Diamond-Blackfan Anemia

Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome (IBMFS) that presents in early infancy and is characterized by severe anemia with mild macrocytosis, reticulocytopenia, and a normocellular bone marrow with a paucity of erythroid precursors. Clinically DBA is typified by failure of red cell terminal differentiation, an array of physical anomalies, and a predisposition to malignancy. Notably the study of DBA has defined a class of IBMFS referred to as “ribosomopathies” as the pathogenesis of DBA involves predominantly (in about 65–70% of patients) autosomal dominant mutations resulting in haploinsufficiency of ribosomal proteins (RP) encoded by 16 verified genes. X-linked mutations in two non-ribosomal genes, GATA1, encoding an erythroid transcription factor, and TSR2, encoding the putative RPS26 chaperone, are responsible for very rare instances of DBA. Tremendous progress using zebrafish and mouse models of DBA has advanced our understanding of the role of nucleolar stress (p53-dependent) and p53-independent mechanisms in the development of the DBA phenotype, providing strategies for therapeutic intervention. DBA is also confirmed to be a cancer predisposition syndrome. Our increasing understanding of the pathophysiology of DBA is leading to new therapeutic approaches such as ongoing open trials involving the modulation of mTOR and the TGFβ/activin pathways, with agents leucine and Sotatercept, respectively. In addition, trials with HDAC inhibitors, prolyl hydroxylase inhibitors, or PPAR-α agonists that are ongoing in other anemias may also provide useful insights for directing future therapies for patients with DBA.