Background/Hypotheses: Diamond Blackfan Anemia (DBA) is a disease that results in anemia, birth defects, and increased risk of cancer. The treatment for patients with DBA includes red cell transfusions, which can lead to iron overload in the heart and liver. Other treatments for DBA, including steroids and stem cell transplantation, suppress the immune systems leading to serious infections.

Approximately 25% of DBA patients have mutations in a ribosome protein known as RPS19. To understand the reasons why DBA patients develop anemia, we identified a protein, Nemo-Like Kinase (NLK) that is hyperactive in human cord blood stem cells with insufficient RPS19 (a cell model of DBA). We hypothesize that abnormal activity of NLK results in signals in the red cell precursors that lead to anemia. The goal of this project is to study 1) how NLK leads to anemia in DBA and 2) how drugs that inhibit NLK activity improves red cell production in DBA.

Critical problem: It is not known how RPS19 insufficiency in bone marrow cells leads to anemia. The studies proposed in this application will address the molecular pathways involved in the pathogenesis of DBA and potentially new ways to treat this disease.

Specific BMF disease to be researched: Diamond Blackfan Anemia

Innovative aspects: This is the first study describing the role of Nemo-Like Kinase in the pathogenesis of DBA. We will use innovative molecular techniques to study the downstream effects of NLK activity in RPS19-insufficient immature blood cells.

Impact: Short term, this research will provide new information about the role of NLK in red blood cell development and causes of DBA and thus, will advance the field. Long term, this study will potentially provide new targets for therapy to treat DBA patients and improve their quality of life.