β-thalassemia: A model for elucidating the dynamic regulation of ineffective erythropoiesis and iron metabolism

Blood

Volumn 118, Issue 16, 2011, Pages 4321-4330

  Ginzburg, Yelena ^a   Rivella, Stefano ^b  

^a NEW YORK BLOOD CENTER   (United States)

^b WEILL CORNELL MEDICAL COLLEGE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

APOTRANSFERRIN; AZACITIDINE; BETA GLOBIN; BUTYRIC ACID DERIVATIVE; ERYTHROPOIETIN; HEMOGLOBIN F; HEPCIDIN; HYDROXYUREA; IRON CHELATING AGENT; IRON DEXTRAN; JANUS KINASE 2 INHIBITOR; TRANSFERRIN;

ALLOGENEIC STEM CELL TRANSPLANTATION; ANTIBIOTIC PROPHYLAXIS; APOPTOSIS; BETA THALASSEMIA; CELL CYCLE; CELL DIFFERENTIATION; CELL PROLIFERATION; CHELATION THERAPY; DISEASE ASSOCIATION; DRUG EFFICACY; DRUG MEGADOSE; DYSERYTHROPOIESIS; ERYTHROCYTE LIFESPAN; ERYTHROCYTE TRANSFUSION; ERYTHROPOIESIS; EXTRAMEDULLARY HEMATOPOIESIS; GENE MUTATION; GLOBIN SYNTHESIS; HEART FAILURE; HEMOGLOBIN SYNTHESIS; HUMAN; HYPERSPLENISM; IN VIVO STUDY; INEFFECTIVE ERYTHROPOIESIS; IRON ABSORPTION; IRON CHELATION; IRON INTAKE; IRON METABOLISM; IRON OVERLOAD; IRON RESTRICTION; IRON TRANSPORT; LIPID PEROXIDATION; MYOCARDIAL DISEASE; NONHUMAN; NUCLEAR MAGNETIC RESONANCE IMAGING; PRIORITY JOURNAL; PROTEIN EXPRESSION; PULMONARY HYPERTENSION; QUALITY OF LIFE; REVIEW; SPLENECTOMY; SPLENOMEGALY; STEADY STATE; THALASSEMIA MAJOR; THROMBOSIS;

EID: 80054838641     PISSN: 00064971     EISSN: 15280020     Source Type: Journal    
DOI: 10.1182/blood-2011-03-283614     Document Type: Review

References (100)

1. .Weatherall DJ. Pathophysiology of thalassaemia. Baillieres Clin Haematol. 1998;11(1):127-146. (Pubitemid 29039020)
2. Centis F, Tabellini L, Lucarelli G, et al. The importance of erythroid expansion in determining the extent of apoptosis in erythroid precursors in patients with beta-thalassemia major. Blood. 2000; 96(10):3624-3629.
3. Olivieri NF. The beta-thalassemias. N Engl J Med. 1999;341(2):99-109.
4. Pippard MJ, Callender ST,Warner GT,Weatherall DJ. Iron absorption and loading in beta-thalassaemia intermedia. Lancet. 1979;2(8147):819-821. (Pubitemid 10205108)
5. Kazazian HH Jr. The thalassemia syndromes: molecular basis and prenatal diagnosis in 1990. Semin Hematol. 1990;27(3):209-228.
6. Borgna-Pignatti C, Rugolotto S, De Stefano P, et al. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica. 2004;89(10): 1187-1193. (Pubitemid 39390442)
7. Olivieri NF, Brittenham GM. Iron-chelating therapy and the treatment of thalassemia. Blood. 1997;89(3):739-761. (Pubitemid 27121266)
8. Camaschella C, Cappellini MD. Thalassemia intermedia. Haematologica. 1995;80(1):58-68.
9. Cao A, Galanello R. Beta-thalassemia. Genet Med. 2010;12(2):61-76.
10. Neufeld EJ. Oral chelators deferasirox and deferiprone for transfusional iron overload in thalassemia major: new data, new questions. Blood. 2006;107(9):3436-3441.
11. Cappellini MD, Porter J, El-Beshlawy A, et al. Tailoring iron chelation by iron intake and serum ferritin: the prospective EPIC study of deferasirox in 1744 patients with transfusion-dependent anemias. Haematologica. 2010;95(4):557-566.
12. Taher AT, Musallam KM, Karimi M, et al. Overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: the OPTIMAL CARE study. Blood. 2010;115(10):1886-1892.
13. Cappellini MD, Motta I, Musallam KM, Taher AT. Redefining thalassemia as a hypercoagulable state. Ann N Y Acad Sci. 2010;1202:231-236.
14. Taher A, Isma'eel H, Mehio G, et al. Prevalence of thromboembolic events among 8,860 patients with thalassaemia major and intermedia in the Mediterranean area and Iran. Thromb Haemost. 2006;96(4):488-491. (Pubitemid 44560684)
15. Wilber A, Nienhuis AW, Persons DA. Transcriptional regulation of fetal to adult hemoglobin switching: new therapeutic opportunities. Blood. 2011;117(15)3945-3953.
16. Bauer DE, Orkin SH. Update on fetal hemoglobin gene regulation in hemoglobinopathies. Curr Opin Pediatr. 2011;23(1):1-8.
17. Karimi M. Hydroxyurea in the management of thalassemia intermedia. Hemoglobin. 2009; 33(Suppl 1):S177-S182.
18. Rivella S, Rachmilewitz E. Future alternative therapies for beta-thalassemia. Expert Rev Hematol. 2009;2(6):685-697.
19. Rivella S, May C, Chadburn A, Riviere I, Sadelain M. Anovel murine model of Cooley anemia and its rescue by lentiviral-mediated human beta-globin gene transfer. Blood. 2003;101(8):2932-2939. (Pubitemid 36857977)
20. Breda L, Gambari R, Rivella S. Gene therapy in thalassemia and hemoglobinopathies. Mediterr J Hematol Infect Dis. 2009;1(1):e2009008.
21. Breda L, Kleinert DA, Casu C, et al. A preclinical approach for gene therapy of beta-thalassemia. Ann N Y Acad Sci. 2010;1202:134-140.
22. Cavazzana-Calvo M, Payen E, Negre O, et al. Transfusion independence and HMGA2 activation after gene therapy of human beta-thalassaemia. Nature. 2010;467(7313):318-322.
23. Semenza GL, Nejfelt MK, Chi SM, Antonarakis SE. Hypoxia-inducible nuclear factors bind to an enhancer element located 3′ to the human erythropoietin gene. Proc Natl Acad Sci U S A. 1991; 88(13):5680-5684. (Pubitemid 21914809)
24. Seubert N, Royer Y, Staerk J, et al. Active and inactive orientations of the transmembrane and cytosolic domains of the erythropoietin receptor dimer. Mol Cell. 2003;12(5):1239-1250. (Pubitemid 37487931)
25. .Wojchowski DM, Gregory RC, Miller CP, Pandit AK, Pircher TJ. Signal transduction in the erythropoietin receptor system. Exp Cell Res. 1999;253(1):143-156.
26. Socolovsky M, Fallon AE, Wang S, Brugnara C, Lodish HF. Fetal anemia and apoptosis of red cell progenitors in Stat5a-/-5b-/- mice: a direct role for Stat5 in Bcl-X(L) induction. Cell. 1999;98(2):181-191.
27. Fang J, Menon M, Kapelle W, et al. EPO modulation of cell-cycle regulatory genes, and cell division, in primary bone marrow erythroblasts. Blood. 2007;110(7):2361-2370. (Pubitemid 47523156)
28. Libani IV, Guy EC, Melchiori L, et al. Decreased differentiation of erythroid cells exacerbates ineffective erythropoiesis in beta-thalassemia. Blood. 2008;112(3):875-885.
29. Rivella S. Ineffective erythropoiesis and thalassemias. Curr Opin Hematol. 2009;16(3)187-194.
30. Melchiori L, Gardenghi S, Rivella S. Beta-thalassemia: HiJAKing ineffective erythropoiesis and iron overload. Adv Hematol. 2010;2010:938640.
31. Cappellini MD, Tavazzi D, Duca L, et al. Metabolic indicators of oxidative stress correlate with haemichrome attachment to membrane, band 3 aggregation and erythrophagocytosis in beta-thalassaemia intermedia. Br J Haematol. 1999; 104(3):504-512. (Pubitemid 29119274)
32. Kuypers FA, Yuan J, Lewis RA, et al. Membrane phospholipid asymmetry in human thalassemia. Blood. 1998;91(8):3044-3051. (Pubitemid 28227558)
33. Skow LC, Burkhart BA, Johnson FM, et al. A mouse model for beta-thalassemia. Cell. 1983; 34(3):1043-1052.
34. Yang B, Kirby S, Lewis J, Detloff PJ, Maeda N, Smithies O.Amouse model for beta 0-thalassemia. Proc Natl Acad Sci U S A. 1995;92(25):11608-11612.
35. Ciavatta DJ, Ryan TM, Farmer SC, Townes TM. Mouse model of human beta zero thalassemia: targeted deletion of the mouse beta maj- and beta min-globin genes in embryonic stem cells. Proc Natl Acad Sci U S A. 1995;92(20):9259-9263.
36. Finch CA, Deubelbeiss K, Cook JD, et al. Ferrokinetics in man. Medicine (Baltimore). 1970;49(1): 17-53.
37. Cazzola M, Finch CA. Iron balance in thalassemia. Prog Clin Biol Res. 1989;309:93-100.
38. Yuan J, Angelucci E, Lucarelli G, et al. Accelerated programmed cell death (apoptosis) in erythroid precursors of patients with severe betathalassemia (Cooley's anemia). Blood. 1993; 82(2):374-377. (Pubitemid 23206098)
39. Fiorelli G, Fargion S, Piperno A, Battafarano N, Cappellini MD. Iron metabolism in thalassemia intermedia. Haematologica. 1990;75(Suppl 5):89-95. (Pubitemid 20359675)
40. Origa R, Galanello R, Ganz T, et al. Liver iron concentrations and urinary hepcidin in beta-thalassemia. Haematologica. 2007;92(5):583-588. (Pubitemid 350144260)
41. Gardenghi S, Marongiu MF, Ramos P, et al. Ineffective erythropoiesis in beta-thalassemia is characterized by increased iron absorption mediated by down-regulation of hepcidin and up-regulation of ferroportin. Blood. 2007;109(11):5027-5035. (Pubitemid 46827803)
42. Ginzburg YZ, Rybicki AC, Suzuka SM, et al. Exogenous iron increases hemoglobin in beta-thalassemic mice. Exp Hematol. 2009;37(2):172- 183.
43. Gardenghi S, Ramos P, Marongiu MF, et al. Hepcidin as a therapeutic tool to limit iron overload and improve anemia in beta-thalassemic mice. J Clin Invest. 2010;120(12):4466-4477.
44. Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306(5704):2090-2093. (Pubitemid 40007660)
45. Ganz T, Nemeth E. Hepcidin and disorders of iron metabolism. Annu Rev Med. 2011;62:347-360.
46. Truksa J, Peng H, Lee P, Beutler E. Bone morphogenetic proteins 2, 4, and 9 stimulate murine hepcidin 1 expression independently of Hfe, transferrin receptor 2 (Tfr2), and IL-6. Proc Natl Acad Sci U S A. 2006;103(27):10289-10293. (Pubitemid 44051159)
47. Babitt JL, Huang FW, Wrighting DM, et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet. 2006; 38(5):531-539.
48. .Wang RH, Li C, Xu X, et al. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab. 2005;2(6):399-409.
49. Feder JN, Penny DM, Irrinki A, et al. The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proc Natl Acad Sci U S A. 1998; 95(4):1472-1477. (Pubitemid 28103416)
50. Lebron JA, Bennett MJ, Vaughn DE, et al. Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor. Cell. 1998;93(1):111-123. (Pubitemid 28173557)
51. Giannetti AM, Bjorkman PJ. HFE and transferrin directly compete for transferrin receptor in solution and at the cell surface. J Biol Chem. 2004; 279(24):25866-25875. (Pubitemid 38756852)
52. Robb A, Wessling-Resnick M. Regulation of transferrin receptor 2 protein levels by transferrin. Blood. 2004;104(13):4294-4299. (Pubitemid 39620185)
53. Johnson MB, Enns CA. Diferric transferrin regulates transferrin receptor 2 protein stability. Blood. 2004;104(13):4287-4293. (Pubitemid 39620184)
54. Goswami T, Andrews NC. Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing. J Biol Chem. 2006; 281(39):28494-28498. (Pubitemid 44506991)
55. Schmidt PJ, Toran PT, Giannetti AM, Bjorkman PJ, Andrews NC. The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression. Cell Metab. 2008;7(3):205-214. (Pubitemid 351285524)
56. Li H, Ginzburg YZ. Crosstalk between iron metabolism and erythropoiesis. Adv Hematol. 2010; 2010:605435.
57. Du X, She E, Gelbart T, et al. The serine protease TMPRSS6 is required to sense iron deficiency. Science. 2008;320(5879):1088-1092. (Pubitemid 351929552)
58. Finberg KE, Heeney MM, Campagna DR, et al. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet. 2008; 40(5):569-571. (Pubitemid 351601217)
59. Melis MA, Cau M, Congiu R, et al. A mutation in the TMPRSS6 gene, encoding a transmembrane serine protease that suppresses hepcidin production, in familial iron deficiency anemia refractory to oral iron. Haematologica. 2008;93(10):1473-1479.
60. Silvestri L, Pagani A, Nai A, De Domenico I, Kaplan J, Camaschella C. The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell Metab. 2008;8(6):502-511.
61. Babitt JL, Huang FW, Xia Y, Sidis Y, Andrews NC, Lin HY. Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J Clin Invest. 2007;117(7):1933-1939. (Pubitemid 47036327)
62. Andrews NC. Disorders of iron metabolism. N Engl J Med. 1999;341(26):1986-1995. (Pubitemid 30010408)
63. Ponka P, Beaumont C, Richardson DR. Function and regulation of transferrin and ferritin. Semin Hematol. 1998;35(1):35-54. (Pubitemid 28047041)
64. Rouault TA. The role of iron regulatory proteins in mammalian iron homeostasis and disease. Nat Chem Biol. 2006;2(8):406-414. (Pubitemid 44114917)
65. Huebers HA, Csiba E, Huebers E, Finch CA. Competitive advantage of diferric transferrin in delivering iron to reticulocytes. Proc Natl Acad Sci U S A. 1983;80(1):300-304.
66. Huebers HA, Josephson B, Huebers E, Csiba E, Finch CA. Occupancy of the iron binding sites of human transferrin. Proc Natl Acad Sci U S A. 1984;81(14):4326-4330. (Pubitemid 14052437)
67. Bartnikas TB, Andrews NC, Fleming MD. Transferrin is a major determinant of hepcidin expression in hypotransferrinemic mice. Blood. 2011; 117(2):630-637.
68. Galy B, Ferring D, Minana B, et al. Altered body iron distribution and microcytosis in mice deficient in iron regulatory protein 2 (IRP2). Blood. 2005; 106(7):2580-2589. (Pubitemid 41510837)
69. Cooperman SS, Meyron-Holtz EG, Olivierre-Wilson H, Ghosh MC, McConnell JP, Rouault TA. Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2. Blood. 2005;106(3):1084-1091. (Pubitemid 41076458)
70. Kerenyi MA, Grebien F, Gehart H, et al. Stat5 regulates cellular iron uptake of erythroid cells via IRP-2 and TfR-1. Blood. 2008;112(9):3878-3888.
71. Schranzhofer M, Schifrer M, Cabrera JA, et al. Remodeling the regulation of iron metabolism during erythroid differentiation to ensure efficient heme biosynthesis. Blood. 2006;107(10):4159-4167. (Pubitemid 43726827)
72. Canonne-Hergaux F, Zhang AS, Ponka P, Gros P. Characterization of the iron transporter DMT1 (NRAMP2/DCT1) in red blood cells of normal and anemic mk/mk mice. Blood. 2001;98(13):3823-3830.
73. Zhang DL, Hughes RM, Ollivierre-Wilson H, Ghosh MC, Rouault TA. A ferroportin transcript that lacks an iron-responsive element enables duodenal and erythroid precursor cells to evade translational repression. Cell Metab. 2009;9(5): 461-473.
74. Keel SB, Doty RT, Yang Z, et al. A heme export protein is required for red blood cell differentiation and iron homeostasis. Science. 2008;319(5864): 825-828. (Pubitemid 351225875)
75. Forejtnikova H, Vieillevoye M, Zermati Y, et al. Transferrin receptor 2 is a component of the erythropoietin receptor complex and is required for efficient erythropoiesis. Blood. 2010;116(24): 5357-5367.
76. Nicolas G, Viatte L, Bennoun M, Beaumont C, Kahn A, Vaulont S. Hepcidin, a new iron regulatory peptide. Blood Cells Mol Dis. 2002;29(3): 327-335.
77. Vokurka M, Krijt J, Sulc K, Necas E. Hepcidin mRNA levels in mouse liver respond to inhibition of erythropoiesis. Physiol Res. 2006;55(6):667-674. (Pubitemid 46021227)
78. Pinto JP, Ribeiro S, Pontes H, et al. Erythropoietin mediates hepcidin expression in hepatocytes through EPOR signaling and regulation of C/EBP-alpha. Blood. 2008;111(12):5727-5733.
79. Pak M, Lopez MA, Gabayan V, Ganz T, Rivera S. Suppression of hepcidin during anemia requires erythropoietic activity. Blood. 2006;108(12):3730-3735. (Pubitemid 44864551)
80. Kattamis A, Papassotiriou I, Palaiologou D, et al. The effects of erythropoetic activity and iron burden on hepcidin expression in patients with thalassemia major. Haematologica. 2006;91(6):809-812. (Pubitemid 44014549)
81. .Weizer O, Adamsky K, Breda L, et al. Hepcidin expression in cultured liver cells responds differently to iron overloaded sera derived from patients with thalassemia and hemochromatosis [abstract]. Blood. 2004;104(11):Abstract 3196
82. Finch C. Regulators of iron balance in humans. Blood. 1994;84(6):1697-1702. (Pubitemid 24286117)
83. 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.
84. Vilmos P, Gaudenz K, Hegedus Z, Marsh JL. The Twisted gastrulation family of proteins, together with the IGFBP and CCN families, comprise the TIC superfamily of cysteine rich secreted factors. Mol Pathol. 2001;54(5):317-323. (Pubitemid 32928258)
85. Tamary H, Shalev H, Perez-Avraham G, et al. Elevated growth differentiation factor 15 expression in patients with congenital dyserythropoietic anemia type I. Blood. 2008;112(13):5241-5244.
86. Ramirez JM, Schaad O, Durual S, et al. Growth differentiation factor 15 production is necessary for normal erythroid differentiation and is increased in refractory anaemia with ring-sideroblasts. Br J Haematol. 2009;144(2):251-262.
87. Casanovas G, Swinkels DW, Altamura S, et al. Growth differentiation factor 15 in patients with congenital dyserythropoietic anaemia (CDA) type II [published online ahead of print April 8, 2011]. J Mol Med. doi: 10.1007/s00109-011-0751-5.
88. Ramos P, Melchiori L, Gardenghi S, et al. Iron metabolism and ineffective erythropoiesis in beta-thalassemia mouse models. Ann N Y Acad Sci. 2010;1202:24-30.
89. Rivella S, Nemeth E, Miller JL. Crosstalk between erythropoiesis and iron metabolism. Adv Hematol. 2010;2010:317095.
90. Li H, Rybicki AC, Suzuka SM, et al. Transferrin therapy ameliorates disease in beta-thalassemic mice. Nat Med. 2010;16(2):177-182.
91. Levy JE, Jin O, Fujiwara Y, Kuo F, Andrews NC. Transferrin receptor is necessary for development of erythrocytes and the nervous system. Nat Genet. 1999;21(4):396-399. (Pubitemid 29159576)
92. Brugnara C, Colella GM, Cremins J, et al. Effects of subcutaneous recombinant human erythropoietin in normal subjects: development of decreased reticulocyte hemoglobin content and iron-deficient erythropoiesis. J Lab Clin Med. 1994;123(5):660-667.
93. Cavill I, Macdougall IC. Functional iron deficiency. Blood. 1993;82(4):1377.
94. Pootrakul P,Wattanasaree J, Anuwatanakulchai M, Wasi P. Increased red blood cell protoporphyrin in thalassemia: a result of relative iron deficiency. Am J Clin Pathol. 1984;82(3):289-293. (Pubitemid 14031070)
95. Beguin Y, Stray SM, Cazzola M, Huebers HA, Finch CA. Ferrokinetic measurement of erythropoiesis. Acta Haematol. 1988;79(3):121-126.
96. Gardenghi S, Grady RW, Rivella S. Anemia, ineffective erythropoiesis, and hepcidin: interacting factors in abnormal iron metabolism leading to iron overload in beta-thalassemia. Hematol Oncol Clin North Am. 2010;24(6):1089-1107.
97. 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)
98. Kearney SL, Nemeth E, Neufeld EJ, et al. Urinary hepcidin in congenital chronic anemias. Pediatr Blood Cancer. 2007;48(1):57-63. (Pubitemid 44871594)
99. Eldor A, Rachmilewitz EA. The hypercoagulable state in thalassemia. Blood. 2002;99(1):36-43.
100. Taher AT, Otrock ZK, Uthman I, Cappellini MD. Thalassemia and hypercoagulability. Blood Rev. 2008;22(5):283-292.