Activin signaling in normal and disordered erythropoiesis ABSTRACT Disorders associated with anemia such as ?-thalassemia (BT) and myelodysplastic syndrome (MDS) are a major clinical challenge in the United States, as many of these patients require chronic, expensive treatment for survival. Two novel, very similar drugs, Sotatercept (ACE-011) and Luspatercept (ACE-536), are presently being tested in clinical trials, and they have shown success in improving anemia and bone mass in BT, and delay of disease onset in MDS. Importantly, Sotatercept and Luspatercept contain the extracellular domain of activin receptor 2A (ACVR2A) and 2B (ACVR2B), respectively, and they use a non-erythropoietin (EPO)- dependent pathway to enhance red blood cell (RBC) production. Their proposed mechanism of action is to trap transforming growth factor (TGF) ?-like ligands, thereby modulating activin signaling via altered modification of the intracellular SMAD complex. Studies in BT mice suggest that the target of these drugs is the TGF?-like ligand growth differentiation factor 11 (GDF11). Moreover, it has been proposed that GDF11 is upregulated in erythroid cells of BT and MDS mice, inhibiting late-stage erythroid differentiation via SMAD complex phosphorylation. However, these results are not consistent with our preliminary data showing that Gdf11 deletion failed to recapitulate the phenotype observed in animals treated with RAP-536 (the mouse counterpart of Luspatercept). In addition, Gdf11-deleted mice continued to respond to RAP-536. Thus, we hypothesize that GDF11 is not the sole target responsible for the improvements observed in RAP-536-treated BT mice or that lack of GDF11 is required, but not sufficient, for increased RBC production. Of note, these drugs also increase erythropoiesis in normal individuals and mice. Here, we propose to investigate the pathways involved in normal and ineffective erythropoiesis using wild-type (WT) and BT mice, respectively, with the following specific aims (SA): 1. Characterize the mechanisms by which RAP-536 increases erythropoiesis in WT mice and improves anemia in BT mice. We will characterize erythropoiesis in RAP-536 treated, WT and BT mice, and if this drug promotes macrophage-erythroblast interaction. 2. Investigate the consequences of simultaneous inhibition of the candidate ligands responsible for the increased erythropoiesis mediated by RAP-536. We will inhibit GDF11, GDF8, which is highly homologous to GDF11, and Activin-B, individually and in combination in WT and BT mice, to determine whether their inactivation is necessary for enhanced erythropoiesis. 3. Identify which cell types respond to RAP-536 administration by targeting the candidate Acvr2A/B receptors in erythroid and myeloid cells. We will use transgenic, SMAD-responsive, reporter mice to identify which cells show altered pathway activity following RAP-536 treatment. To further identify the cells that are responsible for the erythroid phenotype in RAP-536-treated, BT mice, we will use mouse lines with cell-type-specific deletions of Acvr2A and Acvr2B. Such insight should result in important clinical advances in treating BT, MDS, and other anemias, such as anemia of inflammation.
| Aschemeyer, Sharraya; Qiao, Bo; Stefanova, Deborah et al. (2018) Structure-function analysis of ferroportin defines the binding site and an alternative mechanism of action of hepcidin. Blood 131:899-910 |
| Oikonomidou, Paraskevi Rea; Rivella, Stefano (2018) What can we learn from ineffective erythropoiesis in thalassemia? Blood Rev 32:130-143 |
| Casu, Carla; Nemeth, Elizabeta; Rivella, Stefano (2018) Hepcidin agonists as therapeutic tools. Blood 131:1790-1794 |
| Gupta, Ritama; Musallam, Khaled M; Taher, Ali T et al. (2018) Ineffective Erythropoiesis: Anemia and Iron Overload. Hematol Oncol Clin North Am 32:213-221 |
| Casu, Carla; Presti, Vania Lo; Oikonomidou, Paraskevi Rea et al. (2018) Short-term administration of JAK2 inhibitors reduces splenomegaly in mouse models of ?-thalassemia intermedia and major. Haematologica 103:e46-e49 |
| Hotz, Meghan J; Qing, Danielle; Shashaty, Michael G S et al. (2018) Red Blood Cells Homeostatically Bind Mitochondrial DNA through TLR9 to Maintain Quiescence and to Prevent Lung Injury. Am J Respir Crit Care Med 197:470-480 |
| Guerra, Amaliris; Musallam, Khaled M; Taher, Ali T et al. (2018) Emerging Therapies. Hematol Oncol Clin North Am 32:343-352 |
| Khorramian, Eeman; Fung, Eileen; Chua, Kristine et al. (2017) In a Mouse Model of Sepsis, Hepcidin Ablation Ameliorates Anemia More Effectively than Iron and Erythropoietin Treatment. Shock 48:490-497 |
| Pasricha, Sant-Rayn; Lim, Pei Jin; Duarte, Tiago L et al. (2017) Hepcidin is regulated by promoter-associated histone acetylation and HDAC3. Nat Commun 8:403 |
| Li, Huihui; Choesang, Tenzin; Bao, Weili et al. (2017) Decreasing TfR1 expression reverses anemia and hepcidin suppression in ?-thalassemic mice. Blood 129:1514-1526 |
Showing the most recent 10 out of 55 publications
