The Novel Histone Deacetylase Inhibitor, LBH589, Induces Expression of DNA Damage Response Genes and Apoptosis in Ph-Acute Lymphoblastic Leukemia Cells.

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 non-T non-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 (H3 and H4) 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 induces 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. Chromatin immunoprecipitation (ChIP) assays demonstrated increased histone acetylation at the GADD45G promoter following LBH589 treatment. Finally, 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%). Thus, LBH589 possesses potent growth inhibitory activity against Ph⁻ ALL cells associated with upregulation of genes critical for DNA repair. These findings provide a rationale for exploring the clinical activity of LBH589 in the treatment of patients with Ph⁻ ALL.