A160

Shwachman- Diamond Syndrome (SDS) is an autosomal recessive disorder distinguished by skeletal malformations, exocrine pancreatic insufficiency, bone marrow failure, and a pediatric predisposition to acute myeloid leukemia and myeloid dysplastic syndrome (MDS). SDS presents a disease model from which to gain insight into the molecular development and progression of leukemias and MDS. Produced by mutations in the Shwachman Bodian Diamond Syndrome (SBDS) gene, SDS affects approximately 1 in 75,000 children worldwide. Currently bone marrow transplant provides a therapeutic option for the hematological disorder. However, this procedure carries the risk of complications. To address the need for pharmacotherapeutics for SDS and related bone marrow syndromes, we have launched a drug discovery initiative that has yielded promising results. Using a Saccharomyces cerevisiae model system in which sdo1, the yeast ortholog of SBDS, was conditionally inactivated, we collaborated with the Institute for Chemistry and Cell Biology to perform a high throughput screen of 68,000 compounds. The screen uncovered 330 hits that reverse the slow growth phenotype associated with the mutation, including Trichostatin A (TSA), which possesses potent histone deacetylase (HDAC) inhibitory activity. Cell proliferation assays demonstrated that TSA effectively rescues the slow growth of sdo1- yeast strains, raising it 5.91 standard deviations above controls. Given that HDAC inhibitors have generated considerable interest as therapeutics for a wide variety of diseases, including cancer, we are looking forward to extending our studies by examining the efficacy of TSA in mammalian cell models of SDS.

Sixth AACR International Conference on Frontiers in Cancer Prevention Research-- Dec 5-8, 2007; Philadelphia, PA