Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease
- 28 June 2010
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 107 (28), 12617-12622
- https://doi.org/10.1073/pnas.1006774107
Abstract
The worldwide burden of sickle cell disease is enormous, with over 200,000 infants born with the disease each year in Africa alone. Induction of fetal hemoglobin is a validated strategy to improve symptoms and complications of this disease. The development of targeted therapies has been limited by the absence of discrete druggable targets. We developed a unique bead-based strategy for the identification of inducers of fetal hemoglobin transcripts in primary human erythroid cells. A small-molecule screen of bioactive compounds identified remarkable class-associated activity among histone deacetylase (HDAC) inhibitors. Using a chemical genetic strategy combining focused libraries of biased chemical probes and reverse genetics by RNA interference, we have identified HDAC1 and HDAC2 as molecular targets mediating fetal hemoglobin induction. Our findings suggest the potential of isoform-selective inhibitors of HDAC1 and HDAC2 for the treatment of sickle cell disease.Keywords
This publication has 33 references indexed in Scilit:
- Chemical phylogenetics of histone deacetylasesNature Chemical Biology, 2010
- Development of the pan-DAC inhibitor panobinostat (LBH589): Successes and challengesCancer Letters, 2009
- DNA polymorphisms at the BCL11A , HBS1L-MYB , and β- globin loci associate with fetal hemoglobin levels and pain crises in sickle cell diseaseProceedings of the National Academy of Sciences of the United States of America, 2008
- Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of β-thalassemiaProceedings of the National Academy of Sciences of the United States of America, 2008
- Signature-Based Small Molecule Screening Identifies Cytosine Arabinoside as an EWS/FLI Modulator in Ewing SarcomaPLoS Medicine, 2007
- Chromosome Conformation Capture Carbon Copy (5C): A massively parallel solution for mapping interactions between genomic elementsGenome Research, 2006
- HbF reactivation in sibling BFU-E colonies: synergistic interaction of kit ligand with low-dose dexamethasoneBlood, 2003
- Effect of Hydroxyurea on the Frequency of Painful Crises in Sickle Cell AnemiaThe New England Journal of Medicine, 1995
- Hydroxyurea enhances fetal hemoglobin production in sickle cell anemia.JCI Insight, 1984
- Augmentation of Fetal-Hemoglobin Production in Anemic Monkeys by HydroxyureaThe New England Journal of Medicine, 1984