Myelodysplastic syndrome

The role of TGFβ in hematopoiesis and myeloid disorders

Article metrics


The role of transforming growth factor-β (TGFβ) signaling in embryological development and tissue homeostasis has been thoroughly characterized. Its canonical downstream cascade is well known, even though its true complexity and other non-canonical pathways are still being explored. TGFβ signaling has been described as an important pathway involved in carcinogenesis and cancer progression. In the hematopoietic compartment, the TGFβ pathway is an important regulator of proliferation and differentiation of different cell types and has been implicated in the pathogenesis of a diverse variety of bone marrow disorders. Due to its importance in hematological diseases, novel inhibitors of this pathway are being developed against a number of hematopoietic disorders, including myelodysplastic syndromes (MDS). In this review, we provide an overview of the TGFβ pathway, focusing on its role in hematopoiesis and impact on myeloid disorders. We will discuss therapeutic interventions with promising results against MDS.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3


  1. 1.

    Sporn MB. The early history of TGF-β, and a brief glimpse of its future. Cytokine Growth Factor Rev. 2006;17:3–7.

  2. 2.

    Massagué J. How cells read TGF-β signals. Nat Rev Mol Cell Biol. 2000;1:169–78.

  3. 3.

    Huminiecki L, Goldovsky L, Freilich S, Moustakas A, Ouzounis C, Heldin CH. Emergence, development and diversification of the TGF-β signalling pathway within the animal kingdom. BMC Evol Biol. 2009;9:1–17.

  4. 4.

    Wu MY, Hill CS. TGF-β superfamily signaling in embryonic development and homeostasis. Dev Cell. 2009;16:329–43.

  5. 5.

    David CJ, Massagué J. Contextual determinants of TGFβ. Nat Rev Mol Cell Biol. 2018;19:25–7.

  6. 6.

    Hu H, Chen D, Wang Y, Feng Y, Cao G, Vaziri al. Chemico-biological interactions new insights into TGF-β/Smad signaling in tissue fibrosis. Chem Biol Interact. 2018;292:76–83.

  7. 7.

    Sanjabi S, Oh SA, Li MO. Regulation of the immune response by TGF-β: from conception to autoimmunity and infection. Cold Spring Harb Perspect Biol. 2017;9:a022236.

  8. 8.

    Gordon KJ, Blobe GC. Role of transforming growth factor-β superfamily signaling pathways in human disease. Biochim Biophys Acta - Mol Basis Dis. 2008;1782:197–228.

  9. 9.

    Wakefield LM, Hill CS. Beyond TGFβ: roles of other TGFβ superfamily members in cancer. Nat Rev Cancer. 2013;13:328–41.

  10. 10.

    Galat A. Common structural traits for cystine knot domain of the TGFβ superfamily of proteins and three-fingered ectodomain of their cellular receptors. Cell Mol Life Sci. 2011;68:3437–51.

  11. 11.

    Massagué J. TGFβ signalling in context. Nat Rev Mol Cell Biol. 2012;13:616–30.

  12. 12.

    Karagiannis GS, Musrap N, Saraon P, Treacy A, Schaeffer DF, Kirsch R, et al. Bone morphogenetic protein antagonist gremlin-1 regulates colon cancer progression. Biol Chem. 2015;396:163–83.

  13. 13.

    Wiater E, Harrison CA, Lewis KA, Gray PC, Vale WW. Identification of distinct inhibin and transforming growth factor β-binding sites on betaglycan: functional separation of betaglycan co-receptor actions. J Biol Chem. 2006;281:17011–22.

  14. 14.

    Gray PC, Vale W. Cripto/GRP78 modulation of the TGF-β pathway in development and oncogenesis. FEBS Lett. 2012;586:1836–45.

  15. 15.

    Huang F, Chen Y-G. Regulation of TGF-β receptor activity. Cell Biosci. 2012;2:9.

  16. 16.

    Rojas A, Padidam M, Cress D, Grady WM. TGF-β receptor levels regulate the specificity of signaling pathway activation and biological effects of TGF-β. Biochim Biophys Acta - Mol Cell Res. 2009;1793:1165–73.

  17. 17.

    Pasteuning-Vuhman S, Boertje-Van Der Meulen JW, Van Putten M, Overzier M, Ten Dijke P, Kiełbasa SM, et al. New function of the myostatin/activin type I receptor (ALK4) as a mediator of muscle atrophy and muscle regeneration. FASEB J. 2017;31:238–55.

  18. 18.

    Huse M, Muir TW, Xu L, Chen Y-G, Kuriyan J, Massagué J. The TGFβ receptor activation process. Mol Cell. 2001;8:671–82.

  19. 19.

    Attisano L, Wrana JL. Smads as transcriptional co-modulators. Curr Opin Cell Biol. 2000;12:235–43.

  20. 20.

    Miyazono K. TGF-β signaling by Smad proteins. Cytokine Growth Factor Rev. 2000;11:15–22.

  21. 21.

    Gahloth D, Levy C, Walker L, Taylor S, Woodman P, Tabernero L, et al. Structural basis for specific interaction of TGFβ signaling regulators SARA/Endofin with HD-PTP. Struct Des. 2017;25:1011–24.

  22. 22.

    Shi Y, Massagué J. Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell. 2003;113:685–700.

  23. 23.

    Yan X, Liu Z, Chen Y. Regulation of TGF-β signaling by Smad7. Acta Biochim Biophys Sin (Shanghai). 2009;41:263–72.

  24. 24.

    Hocevar BA, Smine A, Xu XX, Howe PH. The adaptor molecule disabled-2 links the transforming growth factor β receptors to the Smad pathway. EMBO J. 2001;20:2789–801.

  25. 25.

    Hannigan A, Smith P, Kalna G, Lo Nigro C, Orange C, O’Brien DI, et al. Epigenetic downregulation of human disabled homolog 2 switches TGF-β from a tumor suppressor to a tumor promoter. J Clin Invest. 2010;120:2842–57.

  26. 26.

    Zhang YE. Non-Smad signaling pathways of the TGF-β family. Cold Spring Harb Perspect Biol. 2016;19:1–19.

  27. 27.

    Hill CS. Nucleocytoplasmic shuttling of Smad proteins. Cell Res. 2009;19:36–46.

  28. 28.

    Morikawa M, Koinuma D, Miyazono K, Heldin CH. Genome-wide mechanisms of Smad binding. Oncogene. 2013;32:1609–15.

  29. 29.

    Mullen AC, Orlando DA, Newman JJ, Lovén J, Kumar RM, Bilodeau S, et al. Master transcription factors determine cell-type-specific responses to TGF-β signaling. Cell. 2011;147:565–76.

  30. 30.

    Massagué J, Seoane J, Wotton D. Smad transcription factors. Genes Dev. 2005;19:2783–810.

  31. 31.

    Söderberg SS, Karlsson G, Karlsson S. Complex and context dependent regulation of hematopoiesis by TGF-β superfamily signaling. Ann N Y Acad Sci. 2009;1176:55–69.

  32. 32.

    Chen W, Ten Dijke P. Immunoregulation by members of the TGFβ superfamily. Nat Rev Immunol. 2016;16:723–40.

  33. 33.

    Zhang J, Li L. BMP signaling and stem cell regulation. Dev Biol. 2005;284:1–11.

  34. 34.

    Fortunel NO, Hatzfeld A, Hatzfeld JA. Transforming growth factor-β: pleiotropic role in the regulation of hematopoiesis. Blood. 2000;96:2022–36.

  35. 35.

    Hinge A, Filippi M-D. Deconstructing the complexity of TGFβ signaling in hematopoietic stem cells: quiescence and beyond. Curr Stem Cell Rep. 2016;2:388–97.

  36. 36.

    Batard P, Monier MN, Fortunel N, Ducos K, Sansilvestri-Morel P, Phan T, et al. TGF-β1 maintains hematopoietic immaturity by a reversible negative control of cell cycle and induces CD34 antigen up-modulation. J Cell Sci. 2000;113(Pt 3):383–90.

  37. 37.

    Yamazaki S, Iwama A, Takayanagi S, Eto K, Ema H, Yamazaki al. TGF-β as a candidate bone marrow niche signal to induce hematopoietic stem cell hibernation. 2009;113:1250–6.

  38. 38.

    Hatzfeld J, Li ML, Brown EL, Sookdeo H, Levesque JP, O’Toole T, et al. Release of early human hematopoietic progenitors from quiescence by antisense transforming growth factor β1 or Rb oligonucleotides. J Exp Med. 1991;174:925–9.

  39. 39.

    Challen GA, Boles NC, Chambers SM, Goodell MA. Distinct hematopoietic stem cell subtypes are differentially regulated by TGF-β1. Cell Stem Cell. 2010;6:265–78.

  40. 40.

    Blank U, Karlsson S. TGF-beta signaling in the control of hematopoietic stem cells. Blood. 2015;125:3542–50.

  41. 41.

    Shastri A, Will B, Steidl U, Verma A. Stem and progenitor cell alterations in myelodysplastic syndromes. Blood. 2017;129:1586–94.

  42. 42.

    Loffredo FS, Steinhauser ML, Jay SM, Gannon J, Pancoast JR, Yalamanchi P, et al. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell. 2013;153:828–39.

  43. 43.

    Bulycheva E, Rauner M, Medyouf H, Theurl I, Bornhäuser M, Hofbauer LC, et al. Myelodysplasia is in the niche: novel concepts and emerging therapies. Leukemia. 2015;29:259–68.

  44. 44.

    Shi M, Zhu J, Wang R, Chen X, Mi L, Walz T, et al. Latent TGF-β structure and activation. Nature. 2011;474:343–51.

  45. 45.

    Yamazaki S, Ema H, Karlsson G, Yamaguchi T, Miyoshi H, Shioda S, et al. Nonmyelinating schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche. Cell. 2011;147:1146–58.

  46. 46.

    Penheiter SG, Deep Singh R, Repellin CE, Wilkes MC, Edens M, Howe PH, et al. Type II transforming growth factor-receptor recycling is dependent upon the clathrin adaptor protein Dab2. Mol Biol Cell. 2010;21:4009–19.

  47. 47.

    Zhao M, Perry JM, Marshall H, Venkatraman A, Qian P, He XC, et al. Megakaryocytes maintain homeostatic quiescence and promote post-injury regeneration of hematopoietic stem cells. Nat Med. 2014;20:1321–6.

  48. 48.

    Crane JL, Cao X. Bone marrow mesenchymal stem cells and TGF-β signaling in bone remodeling. J Clin Invest. 2014;124:466–72.

  49. 49.

    Li J, Hale J, Bhagia P, Xue F, Chen L, Jaffray J, et al. Isolation and transcriptome analyses of human erythroid progenitors: BFU-E and CFU-E. Blood. 2014;124:3636–46.

  50. 50.

    Gao X, Lee HY, Da Rocha EL, Zhang C, Lu YF, Li D, et al. TGF-β inhibitors stimulate red blood cell production by enhancing self-renewal of BFU-E erythroid progenitors. Blood. 2016;128:2637–41.

  51. 51.

    Zermati Y, Fichelson S, Valensi F, Freyssinier JM, Rouyer-Fessard P, Cramer E, et al. Transforming growth factor inhibits erythropoiesis by blocking proliferation and accelerating differentiation of erythroid progenitors. Exp Hematol. 2000;28:885–94.

  52. 52.

    He W, Dorn DC, Erdjument-Bromage H, Tempst P, Moore MAS, Massagué J. Hematopoiesis controlled by distinct TIF1γ and Smad4 branches of the TGFβ pathway. Cell. 2006;125:929–41.

  53. 53.

    Shav-Tal Y, Zipori D. The role of activin a in regulation of hemopoiesis. Stem Cells. 2002;20:493–500.

  54. 54.

    Maguer-Satta V, Bartholin L, Jeanpierre S, Ffrench M, Martel S, Magaud JP, et al. Regulation of human erythropoiesis by activin A, BMP2, and BMP4, members of the TGFβ family. Exp Cell Res. 2003;282:110–20.

  55. 55.

    Fuchs O, Simakova O, Klener P, Cmejlova J, Zivny J, Zavadil J, et al. Inhibition of Smad5 in human hematopoietic progenitors blocks erythroid differentiation induced by BMP4. Blood Cells, Mol Dis. 2002;28:221–33.

  56. 56.

    Mies A, Platzbecker U. Increasing the effectiveness of hematopoiesis in myelodysplastic syndromes: erythropoiesis-stimulating agents and transforming growth factor-β superfamily inhibitors. Semin Hematol. 2017;54:141–6.

  57. 57.

    Suragani RNVS, Cadena SM, Cawley SM, Sako D, Mitchell D, Li R, et al. Transforming growth factor-β superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis. Nat Med. 2014;20:408–14.

  58. 58.

    Dussiot M, Maciel TT, Fricot A, Chartier C, Negre O, Veiga J, et al. An activin receptor IIA ligand trap corrects ineffective erythropoiesis in β-thalassemia. Nat Med. 2014;20:398–407.

  59. 59.

    Keller JR, Jacobsen SE, Sill KT, Ellingsworth LR, Ruscetti FW. Stimulation of granulopoiesis by transforming growth factor β: synergy with granulocyte/macrophage-colony-stimulating factor. Proc Natl Acad Sci USA. 1991;88:7190–4.

  60. 60.

    Celada A, Maki RA. Transforming growth factor-β enhances the M-CSF and GM-CSF-stimulated proliferation of macrophages. J Immunol. 1992;148:1102–5.

  61. 61.

    Fan BK, Ruan Q, Sensenbrenner L, Chen B. Transforming growth factor-β1 bifunctionally regulates murine macrophage proliferation. Blood. 1992;79:1679–86.

  62. 62.

    Jacobsen SE, Ruscetti FW, Roberts AB, Keller JR. TGF-β is a bidirectional modulator of cytokine receptor expression on murine bone marrow cells. Differential effects of TGF-β1 and TGF-β3. J Immunol. 1993;151:4534–44.

  63. 63.

    Liu K, Nussenzweig MC. Origin and development of dendritic cells. Immunol Rev. 2010;234:45–54.

  64. 64.

    Borkowski TA, Letterio JJ, Farr AG, Udey MC. A role for endogenous transforming growth factor β1 in Langerhans cell biology: the skin of transforming growth factor β1 null mice is devoid of epidermal Langerhans cells. J Exp Med. 1996;184:2417–22.

  65. 65.

    Seeger P, Musso T, Sozzani S. The TGF-β superfamily in dendritic cell biology. Cytokine Growth Factor Rev. 2015;26:647–57.

  66. 66.

    Seré KM, Lin Q, Felker P, Rehage N, Klisch T, Ortseifer I, et al. Dendritic cell lineage commitment is instructed by distinct cytokine signals. Eur J Cell Biol. 2012;91:515–23.

  67. 67.

    Felker P, Sere K, Lin Q, Becker C, Hristov M, Hieronymus T, et al. TGF-β1 accelerates dendritic cell differentiation from common dendritic cell progenitors and directs subset specification toward conventional dendritic cells. J Immunol. 2010;185:5326–35.

  68. 68.

    Wen Q, Goldenson B, Crispino JD. Normal and malignant megakaryopoiesis. Expert Rev Mol Med. 2011;13:e32.

  69. 69.

    Greenberg SM, Chandrasekhar C, Golan DE, Handin RI. Transforming growth factor β inhibits endomitosis in the Dami human megakaryocytic cell line. Blood. 1990;76:533–7.

  70. 70.

    Kuter DJ, Gminski DM, Rosenberg RD. Transforming growth factor beta inhibits megakaryocyte growth and endomitosis. Blood. 1992;79:619–26.

  71. 71.

    Gañán-Gómez I, Wei Y, Starczynowski DT, Colla S, Yang H, Cabrero-Calvo M, et al. Deregulation of innate immune and inflammatory signaling in myelodysplastic syndromes. Leukemia. 2015;29:1458–69.

  72. 72.

    Zhou L, McMahon C, Bhagat T, Alencar C, Yu Y, Fazzari M, et al. Reduced SMAD7 leads to overactivation of TGF-β signaling in MDS that can be reversed by a specific inhibitor of TGF-β receptor I kinase. Cancer Res. 2011;71:955–63.

  73. 73.

    Bhagat TD, Zhou L, Sokol L, Kessel R, Caceres G, Gundabolu K, et al. MiR-21 mediates hematopoietic suppression in MDS by activating TGF-β signaling. Blood. 2013;121:2875–81.

  74. 74.

    Zhou L, Nguyen AN, Sohal D, Ma JY, Pahanish P, Gundabolu K, et al. Inhibition of the TGF-β receptor I kinase promotes hematopoiesis in MDS. Blood. 2008;112:3434–43.

  75. 75.

    Kim S-J, Letterio J. Transforming growth factor-β signaling in normal and malignant hematopoiesis. Leukemia. 2003;17:1731–7.

  76. 76.

    Jakubowiak A, Pouponnot C, Berguido F, Frank R, Mao S, Massagué J, et al. Inhibition of the transforming growth factor β1 signaling pathway by the AML1/ETO leukemia-associated fusion protein. J Biol Chem. 2000;275:40282–7.

  77. 77.

    Kurokawa M, Mitani K, Imai Y, Ogawa S, Yazaki Y, Hirai H. The t(3;21) fusion product, AML1/Evi-1, interacts with Smad3 and blocks transforming growth factor-β-mediated growth inhibition of myeloid cells. Blood. 1998;92:4003–12.

  78. 78.

    Lin H-K, Bergman S, Pandolfi PP. Cytoplasmic PML function in TGF-β signalling. Nature. 2004;431:205–11.

  79. 79.

    Singh AA, Mandoli A, Prange KHM, Laakso M, Martens JHA. AML associated oncofusion proteins PML-RARA, AML1-ETO and CBFB-MYH11 target RUNX/ETS-factor binding sites to modulate H3ac levels and drive leukemogenesis. Oncotarget. 2017;8:12855–65.

  80. 80.

    Wolfraim LA, Fernandez TM, Mamura M, Fuller WL, Kumar R, Cole DE, et al. Loss of Smad3 in acute T-cell lymphoblastic leukemia. N Engl J Med. 2004;351:552–9.

  81. 81.

    Ford AM, Palmi C, Bueno C, Hong D, Cardus P, Knight D, et al. The TEL-AML1 leukemai fusion gene dysregulates the TGF-β pathway in early B lineage progenitor cells. J Clin Invest. 2009;119:826–36.

  82. 82.

    Arnulf B, Villemain A, Nicot C, Mordelet E, Charneau P, Kersual J, et al. Human T-cell lymphotropic virus oncoprotein Tax represses TGFβ1 signaling in human T cells via c-Jun activation: a potential mechanism of HTLV-I leukemogenesis. Blood. 2002;100:4129–38.

  83. 83.

    Zhu B, Zhang J, Chen J, Li C, Wang X. Molecular biological characteristics of the recruitment of hematopoietic stem cells from bone marrow niche in chronic myeloid leukemia. Int J Clin Exp Pathol. 2015;8:12595–607.

  84. 84.

    Zhu X, Wang L, Zhang B, Li J, Dou X, Zhao RC. TGF-β1-induced PI3K/Akt/NF-κB/MMP9 signalling pathway is activated in Philadelphia chromosome-positive chronic myeloid leukaemia hemangioblasts. J Biochem. 2011;149:405–14.

  85. 85.

    Atfi A, Abécassis L, Bourgeade MF. Bcr-Abl activates the AKT/FoxO3 signalling pathway to restrict transforming growth factor-β-mediated cytostatic signals. EMBO Rep. 2005;6:985–91.

  86. 86.

    Naka K, Hoshii T, Muraguchi T, Tadokoro Y, Ooshio T, Kondo Y, et al. TGF-β-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature. 2010;463:676–80.

  87. 87.

    Zauli G, Visani G, Catani L, Vianelli N, Gugliotta L, Capitani S. Reduced responsiveness of bone marrow megakaryocyte progenitors to platelet‐derived transforming growth factor β1, produced in normal amount, in patients with essential thrombocythaemia. Br J Haematol. 1993;83:14–20.

  88. 88.

    Kuroda H, Matsunaga T, Terui T, Tanaka I, Takimoto R, Fujikawa K, et al. Decrease of Smad4 gene expression in patients with essential thrombocythaemia may cause an escape from suppression of megakaryopoiesis by transforming growth factor-β1. Br J Haematol. 2004;124:211–20.

  89. 89.

    Chagraoui H, Komura E, Tulliez M, Giraudier S, Vainchenker W, Wendung F. Prominent role of TGF-β1 in thrombopoietin-induced myelofibrosis in mice. Blood. 2002;100:3495–503.

  90. 90.

    Vannucchi AM, Bianchi L, Paoletti F, Pancrazzi A, Torre E, Nishikawa M, et al. A pathobiologic pathway linking thrombopoietin, GATA-1, and TGF-β1 in the development of myelofibrosis. Blood. 2005;105:3493–501.

  91. 91.

    Paulson RF. Targeting a new regulator of erythropoiesis to alleviate anemia. Nat Med. 2014;20:334–5.

  92. 92.

    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. Br J Haematol. 2014;165:870–82.

  93. 93.

    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. Exp Hematol. 2013;41:155–66.

  94. 94.

    Schneider RK, Schenone M, Ferreira MV, Kramann R, Joyce CE, Hartigan C, et al. Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 and S100A9. Nat Med. 2016;22:288–97.

  95. 95.

    Mei Y, Zhao B, Basiorka AA, Yang J, Cao L, Zhang J, et al. Age-related inflammatory bone marrow microenvironment induces ineffective erythropoiesis mimicking del(5q) MDS. Leukemia. 2018;32:1023–33.

  96. 96.

    Dolatshad H, Pellagatti A, Fernandez-Mercado M, Yip BH, Malcovati L, Attwood M, et al. Disruption of SF3B1 results in deregulated expression and splicing of key genes and pathways in myelodysplastic syndrome hematopoietic stem and progenitor cells. Leukemia. 2015;29:1092–103.

  97. 97.

    Huang Y, Hale J, Wang Y, Li W, Zhang S, Zhang J, et al. SF3B1 deficiency impairs human erythropoiesis via activation of p53 pathway: implications for understanding of ineffective erythropoiesis in MDS. J Hematol Oncol. 2018;11:1–12.

  98. 98.

    Obeng EA, Chappell RJ, Seiler M, Chen MC, Campagna DR, Schmidt PJ, et al. Physiologic expression of Sf3b1K700E causes impaired erythropoiesis, aberrant splicing, and sensitivity to therapeutic spliceosome modulation. Cancer Cell. 2016;30:404–17.

  99. 99.

    Qu X, Zhang S, Wang S, Wang Y, Li W, Huang Y, et al. TET2 deficiency leads to stem cell factor dependent clonal expansion of dysfunctional erythroid progenitors. Blood 2018;132. blood-2018-05-853291.

  100. 100.

    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;89:766–70.

  101. 101.

    Platzbecker U, Germing U, Götze 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;18:1338–47.

  102. 102.

    Fenaux P, Platzbecker U, Mufti GJ, Garcia-Manero G, Buckstein R, Santini V, et al. The Medalist trial: results of a phase 3, randomized, double-blind, placebo-controlled study of luspatercept to treat anemia in patients with very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts (RS) who require red blood cell (RBC) transfusions. Blood. 2018;132:1 LP–1.

  103. 103.

    Motta I, Scaramellini N, Cappellini MD. Investigational drugs in phase I and phase II clinical trials for thalassemia. Expert Opin Investig Drugs. 2017;26:793–802.

  104. 104.

    Cappellini MD, Viprakasit V, Taher A, Georgiev P, Kuo KHM, Coates TD, et al. The Believe trial: results of a phase 3, randomized, double-blind, placebo-controlled study of luspatercept in adult beta-thalassemia patients who require regular red blood cell (RBC) transfusions. Blood. 2018;132:163 LP–163.

  105. 105.

    Lotinun S, Pearsall RS, Davies MV, Marvell TH, Monnell TE, Ucran J, et al. A soluble activin receptor type IIA fusion protein (ACE-011) increases bone mass via a dual anabolic-antiresorptive effect in Cynomolgus monkeys. Bone. 2010;46:1082–8.

  106. 106.

    Mies A, Hermine O, Platzbecker U. Activin receptor II ligand traps and their therapeutic potential in myelodysplastic syndromes with ring sideroblasts. Curr Hematol Malig Rep. 2016;11:416–24.

  107. 107.

    Langdon JM, Barkataki S, Berger AE, Cheadle C, Xue QL, Sung V, et al. RAP-011, an activin receptor ligand trap, increases hemoglobin concentration in hepcidin transgenic mice. Am J Hematol. 2015;90:8–14.

  108. 108.

    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-IgGl) in postmenopausal women. J Bone Miner Res. 2009;24:744–52.

  109. 109.

    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;43:63–72.

  110. 110.

    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;165:814–23.

  111. 111.

    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;24:1517–25.

  112. 112.

    Lahn M, Herbertz S, Sawyer JS, Stauber AJ, Gueorguieva I, Driscoll KE, et al. Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway. Drug Des Devel Ther. 2015;9:4479.

  113. 113.

    Ikeda M, Takahashi H, Kondo S, Lahn MMF, Ogasawara K, Benhadji KA, et al. Phase 1b study of galunisertib in combination with gemcitabine in Japanese patients with metastatic or locally advanced pancreatic cancer. Cancer Chemother Pharmacol. 2017;79:1169–77.

  114. 114.

    Valcarcel D, Verma A, Platzbecker U, Santini V, Giagounidis A, Diez-Campelo M, et al. Phase 2 study of monotherapy galunisertib (LY2157299 monohydrate) in very low-, low-, and intermediate-risk patients with myelodysplastic syndromes. Blood. 2015;126:1669.

  115. 115.

    Yoon JH, Jung SM, Park SH, Kato M, Yamashita T, Lee IK, et al. Activin receptor-like kinase5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby derepressing eomesodermin in cytotoxic T lymphocytes. EMBO Mol Med. 2013;5:1720–39.

  116. 116.

    Naka K, Ishihara K, Jomen Y, Jin CH, Kim DH, Gu YK, et al. Novel oral transforming growth factor-β signaling inhibitor EW-7197 eradicates CML-initiating cells. Cancer Sci. 2016;107:140–8.

Download references


This work is supported in part by the University of Texas MD Anderson Cancer Center Support Grant CA016672 and the University of Texas MD Anderson MDS/AML Moon Shot.

Author information

Correspondence to Guillermo Garcia-Manero.

Ethics declarations

Conflict of interest

GG-M declares support and an advisory role for Celgene Corporation and Acceleron Pharma. The remaining authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark