Diamond-Blackan anemia (DBA) is the first ribosomopathy described and one of the constitutional inherited bone marrow failure syndromes. Erythroblastopenia is the major characteristic feature of the disease, which is a model for ribosomal diseases, related to a heterozygous allelic variation in one of the 20 ribosomal protein (RP) genes of either small or large ribosomal subunit. The salient feature of classical DBA is a defect in ribosomal RNA (rRNA) maturation, generating a nucleolar stress leading to stabilization of p53 and activation of its targets that result in cell cycle arrest and apoptosis. While the activation of p53 may not explain all aspects of erythroid tropism of DBA, the involvement of GATA1/HSP70 and of the globin/heme imbalance with an excess of the toxic free heme leading to reactive oxygen species (ROS) production account for defective erythropoiesis in DBA. Despite significant progress in defining molecular basis of DBA and increased understanding of the mechanistic basis for DBA pathophysiology, progress in developing new therapeutic options has been limited. However, there is hope for better future due to recent advances in gene therapy, better outcomes with stem cell transplantation and discoveries of putative new drugs by systematic drug screening using large chemical libraries.Copyright © 2020 American Society of Hematology.
