Harnessing single-cell technologies in the search for new therapies for Diamond-Blackfan anemia

The emergence of multi-omic single-cell technologies over the last decade has led to improved insights into both normal hematopoiesis and its perturbation in a variety of hematological disorders. Diamond-Blackfan anemia (DBA) is one such disorder where single-cell assays have helped to delineate the cellular and molecular defects underlying the disease. DBA is caused by heterozygous loss of function germline variants in genes encoding ribosomal proteins (RPs). Despite the widespread role of ribosomes in hematopoiesis, the most frequent and severe cytopenia in DBA is anemia. In this review we will discuss how single cell studies- including clonogenic cell culture assays, fluorescence activated cell sorting (FACS) and single cell RNA sequencing (scRNAseq)-have led to insights into the pathogenesis of DBA. The main therapies are regular blood transfusions, glucocorticoids or hematopoietic stem cell transplantation (HSCT) but all are associated with significant morbidity and mortality. We will therefore outline how single-cell studies can inform new therapies for DBA. Furthermore, we will discuss how DBA serves as a useful model for understanding normal erythropoiesis in terms of its cellular hierarchy, molecular regulation during homeostasis and in response to ‘stress’.