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DNA Damage and Cellular Stress Responses

Histone Deacetylase Inhibitors (HDI) Cause DNA Damage in Leukemia Cells: A Mechanism for Leukemia-Specific HDI-Dependent Apoptosis?

¹Department of Haematological Medicine, Leukemia Sciences Laboratories, The Rayne Institute, GKT School of Medicine, Denmark Hill campus, London, United Kingdom; ²Institut National de la Sante et de la Recherche Medicale U718, Institût Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France; ³School of Biosciences, Cardiff University, Cardiff, United Kingdom; and ⁴Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland

^* To whom correspondence should be addressed. E-mail: frassool{at}som.umaryland.edu.

	Abstract

Histone deacetylase inhibitors (HDI) increase gene expression through induction of histone acetylation. However, it remains unclear whether increases in specific gene expression events determine the apoptotic response following HDI administration. Herein, we show that a variety of HDI trigger in hematopoietic cells not only widespread histone acetylation and DNA damage responses but also actual DNA damage, which is significantly increased in leukemic cells compared with normal cells. Thus, increase in H2AX and ataxia telangiectasia mutated (ATM) phosphorylation, early markers of DNA damage, occurs rapidly following HDI administration. Activation of the DNA damage and repair response following HDI treatment is further emphasized by localizing DNA repair proteins to regions of DNA damage. These events are followed by subsequent apoptosis of neoplastic cells but not normal cells. Our data indicate that induction of apoptosis by HDI may result predominantly through accumulation of excessive DNA damage in leukemia cells, leading to activation of apoptosis. (Mol Cancer Res 2006;4(8):1-11)

Key Words: hematologic, other, leukemias and cellular stress responses, DNA damage and repair mechanisms, small molecules and other therapeutic agents

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