dr Bradner for sharing the reagents, the Mizushima and Levine laboratories for valuable methodological advice, and C Reimer and L Queißer for technical assistance. This work was supported by a grant to JHK and DR from the Wilhelm Sander-Foundation (2011.057.1), the German Research Foundation (DFG; KL-2374/1-1) and to SHO from the NIH. JHK is a fellow of the Emmy Noether-Programme from the DFG (KL-2374/2-1). SHO is an Investigator of the Howard Hughes Medical Institute. GMNB and MVS were supported by the DFG (BE-2089/2-1 and EXC62/1), NS by the SFB/TR77, ML by the DFG (LE-953/8-1 and LE-953/6-1) and the Mildred-Scheel-Stiftung (#109891) and KH by the Hannover Biomedical Research School. ZL was a Fellow of the Leukemia & Lymphoma Society and is supported by NIH grant R01 HL107663.

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Author notes

  1. M V Stankov, M El Khatib, G M N Behrens and J H Klusmann: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Immunology and Rheumatology, Hannover Medical School, Hannover, Germany

    M V Stankov & G M N Behrens

  2. Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany

    M El Khatib, B Kumar Thakur, K Heitmann, J Schoening, D Reinhardt & J H Klusmann

  3. Department of Dermatology, Section of Molecular Dermatology, Venerology and Allergology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

    D Panayotova-Dimitrova & M Leverkus

  4. Division of Pediatric Oncology, Universitäts-Kinderklinik Zurich, Zurich, Switzerland

    J P Bourquin

  5. Department of Gastroenterology, Hepatology and Endocrinology Hannover Medical School, Hannover, Germany

    N Schweitzer

  6. Department of Molecular Hematopoiesis, Hannover Medical School, Hannover, Germany

    K Welte

  7. Division of Genetics, Brigham & Women’s Hospital, Boston, MA, USA

    Z Li

  8. Harvard Medical School and Harvard Stem Cell Institute, Boston, MA, USA

    S H Orkin

  9. Department of Pediatric Oncology, Dana Farber Cancer Institute and Children's Hospital, Boston, MA, USA

    S H Orkin

  10. Howard Hughes Medical Institute, Boston, MA, USA

    S H Orkin

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  1. M V Stankov
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Correspondence to G M N Behrens or J H Klusmann.

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The authors declare no conflict of interest.

Additional information

JHK, MVS and ME-K designed and performed the experiments, analyzed the data and wrote the manuscript. GMNB, SHO and ZL designed the experiments, interpreted the data and wrote the manuscript. KH, NS, MEK and DPD designed and performed the experiments, analyzed the data and revised the manuscript. BT designed the experiments and revised the manuscript. JS performed and analyzed the experiments. JPB performed gene expression-based chemical genomics screening. DR, KW and ML provided materials/reagents and revised the manuscript.

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Stankov, M., El Khatib, M., Kumar Thakur, B. et al. Histone deacetylase inhibitors induce apoptosis in myeloid leukemia by suppressing autophagy. Leukemia 28, 577–588 (2014). https://doi.org/10.1038/leu.2013.264

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