Red Cells and Ribosomes

More than two decades ago, researchers discovered that a rare congenital bone marrow failure syndrome, Diamond Blackfan anemia (DBA), is caused by mutations in a ribosomal protein (RP) RPS19. Subsequently, my mentor Dr. Benjamin Ebert identified RPS14 as the gene responsible for the profound macrocytic anemia in the 5q- syndrome, a subtype of myelodysplastic syndrome and additional mutations in other RP genes were identified in DBA. This reinforced the connection between ribosomal abnormalities and defects in erythropoiesis. Moreover, mutations in other genes required for normal ribosome biogenesis have been implicated in other rare congenital bone marrow failure syndromes including Schwachman-Diamond syndrome, X-linked dyskeratosis congenita, Cartilage Hair Hypoplasia and Treacher Collins syndrome. Each of these disorders is associated with specific defects in ribosome biogenesis, which cause distinct clinical phenotypes, most often involving bone marrow failure, and have become collectively known as ribosomopathies. My lab studies the molecular mechanisms by which ribosomal dysfunction leads to bone marrow failure by further characterizing the signaling pathways that are triggered and the subsequent effects on hematopoiesis. We are also studying the effects of specific drugs that have been shown to work in these conditions such as dexamethasone, leucine and lenalidomide to understand their effects in normal and disordered hematopoiesis. The goal of the lab is to make meaningful contributions to the elucidation of the pathophysiology of ribosomopathies, the development of novel therapies and ultimately to improve the care of patients with these rare diseases.