ACTIVIN RECEPTOR LIGAND FOR THR TREATMENT OF BETA-THALASSEMIA: a SERENDIPITOUS DISCOVERY
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Abstract
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.
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References
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https://doi.org/10.3324/haematol.2018.198887
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.
https://doi.org/10.1172/JCI133678
PMid:31961337
4. Aleman-Muench GR, Soldevila G. When versatility matters: activins/inhibins as key regulators of immunity. Immunol Cell Biol. 2012;90(2):137-48.
https://doi.org/10.1038/icb.2011.32
PMid:21537340
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.
https://doi.org/10.1177/153537020623100507
PMid:16636301
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.
https://doi.org/10.1073/pnas.89.5.1553
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.
https://doi.org/10.1016/j.molcel.2004.07.011
PMid:15304227
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.
https://doi.org/10.1016/j.mce.2011.06.030
PMid:21763751
9. Abe Y, Minegishi T, Leung PC. Activin receptor signaling. Growth Factors. 2004;22(2):105-10.
https://doi.org/10.1080/08977190410001704688
PMid:15253386
10. Keutmann HT, Schneyer AL, Sidis Y. The role of follistatin domains in follistatin biological action. Mol Endocrinol. 2004;18(1):228-40.
https://doi.org/10.1210/me.2003-0112
PMid:14563935
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.
https://doi.org/10.1177/153537020222700905
PMid:12324653
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.
https://doi.org/10.1016/j.bbrc.2015.09.044
PMid:26365350
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.
https://doi.org/10.1074/jbc.M206379200
PMid:12194980
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.
https://doi.org/10.1038/35006129
PMid:10746731
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.
https://doi.org/10.1210/endo.143.3.8707
PMid:11861534
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.
https://doi.org/10.1210/en.2003-0670
PMid:14500575
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.
https://doi.org/10.1038/nature02006
PMid:14534577
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.
https://doi.org/10.1002/jcp.27494
PMid:30370618
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.
https://doi.org/10.1016/j.pharmthera.2015.10.006
PMid:26523637
21. Worthington JJ, Klementowicz JE, Travis MA. TGF-?: a sleeping giant awoken by integrins. Trends Biochem Sci. 2011;36(1):47-54.
https://doi.org/10.1016/j.tibs.2010.08.002
PMid:20870411
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.
https://doi.org/10.1111/j.1749-6632.2009.04569.x
PMid:19796233
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.
https://doi.org/10.1016/j.cell.2006.03.045
PMid:16751102
24. Blank U, Karlsson S. TGF-? signaling in the control of hematopoietic stem cells. Blood. 2015;125(23):3542-50.
https://doi.org/10.1182/blood-2014-12-618090
PMid:25833962
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.
https://doi.org/10.1517/13543784.2013.738666
PMid:23127248
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.
https://doi.org/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.
www.mjhid.org Mediterr J Hematol Infect Dis 2020; 12; e2020075 Pag. 10 / 10
https://doi.org/10.1074/jbc.M115.713487
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.
https://doi.org/10.1074/jbc.M110.114959
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.
https://doi.org/10.1073/pnas.0711263105
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.
https://doi.org/10.1359/jbmr.081208
PMid:19049340
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.
https://doi.org/10.1002/jcph.160
PMid:23939631
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.
https://doi.org/10.1038/nm.3512
PMid:24658078
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.
https://doi.org/10.1111/bjh.12838
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.
https://doi.org/10.1182/blood-2013-06-511238
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.
https://doi.org/10.1038/nm.3468
PMid:24658077
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.
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Oct 27, 2020
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Motta, I. (2020) “ACTIVIN RECEPTOR LIGAND FOR THR TREATMENT OF BETA-THALASSEMIA: a SERENDIPITOUS DISCOVERY”, Mediterranean Journal of Hematology and Infectious Diseases, 12(1), p. e2020075. doi: 10.4084/mjhid.2020.075.
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