Post GWAS functional characterization of BCL11A locus toward the development of a treatment for ß-thalassemia

Beta-thalassemia is a genetic disorder characterized by reduced or absent production of hemoglobin, due to a defective synthesis of the beta-globin chains. It is known that the severity of the disease is affected not only by the type of genetic defect but also by genetic conditions able to compensate the imbalance of globin synthesis induced by the disease. The result is a variety of clinical manifestations with increasing severity, ranging from the healthy carrier state until the total transfusion dependency. Coinheritance of alpha-thalassemia and/or hereditary persistence of fetal hemoglobin are the best known examples involved in the clinical amelioration of the beta-thalassemia phenotype. In an effort to discover new modifier genes, for decades research focused on the identification of regulatory factors for the expression of fetal hemoglobin (HbF). Recently, genome-wide association studies conducted in different ethnic groups identified BCL11A gene as one of the main repressor of HbF expression in precursors of mature red blood cells showing the strongest impact on clinical phenotype. Based on this finding we aim to elucidate the BCL11A mechanism of action using different experimental approaches. The results of this study could lead to the development of a beta-thalassemia treatment having BCL11A as a therapeutic target for HbF induction in patients.