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Depsipeptide (FR 901228) promotes histone acetylation, gene transcription, apoptosis and its activity is enhanced by DNA methyltransferase inhibitors in AML1/ETO-positive leukemic cells

Leukemia volume 17, pages 350–358 (2003)Cite this article

Abstract

In t(8;21) acute myeloid leukemia (AML), the AML1/ETO fusion protein promotes leukemogenesis by recruiting histone deacetylase (HDAC) and silencing AML1target genes important for hematopoietic differentiation. We hypothesized that depsipeptide (FR901228), a novel HDAC inhibitor evaluated in ongoing clinical trials, restores gene transcription and cell differentiation in AML1/ETO-positive cells. A dose-dependent increase in H3 and H4 histone acetylation was noted in depsipeptide-treated AML1/ETO-positive Kasumi-1 cells and blasts from a patient with t(8;21) AML. Consistent with this biological effect, we also showed a dose-dependent increase in cytotoxicity, expression of IL-3, here used as read-out for silenced AML1-target genes, upregulation of CD11b with other morphologic changes suggestive of partial cell differentiation in Kasumi-1 cells. Some of these biologic effects were also attained in other myeloid leukemia cell lines, suggesting that depsipeptide has differentiation and cytotoxic activity in AML cells, regardless of the underlying genomic abnormality. Notably, the activity of depsipeptide was enhanced by 5-aza-2′-deoxycytidine, a DNA methyltransferase inhibitor (DNMT). These two agents in combination resulted in enhanced histone acetylation, IL-3 expression, and cytotoxicity, suggesting HDAC and DNMT activities as a potential dual target in future therapeutic strategies for AML1/ETO and other molecular subgroups of AML.

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Acknowledgements

Supported in part by P30CA16058 and K08-CA90469 grants, National Cancer Institute, Bethesda, MD, The Coleman Leukemia Research Foundation, Sidney Kimmel Cancer Foundation, Leukemia and Lymphoma Society of America, Warren Brown Family Foundation, and RPG-00-340-01-CSM grants.

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Author notes

  1. M I Klisovic and E A Maghraby: MIK and EAM have contributed equally in the completion of this work

Authors and Affiliations

  1. Division of Hematology-Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA

    M I Klisovic, E A Maghraby, M Guimond, A R Sklenar, S P Whitman, K K Chan, J Anon, K J Archer, M R Grever, J C Byrd & G Marcucci

  2. Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, USA

    M R Parthun

  3. Division of Human Cancer Genetics Department of Microbiology, The Ohio State University, Columbus, OH, USA

    C Plass

  4. Department of Veterinary Biosciences, The Comprehensive Cancer Center, at The Ohio State University, Columbus, OH, USA

    L J Rush

  5. Department of Hematology-Oncology, Brooke Army Medical Center, Houston, TX, USA

    T Murphy

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  1. M I Klisovic
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Klisovic, M., Maghraby, E., Parthun, M. et al. Depsipeptide (FR 901228) promotes histone acetylation, gene transcription, apoptosis and its activity is enhanced by DNA methyltransferase inhibitors in AML1/ETO-positive leukemic cells. Leukemia 17, 350–358 (2003). https://doi.org/10.1038/sj.leu.2402776

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