The role of Ribosomal Protein Subunit 14 (RPS14) deficiency in the pathogenesis of del(5q) Myelodysplastic Syndromes (MDS) is not well understood. Despite treatment of MDS patients with lenalidomide, 50% of patients will not respond and these patients have an increased risk of acute myeloid leukemia (AML). Patients with anemia may require chronic red cell transfusions resulting in impaired quality of life. Haploinsufficiency of RPS14 is responsible for the anemia phenotype in del(5q) MDS. Therefore, it is critical to understand the mechanisms underlying the defects in erythropoiesis associated with RPS14 deficiency in del(5q) MDS and develop new therapies to treat this disease. To study the molecular pathways downstream of ribosomal protein insufficiency and bone marrow failure, we performed RNA-seq with RPS19 deficient human CD34+ hematopoietic stem and progenitor cells to model Diamond Blackfan Anemia, and found genes that were aberrantly regulated in both RPS19 and RPS14-deficient hematopoietic progenitor cells compared to normal cells. Several of these genes were cytokines and chemokines that regulate inflammatory pathways. The goal of this research is to further define the signaling pathways that contribute to the pathogenesis of RPS14 deficiency in del(5q) MDS and test immune modulatory and anti-inflammatory drugs to rescue the anemia using both human and zebrafish models. We propose three specific aims.
In Aim 1, we will characterize signaling pathways regulating erythropoiesis in RPS14- deficient human MDS models.
In Aim 2, we will characterize signaling pathways regulating erythropoiesis in RPS14-deficient zebrafish.
In Aim 3, we will identify and test known compounds to develop potentially novel therapies to treat erythroid defects in del(5q) MDS. Our studies will increase our understanding of MDS and lead to potentially new approaches to treat del(5q) MDS.
This project is relevant to public health because it focuses on identifying new pathways and development of new approaches to treat anemia in del(5q) MDS. Therefore, results from this work will advance the field and improve the quality of life of MDS patients.
| Sakamoto, K M; Narla, A (2018) Perspective on Diamond-Blackfan anemia: lessons from a rare congenital bone marrow failure syndrome. Leukemia 32:249-251 |
| Danilova, Nadia; Wilkes, Mark; Bibikova, Elena et al. (2018) Innate immune system activation in zebrafish and cellular models of Diamond Blackfan Anemia. Sci Rep 8:5165 |
| Youn, Minyoung; Wang, Nan; LaVasseur, Corinne et al. (2017) Loss of Forkhead box M1 promotes erythropoiesis through increased proliferation of erythroid progenitors. Haematologica 102:826-834 |
| Wilkes, Mark C; Repellin, Claire E; Sakamoto, Kathleen M (2017) Beyond mRNA: The role of non-coding RNAs in normal and aberrant hematopoiesis. Mol Genet Metab 122:28-38 |
