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Selective anti-leukaemic activity of low-dose histone deacetylase inhibitor ITF2357 on AML1/ETO-positive cells

Oncogene volume 27, pages 1767–1778 (2008)Cite this article

Abstract

We analysed the in vitro effects of a new hydroxamate derivative, ITF2357, on AML cells. ITF2357 potently induced histone acetylation. ITF2357 0.1 μM blocked proliferation and induced apoptosis in AML1/ETO-positive Kasumi-1 cells, while AML1/ETO-negative HL60, THP1 and NB4 cell lines were sensitive only to 1 μM ITF2357. Apoptosis was induced by 0.1 μM ITF2357 in AML1/ETO-positive primary blasts and U937-A/E cells induced to express AML1/ETO, but not in U937-A/E cells non-expressing AML1/ETO. In Kasumi-1 cells 0.1 μM ITF2357 induced AML1/ETO degradation through a caspase-dependent mechanism. ITF2357 0.1 μM also determined DNMT1 efflux from, and p300 influx to, the nucleus. Moreover, 0.1 μM ITF2357 determined local H4 acetylation and release of DNMT1, HDAC1 and AML1/ETO, paralleled by recruitment of p300 to the IL-3 gene promoter. ITF2357 treatment, however, did not induce re-expression of IL-3 gene. Accordingly, the methylation level of IL-3 promoter, as well as of several other genes, was unmodified. In conclusion, ITF2357 emerged as an anti-leukaemic agent very potent on AML cells, and on AML1/ETO-positive cells in particular. More relevantly, clearly emerged from our results that ITF2357 could be an ideal agent to treat AML subtypes presenting AML1/ETO fusion protein which determine HDAC involvement in leukaemogenesis.

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Acknowledgements

We thank R Pastorelli for performing Methylation-specific PCR and sequencing. Ministero per la Istruzione, la Università e la Ricerca, Istituto Superiore di Sanità (National Program ‘Stem Cells’), Ente-Cassa di Risparmio di Firenze, Fondazione-Cassa di Risparmio di Volterra. ER was supported by a fellowship from AIRC/FIRC.

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Authors and Affiliations

  1. Dipartimento di Patologia e Oncologia Sperimentali, Università degli Studi di Firenze, Firenze, Italy

    V Barbetti, E Rovida, A Morandi & P Dello Sbarba

  2. UF Ematologia, Università degli Studi di Firenze, AOU Careggi, Firenze, Italy

    A Gozzini, E Spinelli & V Santini

  3. Italfarmaco S.p.A., Milano, Italy

    G Fossati & P Mascagni

  4. Department of Medicine, University of Freiburg, Freiburg, Germany

    M Lübbert

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  1. V Barbetti
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  2. A Gozzini
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Correspondence to V Santini.

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Barbetti, V., Gozzini, A., Rovida, E. et al. Selective anti-leukaemic activity of low-dose histone deacetylase inhibitor ITF2357 on AML1/ETO-positive cells. Oncogene 27, 1767–1778 (2008). https://doi.org/10.1038/sj.onc.1210820

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