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Histone deacetylase inhibitors induce the degradation of the t(8;21) fusion oncoprotein

Oncogene volume 26, pages 91–101 (2007)Cite this article

Abstract

The t(8;21) chromosomal translocation that generates the fusion oncoprotein RUNX1-ETO predominates in leukemia patients of the French-American-British (FAB) class M2 subtype. The oncoprotein has the capacity to promote expansion of hematopoietic stem/progenitor cells and induces leukemia in association with other genetic alterations. Here, we show that RUNX1-ETO undergoes degradation in response to treatment with histone deacetylase inhibitors, one of which, depsipeptide (DEP), is currently undergoing phase II clinical testing in a variety of malignancies. These compounds induce turnover of RUNX1-ETO without affecting the stability of RUNX1-ETO partner proteins. In addition, RUNX1-ETO physically interacts with heat shock protein 90 (HSP90). DEP treatment interrupts the association of RUNX1-ETO with HSP90 and induces proteasomal degradation of RUNX1-ETO. DEP and the HSP90 antagonist 17-allylamino-geldanamycin (17-AAG) both triggered RUNX1-ETO degradation, but without any additive or cooperative effects. These findings may stimulate the development of more rational and effective approaches for treating t(8;21) patients using histone deacetylase inhibitors or HSP90 inhibitors.

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Acknowledgements

We thank the members of the Hiebert lab for helpful discussions and encouragement, the Vanderbilt-Ingram Cancer Center (CA68485) for support and the use of shared resources, and Dr John Wright for assistance in procuring depsipeptide. This work was supported by National Institutes of Health (NIH) grants RO1-CA64140 (SWH) and R01-HL49118 and a VA Merit Review Award (SJB).

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Authors and Affiliations

  1. Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA

    G Yang & S W Hiebert

  2. Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN, USA

    M A Thompson

  3. Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA

    S J Brandt

  4. Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA

    S J Brandt

  5. Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA

    S J Brandt

  6. Tennessee Valley VA Healthcare System, Vanderbilt University School of Medicine, Nashville, TN, USA

    S J Brandt

  7. Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA

    S J Brandt & S W Hiebert

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Correspondence to S W Hiebert.

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Yang, G., Thompson, M., Brandt, S. et al. Histone deacetylase inhibitors induce the degradation of the t(8;21) fusion oncoprotein. Oncogene 26, 91–101 (2007). https://doi.org/10.1038/sj.onc.1209760

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