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Molecular targets for therapy

Runx1 repression by histone deacetylation is critical for Setbp1-induced mouse myeloid leukemia development

Leukemia volume 30, pages 200–208 (2016)Cite this article

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Abstract

Abnormal activation of SETBP1 through overexpression or missense mutations is highly recurrent in various myeloid malignancies; however, it is unclear whether such activation alone is able to induce leukemia development. Here we show that Setbp1 overexpression in mouse bone marrow progenitors through retroviral transduction is capable of initiating leukemia development in irradiated recipient mice. Before leukemic transformation, Setbp1 overexpression significantly enhances the self-renewal of hematopoietic stem cells (HSCs) and expands granulocyte macrophage progenitors (GMPs). Interestingly, Setbp1 overexpression also causes transcriptional repression of critical hematopoiesis regulator gene Runx1 and this effect is crucial for Setbp1-induced transformation. Runx1 repression is induced by Setbp1-mediated recruitment of a nucleosome remodeling deacetylase (NuRD) complex to Runx1 promoters and can be reversed by treatment with histone deacetylase (HDAC) inhibitors Entinostat and Vorinostat. Moreover, treatment with these inhibitors caused efficient differentiation of Setbp1 activation-induced leukemia cells in vitro, and significantly extended the survival of mice transplanted with such leukemias, suggesting that HDAC inhibition could be an effective strategy for treating myeloid malignancies with SETBP1 activation.

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Acknowledgements

This work was supported by the National Institutes of Health (NIH) grants RO1CA143193 (YD) and RO1HL118281 (JPM), USUHS Pediatrics Grant QP86GI (YD) and USUHS Exploratory Grant R0863031 (YD).

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The views presented in this manuscript are those of the authors; no endorsement by the Uniformed Services University of the Health Sciences or the Department of Defense has been given or should be inferred.

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Author notes

  1. J P Maciejewski and Y Du: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA

    B A Vishwakarma, N Nguyen, K O Gudmundsson, V Negi, K Oakley, Y Han & Y Du

  2. Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    H Makishima, N Hosono, B Przychodzen & J P Maciejewski

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  1. B A Vishwakarma
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  2. N Nguyen
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Correspondence to J P Maciejewski or Y Du.

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Vishwakarma, B., Nguyen, N., Makishima, H. et al. Runx1 repression by histone deacetylation is critical for Setbp1-induced mouse myeloid leukemia development. Leukemia 30, 200–208 (2016). https://doi.org/10.1038/leu.2015.200

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