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Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells

Leukemia volume 28, pages 2155–2164 (2014)Cite this article

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A Corrigendum to this article was published on 21 March 2017

Abstract

The histone demethylase LSD1 (KDM1A) demethylates mono- and di-methylated (Me2) lysine (K) 4 on histone H3. High LSD1 expression blocks differentiation and confers a poor prognosis in acute myeloid leukemia (AML). Here, treatment with the novel LSD1 antagonist SP2509 attenuated the binding of LSD1 with the corepressor CoREST, increased the permissive H3K4Me3 mark on the target gene promoters, and increased the levels of p21, p27 and CCAAT/enhancer binding protein α in cultured AML cells. In addition, SP2509 treatment or LSD1 shRNA inhibited the colony growth of AML cells. SP2509 also induced morphological features of differentiation in the cultured and primary AML blasts. SP2509 induced more apoptosis of AML cells expressing mutant NPM1 than mixed-lineage leukemia fusion oncoproteins. Treatment with SP2509 alone significantly improved the survival of immune-depleted mice following tail-vein infusion and engraftment of cultured or primary human AML cells. Co-treatment with pan-HDAC inhibitor (HDI) panobinostat (PS) and SP2509 was synergistically lethal against cultured and primary AML blasts. Compared with each agent alone, co-treatment with SP2509 and PS significantly improved the survival of the mice engrafted with the human AML cells, without exhibiting any toxicity. Collectively, these findings show that the combination of LSD1 antagonist and pan-HDI is a promising therapy warranting further testing against AML.

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Authors and Affiliations

  1. Cancer Center, Houston Methodist Research Institute, Houston, TX, USA

    W Fiskus, B Shah, B P Portier, S G T Devaraj, K Liu, S P Iyer & K N Bhalla

  2. Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA

    S Sharma

  3. Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT, USA

    D Bearss

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  1. W Fiskus
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Correspondence to K N Bhalla.

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Competing interests

DB is founder and Chief Scientific Officer of Salarius Pharmaceuticals; SS is Chief Medical Officer of Salarius Pharmaceuticals. The remaining authors declare no conflict of interest.

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Author contributions

WF, BS, BPP, SGTD and KL performed in vitro experiments in cultured and primary AML cells and analyzed the data. WF performed the in vivo studies in the NOD/SCID and NSG mice. SS and DJB provided a critical new reagent for the studies. SI provided primary AML cells for the in vitro and in vivo studies. KNB conceptualized, planned the experiments, supervised the studies, analyzed the data and prepared the manuscript.

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Fiskus, W., Sharma, S., Shah, B. et al. Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells. Leukemia 28, 2155–2164 (2014). https://doi.org/10.1038/leu.2014.119

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