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Blood, 15 May 2008, Vol. 111, No. 10, pp. 5093-5100. Prepublished online as a Blood First Edition Paper on March 18, 2008; DOI 10.1182/blood-2007-10-117762. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-10-117762v1 111/10/5093    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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Scuto, A. Articles by Jove, R. Search for Related Content PubMed PubMed Citation Articles by Scuto, A. Articles by Jove, R. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 17, 2007 Accepted March 14, 2008 The novel histone deacetylase inhibitor, LBH589, induces expression of DNA damage response genes and apoptosis in Ph- acute lymphoblastic leukemia cells Anna Scuto, Mark Kirschbaum, Claudia Kowolik, Leo Kretzner, Agnes Juhasz, Peter Atadja, Vinod Pullarkat, Ravi Bhatia, Stephen Forman, Yun Yen, and Richard Jove* Molecular Medicine, City of Hope Beckman Research Institute and National Medical Center, Duarte, CA Hematology and Hematopoietic Cell Transplantation, City of Hope Beckman Research Institute and National Medical Center, Duarte, CA Clinical and Molecular Pharmacology, City of Hope Beckman Research Institute and National Medical Center, Duarte, CA Oncology Research, Novartis Pharmaceuticals, Cambridge, MA * Corresponding author; email: rjove{at}coh.org. We investigated the mechanism of action of LBH589, a novel broad-spectrum HDAC inhibitor belonging to the hydroxamate class, in Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL). Two model human Ph- ALL cell lines (T-cell MOLT-4, and pre-B cell Reh) were treated with LBH589 and evaluated for biological and gene expression responses. Low nM concentrations (IC50 5-20 nM) of LBH589 induced cell cycle arrest, apoptosis and histone (H3K9 and H4K8) hyperacetylation. PCR array analysis revealed that LBH589 treatment increased mRNA levels of pro-apoptosis, growth arrest and DNA damage repair genes. Quantitative real-time PCR confirmed that LBH589 induced expression of FANCG, FOXO3A, GADD45A, GADD45B and GADD45G. The most dramatically expressed gene (up to 45-fold induction) observed after treatment with LBH589 is GADD45G. LBH589 treatment was associated with increased histone acetylation at the GADD45G promoter and phosphorylation of histone H2A.X. Furthermore, treatment with LBH589 was active against cultured primary Ph- ALL cells, including those from a relapsed patient, inducing loss of cell viability (up to 70%) and induction of GADD45G mRNA expression (up to 35 fold). Thus, LBH589 possesses potent growth inhibitory activity against Ph- ALL cells associated with upregulation of genes critical for DNA damage response and growth arrest. These findings provide a rationale for exploring the clinical activity of LBH589 in the treatment of patients with Ph- ALL. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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