Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Feb 3;130(2):582-589.
doi: 10.1172/JCI133678.

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

Affiliations
Review

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

Amit Verma et al. J Clin Invest. .

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.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest: R Kumar, RNVSS, and MJA are employees of, and own equity in, Acceleron Pharma. AV has received research funding from GlaxoSmithKline, Incyte, MedPacto, Novartis, Curis and Eli Lilly and Company, has received compensation as a scientific advisor to Novartis, Stelexis Therapeutics, Acceleron Pharma, and Celgene, and has equity ownership in Stelexis Therapeutics.

Figures

Figure 1
Figure 1. Erythroid differentiation pathway.
Pathway starting with an uncommitted hematopoietic stem cell (HSC) and leading to the first committed erythroid progenitor cell (burst-forming unit–erythroid, BFU-E). This marks the start of erythroblast proliferation followed by distinct phases of terminal erythroid differentiation to produce mature red blood cells (RBC). The pathway is depicted as linear for simplicity, but cellular proliferation at early stages amplifies red cell production. MEP, bipotent megakaryocytic-erythroid progenitor; CFU-E, colony-forming unit–erythroid; Pro-EB, proerythroblast; Baso-EB, basophilic erythroblast; Poly-EB, polychromatophilic erythroblast; Ortho-EB, orthochromatic erythroblast; RET, reticulocyte; EPO, erythropoietin. Adapted with permission from Nature Reviews Nephrology (56).
Figure 2
Figure 2. Canonical signaling by SMAD2/3-pathway ligands.
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.
Figure 3
Figure 3. Schematic depiction of SMAD2/3 ligand trapping by luspatercept to treat impaired erythroid maturation and alleviate ineffective erythropoiesis.
(A) Ineffective erythropoiesis is the inability to produce an adequate number of red blood cells despite the presence of increased numbers of immature erythroid precursors driven by elevated EPO in response to general hypoxia. Elevated levels of SMAD2/3 signaling contribute to impaired erythroid maturation. (B) Sequestration of SMAD2/3-pathway ligands by therapeutic treatment with activin receptor–based traps such as luspatercept can restore erythroid maturation and alleviate anemia.

Similar articles

Cited by

References

    1. Isufi I, et al. Transforming growth factor-beta signaling in normal and malignant hematopoiesis. J Interferon Cytokine Res. 2007;27(7):543–552. doi: 10.1089/jir.2007.0009. - DOI - PubMed
    1. Massagué J, Xi Q. TGF-β control of stem cell differentiation genes. FEBS Lett. 2012;586(14):1953–1958. doi: 10.1016/j.febslet.2012.03.023. - DOI - PMC - PubMed
    1. Blank U, Karlsson S. TGF-β signaling in the control of hematopoietic stem cells. Blood. 2015;125(23):3542–3550. doi: 10.1182/blood-2014-12-618090. - DOI - PubMed
    1. Naka K, et al. TGF-β-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature. 2010;463(7281):676–680. doi: 10.1038/nature08734. - DOI - PubMed
    1. Mullen AC, Wrana JL. TGF-β family signaling in embryonic and somatic stem-cell renewal and differentiation. Cold Spring Harb Perspect Biol. 2017;9(7):a022186. doi: 10.1101/cshperspect.a022186. - DOI - PMC - PubMed

Publication types

MeSH terms