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Molecular targets for therapy

Identification of bromodomain-containing protein-4 as a novel marker and epigenetic target in mast cell leukemia

Leukemia volume 29, pages 2230–2237 (2015)Cite this article

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Abstract

Advanced systemic mastocytosis (SM) is a life-threatening neoplasm characterized by uncontrolled growth and accumulation of neoplastic mast cells (MCs) in various organs and a poor survival. So far, no curative treatment concept has been developed for these patients. We identified the epigenetic reader bromodomain-containing protein-4 (BRD4) as novel drug target in aggressive SM (ASM) and MC leukemia (MCL). As assessed by immunohistochemistry and PCR, neoplastic MCs expressed substantial amounts of BRD4 in ASM and MCL. The human MCL lines HMC-1 and ROSA also expressed BRD4, and their proliferation was blocked by a BRD4-specific short hairpin RNA. Correspondingly, the BRD4-targeting drug JQ1 induced dose-dependent growth inhibition and apoptosis in HMC-1 and ROSA cells, regardless of the presence or absence of KIT D816V. In addition, JQ1 suppressed the proliferation of primary neoplastic MCs obtained from patients with ASM or MCL (IC50: 100–500 nm). In drug combination experiments, midostaurin (PKC412) and all-trans retinoic acid were found to cooperate with JQ1 in producing synergistic effects on survival in HMC-1 and ROSA cells. Taken together, we have identified BRD4 as a promising drug target in advanced SM. Whether JQ1 or other BET-bromodomain inhibitors are effective in vivo in patients with advanced SM remains to be elucidated.

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Acknowledgements

We thank Daniela Berger and Gabriele Stefanzl for excellent technical assistance, and Günther Hofbauer and Andreas Spittler (both at the Cell Sorting Core Unit of the Medical University of Vienna) for excellent technical support and advice. This study was supported by Austrian Science Fund, SFB Grant Nos. F4611, F4704-B20 and F4710-B20.

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Authors and Affiliations

  1. Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria

    G Wedeh, S Cerny-Reiterer, G Eisenwort, K Blatt, E Hadzijusufovic, I Sadovnik, W R Sperr & P Valent

  2. LBPA CNRS UMR8113, Ecole Normale Supérieure de Cachan, Cachan, France

    G Wedeh & M Arock

  3. Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria

    S Cerny-Reiterer, G Eisenwort, H Herrmann, E Hadzijusufovic, W R Sperr & P Valent

  4. Department of Radiotherapy, Medical University of Vienna, Vienna, Austria

    H Herrmann

  5. Department of Pathology, Medical University of Vienna, Vienna, Austria

    L Müllauer

  6. Third Medical Department, Division of Hematology, University of Heidelberg, Mannheim, Germany

    J Schwaab & A Reiter

  7. Research Institute of Molecular Pathology (IMP), Vienna, Austria

    T Hoffmann & J Zuber

  8. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    J E Bradner

  9. Division of Clinical Haematology, Guy's Hospital, London, UK

    D Radia

  10. Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria

    G Hoermann

  11. Institute of Pathology, Ludwig Maximilian University, Munich, Germany

    H-P Horny

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  1. G Wedeh
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Correspondence to P Valent.

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Competing interests

JEB is a scientific founder of Tensha Therapeutics, which is developing drug-like derivatives of the JQ1 bromodomain inhibitor as cancer therapeutics, through a license from the Dana-Farber Cancer Institute. H-PH has a consultancy with and received honoraria from Novartis. PV has a consultancy with and received honoraria and research funding from Novartis. The authors declare no other conflict of interest.

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Wedeh, G., Cerny-Reiterer, S., Eisenwort, G. et al. Identification of bromodomain-containing protein-4 as a novel marker and epigenetic target in mast cell leukemia. Leukemia 29, 2230–2237 (2015). https://doi.org/10.1038/leu.2015.138

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