The Role of Nemo-like Kinase in the Pathogenesis and Treatment of Diamond Blackfan Anemia
Abstract
Diamond Blackfan Anemia (DBA) is a genetic disorder that results in pure red cell aplasia, congenital abnormalities, and predisposition to cancer. The current treatment with steroids, chronic transfusions, and stem cell transplantation leads to significant morbidity and even mortality. Approximately 25 percent of patients with DBA have mutations in RPS19. We identified Nemo-Like Kinase (NLK) as being hyperactive in RPS19-insufficient human cord blood CD34+ hematopoietic stem cells. Inhibition of NLK by knockdown or small molecules rescues the erythroid defect in RPS19-insufficient HPSCs. We propose two specific aims. In Aim 1, we will study the effects of NLK inhibitors, SD208 and metformin, on mTOR activity with or without leucine during erythropoiesis in models of DBA. In Aim 2, we will characterize signaling pathways downstream of NLK inhibition or activation in human RPS-insufficient erythroid progenitor cells. In Aim 1, tested the effects of drugs and small molecules that inhibit NLK activity with and without leucine in models of DBA. In Aim 2, we have begun to examine the signaling events downstream of NLK inhibition or activation by RNA-seq and Cytometry Time of Flight in human erythroid progenitors and other DBA models. Our results indicate that drugs that target NLK including metformin and SD208 improve erythropoiesis in DBA models. We will continue to test new therapies for DBA and study the signaling pathways downstream of NLK.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2020
- Accession Number
- AD1113580
Entities
People
- Kathleen M. Sakamoto
Organizations
- Stanford University