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Prepublished online as a Blood First Edition Paper on March 20, 2003; DOI 10.1182/blood-2002-12-3794. This Article Full Text (PDF) All Versions of this Article: 2002-12-3794v1 102/2/652    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Aron, J. L Articles by Byrd, J. C Search for Related Content PubMed PubMed Citation Articles by Aron, J. L Articles by Byrd, J. C Social Bookmarking                   What's this? Submitted December 17, 2002 Accepted March 13, 2003 Depsipeptide (FR901228) induces histone acetylation and inhibition of histone deacetylase in chronic lymphocytic leukemia cells concurrent with activation of caspase-8-mediated apoptosis and downregulation of c-FLIP protein Jennifer L Aron, Mark R Parthun, Guido Marcucci, Shinichi Kitada, Andrew P Mone, Melanie E Davis, Tiansheng Shen, Timothy Murphy, Joseph Wickham, Chris Kanakry, David M Lucas, John C Reed, Michael R Grever, and John C Byrd* Department of Internal Medicine, The Ohio State University, Columbus, OH, USA Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, USA The Burnham Institute, San Diego, CA, USA Department of Medicine, Brook Army Medical Center, San Antonio, TX, USA * Corresponding author; email: byrd-3{at}medctr.osu.edu. Depsipeptide is in clinical trials for chronic lymphocytic leukemia (CLL) based upon earlier observations demonstrating selective in vitro activity in this disease. We sought to determine the relationship of histone H3 and H4 acetylation, inhibition of histone deacetylase, and apoptosis observed in CLL cells to justify a pharmacodynamic endpoint in these clinical trials. Herein we demonstrate that in vitro depsipeptide induces histone H3 and H4 acetylation and histone deacetylase enzyme inhibition at concentrations corresponding to the LC50 for cultured CLL cells (0.038µM of depsipeptide). The changes in histone acetylation are lysine-specific, involving H4 K5, H4 K12, and H3 K9 and to a lesser extent, H4 K8 but not H4 K16 or H3 K14. Depsipeptide-induced apoptosis is caspase-dependent, selectively involving the TNF-receptor (extrinsic pathway) initiating caspase 8 and effector caspase 3. Activation of caspase 8 was accompanied by the down-regulation of FLICE-inhibitory protein (c-FLIP, I-FLICE) without evidence of Fas (CD95) up-regulation. Change in other apoptotic proteins including bcl-2, bax, mcl-1, and XIAP was not observed. Collectively, our results demonstrate a relationship between target enzyme inhibition of histone deacetylase, histone H3 and H4 acetylation and apoptosis involving the TNF-receptor pathway of apoptosis that is not utilized by other therapeutic agents in CLL. These data provide further support for clinical trials of depsipeptide in CLL and suggest usage of histone H3 and H4 acetylation, inhibition of histone deacetylase, and down-regulation of FLIP as pharmacodynamic endpoints for evaluation of this drug in patients in vivo. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: V. M. Klimek, S. Fircanis, P. Maslak, I. Guernah, M. Baum, N. Wu, K. Panageas, J. J. 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