Modified activin receptor IIB ligand trap mitigates ineffective erythropoiesis and disease complications in murine β-thalassemia

Blood

Volumn 123, Issue 25, 2014, Pages 3864-3872

  Suragani, Rajasekhar N V S ^a   Cawley, Sharon M ^a   Li, Robert ^a   Wallner, Samantha ^a   Alexander, Mark J ^a   Mulivor, Aaron W ^a   Gardenghi, Sara ^b   Rivella, Stefano ^b   Grinberg, Asya V ^a   Pearsall, R Scott ^a   Kumar, Ravindra ^a  

^a Acceleron Pharma   (United States)

^b WEILL CORNELL MEDICAL COLLEGE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACTIVIN RECEPTOR IIB; ANTIANEMIC AGENT; CYTOKINE RECEPTOR; ERYTHROPOIETIN; HYBRID PROTEIN; MESSENGER RNA; RAP 536; REACTIVE OXYGEN METABOLITE; SMAD2 PROTEIN; SMAD3 PROTEIN; TRANSFORMING GROWTH FACTOR BETA; UNCLASSIFIED DRUG;

ANEMIA; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BETA THALASSEMIA; BLOOD CHEMISTRY; BONE DENSITY; BONE DISEASE; ENZYME INHIBITION; ERYTHROCYTE LIFESPAN; ERYTHROCYTE STRUCTURE; ERYTHROID PRECURSOR CELL; ERYTHROPOIESIS; IMMUNOHISTOCHEMISTRY; IRON OVERLOAD; MOUSE; NONHUMAN; PRIORITY JOURNAL; SIGNAL TRANSDUCTION; SPLENOMEGALY; THALASSEMIA INTERMEDIA;

ACTIVIN RECEPTORS, TYPE II; ANEMIA; ANIMALS; BETA-GLOBINS; BETA-THALASSEMIA; BLOTTING, WESTERN; CELL DIFFERENTIATION; ERYTHROCYTES; ERYTHROID PRECURSOR CELLS; ERYTHROPOIESIS; HEMOLYSIS; HUMANS; IMMUNOGLOBULIN FC FRAGMENTS; IMMUNOGLOBULIN G; IRON OVERLOAD; MICE; MICE, INBRED C57BL; MICE, KNOCKOUT; MUTATION; REACTIVE OXYGEN SPECIES; RECOMBINANT FUSION PROTEINS; SIGNAL TRANSDUCTION; SMAD2 PROTEIN; SMAD3 PROTEIN;

EID: 84902668877     PISSN: 00064971     EISSN: 15280020     Source Type: Journal    
DOI: 10.1182/blood-2013-06-511238     Document Type: Article

References (46)

1. Rund D, Rachmilewitz E. β-thalassemia. N Engl J Med. 2005;353(11):1135-1146.
2. Ginzburg Y, Rivella S. β-thalassemia: a model for elucidating the dynamic regulation of ineffective erythropoiesis and iron metabolism. Blood. 2011;118(16):4321-4330.
3. Khandros E, Weiss MJ. Protein quality control during erythropoiesis and hemoglobin synthesis. Hematol Oncol Clin North Am. 2010;24(6):1071-1088.
4. Khandros E, Thom CS, D'Souza J, Weiss MJ. Integrated protein quality-control pathways regulate free α-globin in murine β-thalassemia. Blood. 2012;119(22):5265-5275.
5. Fibach E, Rachmilewitz E. The role of oxidative stress in hemolytic anemia. Curr Mol Med. 2008;8(7):609-619.
6. Libani IV, Guy EC, Melchiori L, et al. Decreased differentiation of erythroid cells exacerbates ineffective erythropoiesis in β-thalassemia. Blood. 2008;112(3):875-885.
7. Taher AT, Musallam KM, El-Beshlawy A, et al. Age-related complications in treatment-naïve patients with thalassaemia intermedia. Br J Haematol. 2010;150(4):486-489.
8. Musallam KM, Taher AT, Rachmilewitz EA. β-thalassemia intermedia: a clinical perspective. Cold Spring Harb Perspect Med. 2012;2(7):a013482.
9. Musallam KM, Cappellini MD, Wood JC, Taher AT. Iron overload in non-transfusion-dependent thalassemia: a clinical perspective. Blood Rev. 2012;26(Suppl 1):S16-S19.
10. Elborai Y, Uwumugambi A, Lehmann L. Hematopoietic stem cell transplantation for thalassemia. Immunotherapy. 2012;4(9):947-956.
11. Kwiatkowski JL. Real-world use of iron chelators. Hematol Am Soc Hematol Educ Program. 2011;2011:451-458.
12. Blank U, Karlsson S. The role of Smad signaling in hematopoiesis and translational hematology. Leukemia. 2011;25(9):1379-1388.
13. Shiozaki M, Sakai R, Tabuchi M, et al. Evidence for the participation of endogenous activin A/erythroid differentiation factor in the regulation of erythropoiesis. Proc Natl Acad Sci USA. 1992;89(5):1553-1556.
14. Shav-Tal Y, Zipori D. The role of activin A in regulation of hemopoiesis. Stem Cells. 2002;20(6):493-500. (Pubitemid 35463062)
15. 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.
16. Zhou L, Nguyen AN, Sohal D, et al. Inhibition of the TGF-β receptor I kinase promotes hematopoiesis in MDS. Blood. 2008;112(8):3434-3443.
17. Bowen D. What is ineffective erythropoiesis in myelodysplastic syndromes? Leuk Lymphoma. 1995;18(3-4):243-247.
18. Hu J, Liu J, Xue F, et al. Isolation and functional characterization of human erythroblasts at distinct stages: implications for understanding of normal and disordered erythropoiesis in vivo. Blood. 2013;121(16):3246-3253.
19. Skow LC, Burkhart BA, Johnson FM, et al. A mouse model for β-thalassemia. Cell. 1983;34(3):1043-1052.
20. Sako D, Grinberg AV, Liu J, et al. Characterization of the ligand binding functionality of the extracellular domain of activin receptor type IIb. J Biol Chem. 2010;285(27):21037-21048.
21. Liu Y, Pop R, Sadegh C, Brugnara C, Haase VH, Socolovsky M. Suppression of Fas-FasL coexpression by erythropoietin mediates erythroblast expansion during the erythropoietic stress response in vivo. Blood. 2006;108(1):123-133. (Pubitemid 43990620)
22. Suragani RN, Zachariah RS, Velazquez JG, et al. Heme-regulated eIF2α kinase activated Atf4 signaling pathway in oxidative stress and erythropoiesis. Blood. 2012;119(22):5276-5284.
23. Han AP, Fleming MD, Chen JJ. Heme-regulated eIF2α kinase modifies the phenotypic severity of murine models of erythropoietic protoporphyria and beta-thalassemia. J Clin Invest. 2005;115(6):1562-1570. (Pubitemid 40814664)
24. Cadena SM, Tomkinson KN, Monnell TE, et al. Administration of a soluble activin type IIB receptor promotes skeletal muscle growth independent of fiber type. J Appl Physiol (1985). 2010;109(3):635-642.
25. Pearsall RS, Canalis E, Cornwall-Brady M, et al. A soluble activin type IIA receptor induces bone formation and improves skeletal integrity. Proc Natl Acad Sci USA. 2008;105(19):7082-7087. (Pubitemid 351754533)
26. Gardenghi S, Ramos P, Marongiu MF, et al. Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice. J Clin Invest. 2010;120(12):4466-4477.
27. Ganz T, Nemeth E. Hepcidin and disorders of iron metabolism. Annu Rev Med. 2011;62:347-360.
28. Nai A, Pagani A, Mandelli G, et al. Deletion of TMPRSS6 attenuates the phenotype in a mouse model of β-thalassemia. Blood. 2012;119(21):5021-5029.
29. Tanno T, Bhanu NV, Oneal PA, et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med. 2007;13(9):1096-1101. (Pubitemid 47517510)
30. Tanno T, Porayette P, Sripichai O, et al. Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells. Blood. 2009;114(1):181-186.
31. Perisano C, Marzetti E, Spinelli MS, Calla CA, Graci C, Maccauro G. Physiopathology of bone modifications in β-thalassemia. Anemia. 2012;2012:320737.
32. Vogiatzi MG, Tsay J, Verdelis K, et al. Changes in bone microarchitecture and biomechanical properties in the th3 thalassemia mouse are associated with decreased bone turnover and occur during the period of bone accrual. Calcif Tissue Int. 2010;86(6):484-494.
33. Zhou L, McMahon C, Bhagat T, et al. Reduced SMAD7 leads to overactivation of TGF-beta signaling in MDS that can be reversed by a specific inhibitor of TGF-beta receptor I kinase. Cancer Res. 2011;71(3):955-963.
34. Bhagat TD, Zhou L, Sokol L, et al. miR-21 mediates hematopoietic suppression in MDS by activating TGF-β signaling. Blood. 2013;121(15):2875-2881.
35. Bachegowda L, Gligich O, Mantzaris I, et al. Signal transduction inhibitors in treatment of myelodysplastic syndromes. J Hematol Oncol. 2013;6:50.
36. Zhao N, Zhang AS, Enns CA. Iron regulation by hepcidin. J Clin Invest. 2013;123(6):2337-2343.
37. Paulson RF, Shi L, Wu DC. Stress erythropoiesis: new signals and new stress progenitor cells. Curr Opin Hematol. 2011;18(3):139-145.
38. Li H, Rybicki AC, Suzuka SM, et al. Transferrin therapy ameliorates disease in β-thalassemic mice. Nat Med. 2010;16(2):177-182.
39. -/- mice and ameliorates anemia and iron overload in murine β-thalassemia intermedia. Blood. 2013;121(7):1200-1208.
40. Guo S, Casu C, Gardenghi S, et al. Reducing TMPRSS6 ameliorates hemochromatosis and β-thalassemia in mice. J Clin Invest. 2013;123(4):1531-1541.
41. Ramos P, Casu C, Gardenghi S, et al. Macrophages support pathological erythropoiesis in polycythemia vera and β-thalassemia. Nat Med. 2013;19(4):437-445.
42. Chen JJ. Regulation of protein synthesis by the heme-regulated eIF2α kinase: relevance to anemias. Blood. 2007;109(7):2693-2699.
43. Liu S, Suragani RN, Wang F, et al. The function of heme-regulated eIF2α kinase in murine iron homeostasis and macrophage maturation. J Clin Invest. 2007;117(11):3296-3305. (Pubitemid 350096986)
44. Dussiot M, Maciel TT, Fricot A, et al. An activin receptor IIA ligand trap corrects ineffective erythropoiesis in β-thalassemia. Nat Med. 2014;20(4):398-407.
45. Suragani RN, Cadena SM, Cawley SM, et al. Transforming growth factor-β superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis. Nat Med. 2014;20(4):408-414.
46. Attie KM, Allison MJ, McClure T, et al. A phase 1 study of ACE-536, a regulator of erythroid differentiation, in healthy volunteers. Am J Hematol. 2014;DOI:10.1002/ajh.23732.