Biological basis for efficacy of activin receptor ligand traps in myelodysplastic syndromes.

Abstract

Signaling by the TGF-β superfamily is important in the regulation of hematopoiesis and is dysregulated in myelodysplastic syndromes (MDSs), contributing to ineffective hematopoiesis and clinical cytopenias. TGF-β, activins, and growth differentiation factors exert inhibitory effects on red cell formation by activating canonical SMAD2/3 pathway signaling. In this Review, we summarize evidence that overactivation of SMAD2/3 signaling pathways in MDSs causes anemia due to impaired erythroid maturation. We also describe the basis for biological activity of activin receptor ligand traps, novel fusion proteins such as luspatercept that are promising as erythroid maturation agents to alleviate anemia and related comorbidities in MDSs and other conditions characterized by impaired erythroid maturation.

• Authors: Amit Verma, Rajasekhar Nvs Suragani, Srinivas Aluri, Nishi Shah, Tushar D Bhagat, Mark J Alexander, Rami Komrokji, Ravi Kumar
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 130 Issue 2 Pg. 582-589 (02 03 2020) ISSN: 1558-8238 [Electronic] United States
• PMID: 31961337 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Immunoglobulin Fc Fragments
• Recombinant Fusion Proteins
• SMAD2 protein, human
• SMAD3 protein, human
• Smad2 Protein
• Smad3 Protein
• luspatercept
• Activin Receptors
• Activin Receptors, Type II

Topics

• Activin Receptors (metabolism)
• Activin Receptors, Type II (therapeutic use)
• Animals
• Erythrocytes (metabolism, pathology)
• Erythropoiesis (drug effects)
• Humans
• Immunoglobulin Fc Fragments (therapeutic use)
• Myelodysplastic Syndromes (drug therapy, metabolism, pathology)
• Recombinant Fusion Proteins (therapeutic use)
• Signal Transduction (drug effects)
• Smad2 Protein (metabolism)
• Smad3 Protein (metabolism)