Authors: Annette Romanski, Kerstin Schwarz, Maren Keller, Sarah Wietbrauk, Anja Vogel, Jessica Roos, Claudia Oancea, Boris Brill, Oliver H. Krämer, Hubert Serve, Martin Ruthardt and Gesine Bug

Annette Romanski

Department of Medicine II; Hematology and Oncology; Johann Wolfgang Goethe-University; Frankfurt/Main, Germany
These authors contributed equally to this work.

Kerstin Schwarz

Department of Medicine II; Hematology and Oncology; Johann Wolfgang Goethe-University; Frankfurt/Main, Germany
These authors contributed equally to this work.

Maren Keller

Department of Medicine II; Hematology and Oncology; Johann Wolfgang Goethe-University; Frankfurt/Main, Germany

Sarah Wietbrauk

Department of Medicine II; Hematology and Oncology; Johann Wolfgang Goethe-University; Frankfurt/Main, Germany

Anja Vogel

Department of Medicine II; Hematology and Oncology; Johann Wolfgang Goethe-University; Frankfurt/Main, Germany

Jessica Roos

Department of Medicine II; Hematology and Oncology; Johann Wolfgang Goethe-University; Frankfurt/Main, Germany

Claudia Oancea

Department of Medicine II; Hematology and Oncology; Johann Wolfgang Goethe-University; Frankfurt/Main, Germany

Boris Brill

Institute for Biomedical Research Georg Speyer-Haus; Frankfurt/Main, Germany

Oliver H. Krämer

Institute of Biochemistry and Biophysics; Center for Molecular Biomedicine; Friedrich-Schiller University; Jena, Germany

Hubert Serve

Department of Medicine II; Hematology and Oncology; Johann Wolfgang Goethe-University; Frankfurt/Main, Germany

Martin Ruthardt

Department of Medicine II; Hematology and Oncology; Johann Wolfgang Goethe-University; Frankfurt/Main, Germany

Gesine Bug

Corresponding author: g.bug@em.uni-frankfurt.de
Department of Medicine II; Hematology and Oncology; Johann Wolfgang Goethe-University; Frankfurt/Main, Germany

Abstract:
Acute myeloid leukemia (AML) is a highly malignant disease that is not curable in the majority of patients. Numerous non-random genetic abnormalities are known, among which several translocations such as PLZF/RARα or AML1/ETO are known to aberrantly recruit histone deacetylases. Deacetylase inhibitors (DACi) are promising drugs leading to growth inhibition, cell cycle arrest, premature senescence and apoptosis in malignant cells. It is believed that DACi may have clinical efficacy by eradicating the most primitive population of leukemic stem and progenitor cells, possibly by interfering with self-renewal.

The aim of the study was to investigate the effects of DACi on leukemic stem and progenitor cells using murine transduction-transplantation models of hematopoietic cells harboring the leukemia-associated fusion proteins (LAFP) PLZF/RARα or a truncated AML1/ETO protein (AML1/ETO exon 9). We show that the self-renewal and short-term repopulation capacity of AML1/ETO- or PLZF/RARα-expressing Sca1⁺/lin^- stem and progenitor cells are profoundly inhibited by clinically applicable concentrations of the DACi dacinostat and vorinostat. To further investigate the mechanisms underlying these effects, we examined the impact of DACi on the transcription factor c-MYC and the Polycomb group protein BMI1, which are induced by LAFP and involved in leukemic transformation. In AML1/ETO or PLZF/RARα-positive 32D cells, DACi-mediated antiproliferative effects were associated with downregulation of BMI1 and c-MYC protein levels. Similar effects were demonstrated in primary samples of cytogenetically defined high-risk AML patients. In conclusion, DACi may be effective as maintenance therapy by negatively interfering with signaling pathways that control survival and proliferation of leukemic stem and progenitor cells.

Received: February 21, 2012; Accepted: July 20, 2012; Published Online: August 16, 2012

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