Project leaders: Wei Jiang, Jiyoung Hong, Stuart Orkin

Sickle cell disease (SCD) and the β-thalassemias are genetically heterogeneous chronic diseases with considerable morbidity and mortality. Multiple lines of genetic, biochemical, and clinical evidence have identified hemoglobin (HbF) as a modifier of severity of the globin disorders. Results support a model in which BCL11A coordinates the hemoglobin switch by participating in a multi-protein complex.

Broad Institute scientists have developed a comprehensive strategy to identify small molecule regulators of BCL11A. The first molecular concept is to identify small molecules that directly bind BCL11A, inhibiting its function. Broad researchers will use multiple biophysical assays to screen diverse chemical libraries. The second molecular concept will utilize cell-based assays that measure HbF induction. The team will utilize multiple approaches to identify the small molecule target and determine the mechanism of action.

Discovery biology efforts will complement the hit identification studies. In collaboration with the Proteomics Platform, the team will take a quantitative approach to identify less abundant but more cell-type specific and functionally relevant BCL11A protein partners. The goals of this approach are: to identify the protein complex required for HbF silencing, determine if it requires BCL11A recruitment, establish if it is directly involved in γ-globin transcription, and discover ways to disrupt it. In addition, a genome-wide shRNA screen for HbF induction identified a number of novel repressors of HbF, as well as known genes such as BCL11A. Validation that these repressors functionally regulate HbF will provide context as to whether targeting BCL11A is the best approach to raise HbF, or if other genes regulating BCL11A are more amenable for drug discovery.