ZFIN ID: ZDB-PUB-150626-6
RAP-011 improves erythropoiesis in zebrafish model of Diamond-Blackfan anemia through antagonizing lefty1
Ear, J., Huang, H., Wilson, T., Tehrani, Z., Lindgren, A., Sung, V., Laadem, A., Daniel, T.O., Chopra, R., Lin, S.
Date: 2015
Source: Blood   126(7): 880-90 (Journal)
Registered Authors: Huang, Haigen, Lin, Shuo, Tehrani, Zahra
Keywords: none
MeSH Terms:
  • Activin Receptors, Type II/antagonists & inhibitors
  • Activin Receptors, Type II/blood
  • Anemia, Diamond-Blackfan/blood
  • Anemia, Diamond-Blackfan/drug therapy*
  • Anemia, Diamond-Blackfan/genetics
  • Animals
  • Disease Models, Animal
  • Erythropoiesis/drug effects*
  • Erythropoiesis/genetics
  • Gene Knockdown Techniques
  • Genes, p53
  • Humans
  • Left-Right Determination Factors/antagonists & inhibitors*
  • Left-Right Determination Factors/blood
  • Left-Right Determination Factors/genetics
  • Ligands
  • Recombinant Fusion Proteins/therapeutic use*
  • Ribosomal Proteins/blood
  • Ribosomal Proteins/deficiency
  • Ribosomal Proteins/genetics
  • Signal Transduction/drug effects
  • Zebrafish
  • Zebrafish Proteins/antagonists & inhibitors*
  • Zebrafish Proteins/blood
  • Zebrafish Proteins/genetics
  • beta-Thalassemia/blood
  • beta-Thalassemia/drug therapy
PubMed: 26109203 Full text @ Blood
Diamond-Blackfan Anemia (DBA) is a bone marrow failure disorder characterized by low red blood cell count. Mutations in ribosomal protein genes have been identified in approximately half of all DBA cases. Corticosteriod therapy and bone marrow transplantation are common treatment options for patients; however, significant risks and complications are associated with these treatment options. Therefore, novel therapeutic approaches are needed for treating DBA. Sotatercept, a.k.a ACE-011, (and its murine ortholog RAP-011) acts as an activin receptor type IIA ligand trap, increasing hemoglobin and hematocrit in pharmacologic models, in healthy volunteers, and in patients with β-thalasemia, by expanding late-stage erythroblasts through a mechanism distinct from erythropoietin. Here, we evaluated the effects of RAP-011 in zebrafish models of RPL11 ribosome deficiency. Treatment with RAP-011 dramatically restored hemoglobin levels caused by ribosome stress. In zebrafish embryos, RAP-011 likely stimulates erythropoietic activity by sequestering lefty1 from erythroid cells. These findings identify lefty1 as a signaling component in the development of erythroid cells and rationalize the use of sotatercept in DBA patients.