Signaling Pathways in Pathogenesis of Diamond Blackfan Anemia

Abstract

Abstract : Diamond Blackfan Anemia (DBA) is a disorder that results in pure red cell aplasia, congenital abnormalities, and predisposition to cancer. The current treatment of steroids and chronic transfusions leads to significant morbidity. To understand the mechanism by which RPS19 insufficiency leads to defects in erythropoiesis, we identified a p53 target, microRNA34a (miR34a), as being upregulated in human CD34+ fetal liver cells transduced with RPS19shRNA lentivirus. We hypothesize that RPS19 insufficiency mediates defects in erythropoiesis through upregulation of p53 and miR34a. We have further characterized the role of miR-34a in RPS-19 deficient CD34+ human fetal liver cells. We have identified additional microRNAs that are deregulated in RPS19-deficient CD34+ human fetal liver cells. We have also characterized downstream signaling pathways that regulate erythropoiesis in RPS19-deficient hematopoietic progenitor cells, in particular those that involve inflammation and DNA damage. These studies will provide new insights into the molecular pathways downstream of ribosomal protein insufficiency in hematopoietic stem cells and potentially novel targets for therapy.