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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 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 Citation Map 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 Google Scholar Articles by Scuto, A. Articles by Jove, R. PubMed PubMed Citation Articles by Scuto, A. Articles by Jove, R. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA The novel histone deacetylase inhibitor, LBH589, induces expression of DNA damage response genes and apoptosis in Ph– acute lymphoblastic leukemia cells Anna Scuto1, Mark Kirschbaum2, Claudia Kowolik1, Leo Kretzner3, Agnes Juhasz3, Peter Atadja4, Vinod Pullarkat2, Ravi Bhatia2, Stephen Forman2, Yun Yen3, and Richard Jove1 1 Molecular Medicine, 2 Hematology and Hematopoietic Cell Transplantation, 3 Clinical and Molecular Pharmacology, City of Hope Beckman Research Institute and National Medical Center, Duarte, CA; and 4 Novartis Pharmaceuticals, Cambridge, MA 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 biologic and gene expression responses. Low nanomolar concentrations (IC50: 5-20 nM) of LBH589 induced cell-cycle arrest, apoptosis, and histone (H3K9 and H4K8) hyperacetylation. LBH589 treatment increased mRNA levels of proapoptosis, growth arrest, and DNA damage repair genes including 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 including Ph– ALL cells associated with up-regulation 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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