Biological basis for efficacy of activin receptor ligand traps in myelodysplastic syndromes
Amit Verma, Rajasekhar N.V.S. Suragani, Srinivas Aluri, Nishi Shah, Tushar D. Bhagat, Mark J. Alexander, Rami Komrokji, Ravi Kumar
Amit Verma, Rajasekhar N.V.S. Suragani, Srinivas Aluri, Nishi Shah, Tushar D. Bhagat, Mark J. Alexander, Rami Komrokji, Ravi Kumar
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Review

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 N.V.S. Suragani, Srinivas Aluri, Nishi Shah, Tushar D. Bhagat, Mark J. Alexander, Rami Komrokji, Ravi Kumar

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Figure 2

Canonical signaling by SMAD2/3-pathway ligands.

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Canonical signaling by SMAD2/3-pathway ligands. Ligand binding leads to ...
Ligand binding leads to multimerization of type I and type II receptors, in some cases with the assistance of a coreceptor (type III). Activated type I receptors phosphorylate SMAD2 or SMAD3, which dissociate from type I receptor and oligomerize with SMAD4 to form a heterodimeric complex that translocates into the nucleus, thereby regulating the cellular response. SMAD7, whose stability is regulated by microRNAs (miR-21), can exert feedback effects on the pathway through multiple mechanisms, including inhibition of SMAD2/3 activation. See text for details. While TGF-β, GDF11, and activin B have been implicated in ineffective hematopoiesis, additional SMAD2/3-pathway ligands are likely involved. Note that dimeric ligands and receptors are depicted here as monomers for simplicity. ALK4/5/7, activin receptor–like kinases 4, 5, and 7.