Main Article Content

Irene Motta
Valentina Brancaleoni
Isabella Nava
Paola Delbini
Lorena Duca



b-thalassemia is a hereditary disorder caused by defective production of b-globin chains of hemoglobin (Hb) that leads to an increased a/b globins ratio with subsequent free a-globins. Alpha globin excess causes oxidative stress, RBCs membrane damage, premature death of late-stage erythroid precursors, resulting in ineffective erythropoiesis.

The transforming growth factor b (TGF-b) superfamily signaling acts on biological processes, such as cell quiescence, apoptosis, proliferation, differentiation, and migration, and also plays an important role in the regulation of hematopoiesis. This pathway can lose its physiologic regulation in pathologic conditions, leading to anemia and ineffective erythropoiesis. Activin receptor ligand trap molecules such as Sotatercept and Luspatercept downregulate the TGF-b pathway by inhibiting the Smad2/3 cascade, thus alleviating anemia in patients with b-thalassemia and myelodysplastic syndromes.

In this review, we describe in extenso the TGF-b pathway, as well as the molecular and biological basis of activin receptors ligand traps, focusing on their role in various b-thalassemia experimental models. The most recent results from clinical trials on sotatercept and luspatercept will also be reviewed.


Download data is not yet available.

Abstract 794
PDF Downloads 918
HTML Downloads 270


Galanello R, Origa R. ?-thalassemia. Orphanet J Rare Dis. 2010;5:11.
PMid:20492708 PMCid:PMC2893117
2. Cappellini MD, Porter J, Origa R, Forni GL, Voskaridou E, Galacteros F, et al. Sotatercept, a novel transforming growth factor ? ligand trap, improves anemia in ?-thalassemia: a phase II, open-label, dose-finding study. Haematologica. 2019;104(3):477-84.
PMid:30337358 PMCid:PMC6395345
3. Verma A, Suragani RN, Aluri S, Shah N, Bhagat TD, Alexander MJ, et al. Biological basis for efficacy of activin receptor ligand traps in myelodysplastic syndromes. J Clin Invest. 2020;130(2):582-9.
4. Aleman-Muench GR, Soldevila G. When versatility matters: activins/inhibins as key regulators of immunity. Immunol Cell Biol. 2012;90(2):137-48.
5. Chen YG, Wang Q, Lin SL, Chang CD, Chuang J, Chung J, et al. Activin signaling and its role in regulation of cell proliferation, apoptosis, and carcinogenesis. Exp Biol Med (Maywood). 2006;231(5):534-44.
6. Shiozaki M, Sakai R, Tabuchi M, Nakamura T, Sugino K, Sugino H, et al. Evidence for the participation of endogenous activin A/erythroid differentiation factor in the regulation of erythropoiesis. Proc Natl Acad Sci U S A. 1992;89(5):1553-6.
PMid:1542647 PMCid:PMC48490
7. Greenwald J, Vega ME, Allendorph GP, Fischer WH, Vale W, Choe S. A flexible activin explains the membrane-dependent cooperative assembly of TGF-beta family receptors. Mol Cell. 2004;15(3):485-9.
8. Walton KL, Makanji Y, Harrison CA. New insights into the mechanisms of activin action and inhibition. Mol Cell Endocrinol. 2012;359(1-2):2-12.
9. Abe Y, Minegishi T, Leung PC. Activin receptor signaling. Growth Factors. 2004;22(2):105-10.
10. Keutmann HT, Schneyer AL, Sidis Y. The role of follistatin domains in follistatin biological action. Mol Endocrinol. 2004;18(1):228-40.
11. Welt C, Sidis Y, Keutmann H, Schneyer A. Activins, inhibins, and follistatins: from endocrinology to signaling. A paradigm for the new millennium. Exp Biol Med (Maywood). 2002;227(9):724-52.
12. Wu J, Dong Y, Teng X, Cheng M, Shen Z, Chen W. Follistatin-like 1 attenuates differentiation and survival of erythroid cells through Smad2/3 signaling. Biochem Biophys Res Commun. 2015;466(4):711-6.
13. Hill JJ, Davies MV, Pearson AA, Wang JH, Hewick RM, Wolfman NM, et al. The myostatin propeptide and the follistatin-related gene are inhibitory binding proteins of myostatin in normal serum. J Biol Chem. 2002;277(43):40735-41.
14. Lewis KA, Gray PC, Blount AL, MacConell LA, Wiater E, Bilezikjian LM, et al. Betaglycan binds inhibin and can mediate functional antagonism of activin signalling. Nature. 2000;404(6776):411-4.
15. MacConell LA, Leal AM, Vale WW. The distribution of betaglycan protein and mRNA in rat brain, pituitary, and gonads: implications for a role for betaglycan in inhibin-mediated reproductive functions. Endocrinology. 2002;143(3):1066-75.
16. Chapman SC, Woodruff TK. Betaglycan localization in the female rat pituitary: implications for the regulation of follicle-stimulating hormone by inhibin. Endocrinology. 2003;144(12):5640-9.
17. Miyazono K. Positive and negative regulation of TGF-beta signaling. J Cell Sci. 2000;113 ( Pt 7):1101-9.
18. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-b family signalling. Nature. 2003;425(6958):577-84.
19. Fernandez-Nocelo S, Gallego R, Costoya JA, Arce VM. Expression of myostatin in human hematopoietic cells unveils novel autocrine/paracrine actions for the hormone. J Cell Physiol. 2019;234(5):7236-46.
20. Rochette L, Zeller M, Cottin Y, Vergely C. Growth and differentiation factor 11 (GDF11): Functions in the regulation of erythropoiesis and cardiac regeneration. Pharmacology and Therapeutics. 2015;156:26-33.
21. Worthington JJ, Klementowicz JE, Travis MA. TGF-?: a sleeping giant awoken by integrins. Trends Biochem Sci. 2011;36(1):47-54.
22. Soderberg SS, Karlsson G, Karlsson S. Complex and context dependent regulation of hematopoiesis by TGF-beta superfamily signaling. Ann N Y Acad Sci. 2009;1176:55-69.
23. He W, Dorn DC, Erdjument-Bromage H, Tempst P, Moore MA, Massague J. Hematopoiesis controlled by distinct TIF-1? and Smad4 branches of the TGF-? pathway. Cell. 2006;125(5):929-41.
24. Blank U, Karlsson S. TGF-? signaling in the control of hematopoietic stem cells. Blood. 2015;125(23):3542-50.
25. Fields SZ, Parshad S, Anne M, Raftopoulos H, Alexander MJ, Sherman ML, et al. Activin receptor antagonists for cancer-related anemia and bone disease. Expert Opinion on Investigational Drugs. 2013;22(1):87-101.
26. Tsuchida K, Nakatani M, Hitachi K, Uezumi A, Sunada Y, Ageta H, et al. Activin signaling as an emerging target for therapeutic interventions. Cell Commun Signal. 2009;7:15. doi: 10.1186/1478-811X-7-15.
PMid:19538713 PMCid:PMC2713245
27. Aykul S, Martinez-Hackert E. Transforming Growth Factor-? Family Ligands Can Function as Antagonists by Competing for Type II Receptor Binding. J Biol Chem. 2016;291(20):10792-804. Mediterr J Hematol Infect Dis 2020; 12; e2020075 Pag. 10 / 10
PMid:26961869 PMCid:PMC4865925
28. Sako D, Grinberg AV, Liu J, Davies MV, Castonguay R, Maniatis S, et al. Characterization of the ligand binding functionality of the extracellular domain of activin receptor type IIB. J Biol Chem. 2010;285(27):21037-48.
PMid:20385559 PMCid:PMC2898293
29. Pearsall R, Canalis E, Cornwall-Brady M, Underwood K, Haigis B, Ucran J, et al. A soluble activin type IIA receptor induces bone formation and improves skeletal integrity. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(19):7082-7.
PMid:18460605 PMCid:PMC2383948
30. Ruckle J, Jacobs M, Kramer W, Pearsall AE, Kumar R, Underwood KW, et al. Single-dose, randomized, double-blind, placebo-controlled study of ACE-011 (ActRIIA-IgG1) in post-menopausal women. J Bone Miner Res. 2009;24(4):744-52.
31. Sherman ML, Borgstein NG, Mook L, Wilson D, Yang Y, Chen N, et al. Multiple-dose, safety, pharmacokinetic, and pharmacodynamic study of sotatercept (ActRIIA-IgG1), a Novel erythropoietic agent, in healthy post-menopausal women. Journal of Clinical Pharmacology. 2013;53(11):1121-30.
32. Suragani RNVS, Cadena SM, Cawley SM, Sako D, Mitchell D, Li R, et al. Transforming growth factor-? superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis. Nature Medicine. 2014;20(4):408-14.
33. Carrancio S, Markovics J, Wong P, Leisten J, Castiglioni P, Groza MC, et al. An activin receptor IIA ligand trap promotes erythropoiesis resulting in a rapid induction of red blood cells and haemoglobin. British Journal of Haematology. 2014;165(6):870-82.
PMid:24635723 PMCid:PMC4282119
34. Suragani RN, Cawley SM, Li R, Wallner S, Alexander MJ, Mulivor AW, et al. Modified activin receptor IIB ligand trap mitigates ineffective erythropoiesis and disease complications in murine ?-thalassemia. Blood. 2014;123(25):3864-72.
PMid:24795345 PMCid:PMC4064330
35. Dussiot M, Maciel TT, Fricot A, Chartier C, Negre O, Veiga J, et al. An activin receptor IIA ligand trap corrects ineffective erythropoiesis in ?-thalassemia. Nature Medicine. 2014;20(4):398-407.
36. Iancu-Rubin C, Mosoyan G, Wang J, Kraus T, Sung V, Hoffman R. Stromal cell-mediated inhibition of erythropoiesis can be attenuated by Sotatercept (ACE-011), an activin receptor type II ligand trap. Experimental Hematology. 2013;41(2):155-66.
37. Flotta S, Delbini P, Graziadei G, Marcon A, Sung V, Cappellini MD. Erythropoietic response to a ligand trap of activin receptor II in cultures from ?-thalassemia patients. Haematologica. 2015;100:766.
38. Attie KM, Allison MJ, McClure T, Boyd IE, Wilson DM, Pearsall AE, et al. A phase 1 study of ACE-536, a regulator of erythroid differentiation, in healthy volunteers. Am J Hematol. 2014;89(7):766-70.
PMid:24715706 PMCid:PMC4173124
39. Guerra A, Oikonomidou PR, Sinha S, Zhang J, Presti VL, Hamilton CR, et al. Lack of GDF11 does not improve anemia or prevent the activity of RAP-536 in a mouse model of ?-thalassemia. Blood. 2019;134(6):568-72.
PMid:31151988 PMCid:PMC6688431
40. Martinez PA, Li R, Ramanathan HN, Bhasin M, Pearsall RS, Kumar R, et al. Smad2/3-pathway ligand trap luspatercept enhances erythroid differentiation in murine ?-thalassaemia by increasing GATA-1 availability. Journal of Cellular and Molecular Medicine. 2020.
PMid:32351032 PMCid:PMC7294138
41. Sherman ML, Borgstein NG, Mook L, Wilson D, Yang Y, Chen N, et al. Multiple-dose, safety, pharmacokinetic, and pharmacodynamic study of sotatercept (ActRIIA-IgG1), a novel erythropoietic agent, in healthy post-menopausal women. J Clin Pharmacol. 2013;53(11):1121-30.
42. Abdulkadyrov KM, Salogub GN, Khuazheva NK, Sherman ML, Laadem A, Barger R, et al. Sotatercept in patients with osteolytic lesions of multiple myeloma. Br J Haematol. 2014;165(6):814-23.
PMid:24650009 PMCid:PMC4312883
43. Raftopoulos H, Laadem A, Hesketh PJ, Goldschmidt J, Gabrail N, Osborne C, et al. Sotatercept (ACE-011) for the treatment of chemotherapy-induced anemia in patients with metastatic breast cancer or advanced or metastatic solid tumors treated with platinum-based chemotherapeutic regimens: results from two phase 2 studies. Support Care Cancer. 2016;24(4):1517-25.
PMid:26370220 PMCid:PMC4766217
44. Reblozyl. Accessed June 06, 2020.
45. Piga A, Perrotta S, Gamberini MR, Voskaridou E, Melpignano A, Filosa A, et al. Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with ?-thalassemia. Blood. 2019.
PMid:30617198 PMCid:PMC6440118
46. Cappellini MD, Cohen A, Piga A, Bejaoui M, Perrotta S, Agaoglu L, et al. A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with b-thalassemia. Blood. 2006;107(9):3455-62.
47. Komrokji R, Garcia-Manero G, Ades L, Prebet T, Steensma DP, Jurcic JG, et al. Sotatercept with long-term extension for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes: a phase 2, dose-ranging trial. Lancet Haematol. 2018;5(2):e63-e72.
48. Platzbecker U, Germing U, Gotze KS, Kiewe P, Mayer K, Chromik J, et al. Luspatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS): a multicentre, open-label phase 2 dose-finding study with long-term extension study. Lancet Oncol. 2017;18(10):1338-47.