Identification of bromodomain-containing protein-4 as a novel marker and epigenetic target in mast cell leukemia
| Autor: | Andreas Reiter, Juliana Schwaab, Emir Hadzijusufovic, Sabine Cerny-Reiterer, Harald Herrmann, Gregor Hoermann, Deepti Radia, Katharina Blatt, Hans-Peter Horny, Gregor Eisenwort, Irina Sadovnik, James E. Bradner, Leonhard Müllauer, Johannes Zuber, Michel Arock, Peter Valent, Ghaith Wedeh, Wolfgang R. Sperr, Thomas Hoffmann |
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| Rok vydání: | 2015 |
| Předmět: | |
| Zdroj: | Leukemia. 29:2230-2237 |
| ISSN: | 1476-5551 0887-6924 |
| DOI: | 10.1038/leu.2015.138 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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