β-thalassemias: Paradigmatic diseases for scientific discoveries and development of innovative therapies

Haematologica

Volumn 100, Issue 4, 2015, Pages 418-430

  Rivella, Stefano ^a  

^a WEILL CORNELL MEDICAL COLLEGE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACTIVIN RECEPTOR II TRAP LIGAND; APOTRANSFERRIN; BIM PROTEIN; BONE MORPHOGENETIC PROTEIN 4; ERYTHROPOIETIN; FAS LIGAND; HEMOGLOBIN BETA CHAIN; HEPCIDIN; HYPOXIA INDUCIBLE FACTOR 2ALPHA; HYPOXIA INDUCIBLE FACTOR 2ALPHA INHIBITOR; JANUS KINASE 2; JANUS KINASE 2 INHIBITOR; KRUPPEL LIKE FACTOR 1 PROTEIN; LIGAND; LIM DOMAIN BINDING 1 PROTEIN; MINIHEPCIDIN; MISCELLANEOUS DRUGS AND AGENTS; MITOGEN ACTIVATED PROTEIN KINASE; PEPTIDES AND PROTEINS; PROTEIN BCL 11A; PROTEIN BCL XL; PROTEIN FOG1; PROTEIN KINASE B; STAT5 PROTEIN; STEM CELL FACTOR; STEM CELL FACTOR RECEPTOR; TRANSCRIPTION FACTOR GATA 1; TRANSCRIPTION FACTOR TAL1; TRANSMEMBRANE PROTEASE SERINE 6 INHIBITOR; UNCLASSIFIED DRUG; UNINDEXED DRUG; IRON;

ANEMIA; APOPTOSIS; ARTICLE; BETA THALASSEMIA; BLOOD TRANSFUSION; ERYTHROPOIESIS; GENE EXPRESSION REGULATION; GENE MUTATION; GENE THERAPY; HUMAN; IRON METABOLISM; IRON OVERLOAD; IRON RESPONSIVE ELEMENT; NONHUMAN; OXIDATIVE STRESS; PHASE 1 CLINICAL TRIAL (TOPIC); PHENOTYPE; QUALITY OF LIFE; SIGNAL TRANSDUCTION; SURVIVAL; ANIMAL; BETA-THALASSEMIA; EXPERIMENTAL THERAPY; GENETICS; METABOLISM;

ANIMALS; BETA-GLOBINS; BETA-THALASSEMIA; ERYTHROPOIESIS; HUMANS; IRON; PHENOTYPE; THERAPIES, INVESTIGATIONAL;

EID: 84926317302     PISSN: 03906078     EISSN: 15928721     Source Type: Journal    
DOI: 10.3324/haematol.2014.114827     Document Type: Article

References (173)

1. Giardine B, Borg J, Viennas E, et al. Updates of the HbVar database of human hemoglobin variants and thalassemia mutations. Nucleic Acids Res. 2014;42(Database issue):D1063-1069.
2. Shinar E, Rachmilewitz EA. Oxidative denaturation of red blood cells in thalassemia. Semin Hematol. 1990;27(1):70-82.
3. Yuan J, Kannan R, Shinar E, et al. Isolation, characterization, and immunoprecipitation studies of immune complexes from membranes of beta-thalassemic erythrocytes. Blood. 1992;79(11):3007-3013.
4. Ginzburg Y, Rivella S. beta-thalassemia: a model for elucidating the dynamic regulation of ineffective erythropoiesis and iron metabolism. Blood. 2011;118(16):4321-4330.
5. Musallam KM, Rivella S, Vichinsky E, Rachmilewitz EA. Non-transfusion-dependent thalassemias. Haematologica. 2013; 98(6):833-844.
6. Hershko C, Graham G, Bates GW, Rachmilewitz EA. Non-specific serum iron in thalassaemia: an abnormal serum iron fraction of potential toxicity. Br J Haematol. 1978;40(2):255-263.
7. Breuer W, Hershko C, Cabantchik ZI. The importance of non-transferrin bound iron in disorders of iron metabolism. Transfus Sci. 2000;23(3):185-192.
8. Brissot P, Ropert M, Le Lan C, Loreal O. Non-transferrin bound iron: a key role in iron overload and iron toxicity. Biochim Biophys Acta. 2012;1820(3):403-410.
9. Musallam KM, Cappellini MD, Wood JC, Taher AT. Iron overload in non-transfusiondependent thalassemia: a clinical perspective. Blood Rev. 2012;26 Suppl 1:S16-9.
10. Cappellini MD, Poggiali E, Taher AT, Musallam KM. Hypercoagulability in betathalassemia: a status quo. Expert Rev Hematol. 2012;5(5):505-511; quiz 12.
11. Musallam KM, Taher AT, Karimi M, Rachmilewitz EA. Cerebral infarction in beta-thalassemia intermedia: breaking the silence. Thromb Res. 2012;130(5):695-702.
12. Deisseroth A, Nienhuis A, Lawrence J, Giles R, Turner P, Ruddle FH. Chromosomal localization of human beta globin gene on human chromosome 11 in somatic cell hybrids. Proc Natl Acad Sci USA. 1978;75(3):1456-1460.
13. Maniatis T, Kee SG, Efstratiadis A, Kafatos FC. Amplification and characterization of a beta-globin gene synthesized in vitro. Cell. 1976;8(2):163-182.
14. Edsall JT. Hemoglobin and the origins of the concept of allosterism. Fed Proc. 1980;39(2):226-235.
15. Maquat LE, Kinniburgh AJ, Beach LR, et al. Processing of human beta-globin mRNA precursor to mRNA is defective in three patients with beta+-thalassemia. Proc Natl Acad Sci USA. 1980;77(7):4287-4291.
16. Neu-Yilik G, Gehring NH, Thermann R, Frede U, Hentze MW, Kulozik AE. Splicing and 3' end formation in the definition of nonsense-mediated decay-competent human beta-globin mRNPs. EMBO J. 2001;20(3):532-540.
17. Nathan DG, Lodish HF, Kan YW, Housman D. Beta thalassemia and translation of globin messenger RNA. Proc Natl Acad Sci USA. 1971;68(10):2514-2518.
18. Hahn CK, Lowrey CH. Induction of fetal hemoglobin through enhanced translation efficiency of gamma-globin mRNA. Blood. 2014;124(17):2730-2734.
19. Weatherall DJ, Williams TN, Allen SJ, O'Donnell A. The population genetics and dynamics of the thalassemias. Hematol Oncol Clin North Am. 2010;24(6):1021-1031.
20. Curtin P, Pirastu M, Kan YW, Gobert-Jones JA, Stephens AD, Lehmann H. A distant gene deletion affects beta-globin gene function in an atypical gamma delta beta-thalassemia. J Clin Invest. 1985;76(4):1554-1558.
21. Driscoll MC, Dobkin CS, Alter BP. Gamma delta beta-thalassemia due to a de novo mutation deleting the 5' beta-globin gene activation-region hypersensitive sites. Proc Nal Acad Sci USA. 1989;86(19):7470-7474.
22. Van der Ploeg LH, Konings A, Oort M, Roos D, Bernini L, Flavell RA. gamma-beta-Thalassaemia studies showing that deletion of the gamma-and delta-genes influences beta-globin gene expression in man. Nature. 1980;283(5748):637-642.
23. Kioussis D, Vanin E, deLange T, Flavell RA, Grosveld FG. Beta-globin gene inactivation by DNA translocation in gamma beta-thalassaemia. Nature. 1983;306(5944):662-666.
24. Forrester WC, Epner E, Driscoll MC, et al. A deletion of the human beta-globin locus activation region causes a major alteration in chromatin structure and replication across the entire beta-globin locus. Genes Dev. 1990;4(10):1637-1649.
25. Caterina JJ, Ryan TM, Pawlik KM, et al. Human beta-globin locus control region: analysis of the 5' DNase I hypersensitive site HS 2 in transgenic mice. Proc Natl Acad Sci USA. 1991;88(5):1626-1630.
26. Fraser P, Pruzina S, Antoniou M, Grosveld F. Each hypersensitive site of the human betaglobin locus control region confers a different developmental pattern of expression on the globin genes. Genes Dev. 1993;7(1):106-113.
27. Li Q, Peterson KR, Fang X, Stamatoyannopoulos G. Locus control regions. Blood. 2002;100(9):3077-3086.
28. Kim A, Dean A. Chromatin loop formation in the beta-globin locus and its role in globin gene transcription. Mol Cells. 2012;34 (1):1-5.
29. Grosveld F, van Assendelft GB, Greaves DR, Kollias G. Position-independent, high-level expression of the human beta-globin gene in transgenic mice. Cell. 1987;51(6):975-985.
30. Wijgerde M, Grosveld F, Fraser P. Transcription complex stability and chromatin dynamics in vivo. Nature. 1995;377 (6546):209-213.
31. Lloyd JA, Krakowsky JM, Crable SC, Lingrel JB. Human gamma-to beta-globin gene switching using a mini construct in transgenic mice. Mol Cell Biol. 1992;12(4):1561-1567.
32. Deng W, Lee J, Wang H, et al. Controlling long-range genomic interactions at a native locus by targeted tethering of a looping factor. Cell. 2012;149(6):1233-1244.
33. Behringer RR, Ryan TM, Palmiter RD, Brinster RL, Townes TM. Human gammato beta-globin gene switching in transgenic mice. Genes Dev. 1990;4(3):380-389.
34. Deng W, Rupon JW, Krivega I, et al. Reactivation of developmentally silenced globin genes by forced chromatin looping. Cell. 2014;158(4):849-860.
35. Trimborn T, Gribnau J, Grosveld F, Fraser P. Mechanisms of developmental control of transcription in the murine alpha-and betaglobin loci. Genes Dev. 1999;13(1):112-124.
36. Conley CL, Weatherall DJ, Richardson SN, Shepard MK, Charache S. Hereditary persistence of fetal hemoglobin: a study of 79 affected persons in 15 Negro families in Baltimore. Blood. 1963;21:261-281.
37. Perrine SP, Pace BS, Faller DV. Targeted fetal hemoglobin induction for treatment of beta hemoglobinopathies. Hematol Oncol Clin North Am. 2014;28(2):233-248.
38. Thein SL, Menzel S. Discovering the genetics underlying foetal haemoglobin production in adults. Br J Haematol. 2009;145 (4):455-467.
39. Sankaran VG, Xu J, Orkin SH. Advances in the understanding of haemoglobin switching. Br J Haematol. 2010;149(2):181-194.
40. Sankaran VG. Targeted therapeutic strategies for fetal hemoglobin induction. Hematology Am Soc Hematol Educ Program. 2011;2011:459-465.
41. Dekker J. Gene regulation in the third dimension. Science. 2008;319(5871):1793-1794.
42. Splinter E, de Laat W. The complex transcription regulatory landscape of our genome: control in three dimensions. EMBO J. 2011;30(21):4345-4355.
43. Drissen R, Palstra RJ, Gillemans N, et al. The active spatial organization of the beta-globin locus requires the transcription factor EKLF. Genes Dev. 2004;18(20):2485-2490.
44. Vakoc CR, Letting DL, Gheldof N, et al. Proximity among distant regulatory elements at the beta-globin locus requires GATA-1 and FOG-1. Mol Cell. 2005;17(3):453-462.
45. Song SH, Kim A, Ragoczy T, Bender MA, Groudine M, Dean A. Multiple functions of Ldb1 required for beta-globin activation during erythroid differentiation. Blood. 2010;116(13):2356-2364.
46. Deng W, Blobel GA. Manipulating nuclear architecture. Curr Opin Genet Dev. 2014;25:1-7.
47. Menzel S, Garner C, Gut I, et al. A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome 2p15. Nat Genet. 2007;39(10):1197-1199.
48. Uda M, Galanello R, Sanna S, et al. Genomewide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia. Proc Natl Acad Sci USA. 2008;105(5):1620-1625.
49. Sankaran VG, Menne TF, Xu J, et al. Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Science. 2008;322(5909):1839-1842.
50. Xu J, Peng C, Sankaran VG, et al. Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing. Science. 2011;334(6058):993-996.
51. Miller IJ, Bieker JJ. A novel, erythroid cellspecific murine transcription factor that binds to the CACCC element and is related to the Kruppel family of nuclear proteins. Mol Cell Biol. 1993;13(5):2776-2786.
52. Nuez B, Michalovich D, Bygrave A, Ploemacher R, Grosveld F. Defective haematopoiesis in fetal liver resulting from inactivation of the EKLF gene. Nature. 1995;375(6529):316-318.
53. Borg J, Papadopoulos P, Georgitsi M, et al. Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin. Nat Genet. 2010;42(9):801-805.
54. Satta S, Perseu L, Moi P, et al. Compound heterozygosity for KLF1 mutations associated with remarkable increase of fetal hemoglobin and red cell protoporphyrin. Haematologica. 2011;96(5):767-770.
55. Liu D, Zhang X, Yu L, et al. KLF1 mutations are relatively more common in a thalassemia endemic region and ameliorate the severity of beta-thalassemia. Blood. 2014;124(5):803-811.
56. Breen JJ, Agulnick AD, Westphal H, Dawid IB. Interactions between LIM domains and the LIM domain-binding protein Ldb1. J Biol Chem. 1998;273(8):4712-4717.
57. Jurata LW, Pfaff SL, Gill GN. The nuclear LIM domain interactor NLI mediates homoand heterodimerization of LIM domain transcription factors. J Biol Chem. 1998;273(6):3152-157.
58. Xu Z, Huang S, Chang LS, Agulnick AD, Brandt SJ. Identification of a TAL1 target gene reveals a positive role for the LIM domain-binding protein Ldb1 in erythroid gene expression and differentiation. Mol Cell Biol. 2003;23(21):7585-7599.
59. Cross AJ, Jeffries CM, Trewhella J, Matthews JM. LIM domain binding proteins 1 and 2 have different oligomeric states. J Mol Biol. 2010;399(1):133-144.
60. Wadman IA, Osada H, Grutz GG, et al. The LIM-only protein Lmo2 is a bridging molecule assembling an erythroid, DNA-binding complex which includes the TAL1, E47, GATA-1 and Ldb1/NLI proteins. EMBO J. 1997;16(11):3145-3157.
61. Fujiwara T, O'Geen H, Keles S, et al. Discovering hematopoietic mechanisms through genome-wide analysis of GATA factor chromatin occupancy. Mol Cell. 2009;36(4):667-681.
62. Tripic T, Deng W, Cheng Y, et al. SCL and associated proteins distinguish active from repressive GATA transcription factor complexes. Blood. 2009;113(10):2191-2201.
63. Yu M, Riva L, Xie H, et al. Insights into GATA-1-mediated gene activation versus repression via genome-wide chromatin occupancy analysis. Mol Cell. 2009;36(4):682-695.
64. Soler E, Andrieu-Soler C, de Boer E, et al. The genome-wide dynamics of the binding of Ldb1 complexes during erythroid differentiation. Genes Dev. 2010;24(3):277-289.
65. Li L, Freudenberg J, Cui K, et al. Ldb1-nucleated transcription complexes function as primary mediators of global erythroid gene activation. Blood. 2013;121(22):4575-4585.
66. Haase VH. Regulation of erythropoiesis by hypoxia-inducible factors. Blood Rev. 2013;27(1):41-53.
67. Iscove NN, Sieber F. Erythroid progenitors in mouse bone marrow detected by macroscopic colony formation in culture. Exp Hematol. 1975;3(1):32-43.
68. Heath DS, Axelrad AA, McLeod DL, Shreeve MM. Separation of the erythropoietin-responsive progenitors BFU-E and CFUE in mouse bone marrow by unit gravity sedimentation. Blood. 1976;47(5):777-792.
69. Stephenson JR, Axelrad AA, McLeod DL, Shreeve MM. Induction of colonies of hemoglobin-synthesizing cells by erythropoietin in vitro. Proc Natl Acad Sci USA. 1971;68(7):1542-1546.
70. Li J, Hale J, Bhagia P, et al. Isolation and transcriptome analyses of human erythroid progenitors: BFU-E and CFU-E. Blood. 2014;124(24):3636-3645.
71. 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.
72. Koulnis M, Pop R, Porpiglia E, Shearstone JR, Hidalgo D, Socolovsky M. Identification and analysis of mouse erythroid progenitors using the CD71/TER119 flow-cytometric assay. J Vis Exp. 2011(54). pii:2809.
73. Chen K, Liu J, Heck S, Chasis JA, An X, Mohandas N. Resolving the distinct stages in erythroid differentiation based on dynamic changes in membrane protein expression during erythropoiesis. Proc Nl Acad Sci USA. 2009;106(41):17413-17418.
74. Socolovsky M. Ineffective erythropoiesis in Stat5a-/-5b-/-mice due to decreased survival of early erythroblasts. Blood. 2001;98(12):3261-3273.
75. Koulnis M, Porpiglia E, Porpiglia PA, et al. Contrasting dynamic responses in vivo of the Bcl-xL and Bim erythropoietic survival pathways. Blood. 2012;119(5):1228-1239.
76. Socolovsky M, Murrell M, Liu Y, Pop R, Porpiglia E, Levchenko A. Negative autoregulation by FAS mediates robust fetal erythropoiesis. PLoS Biol. 2007;5(10):e252.
77. Koulnis M, Liu Y, Hallstrom K, Socolovsky M. Negative autoregulation by Fas stabilizes adult erythropoiesis and accelerates its stress response. PloS One. 2011;6(7):e21192.
78. Anderson Sheila A, Nizzi CP, Chang Y-I, et al. The IRP1-HIF-2 Axis Coordinates Iron and Oxygen Sensing with Erythropoiesis and Iron Absorption. Cell Metab. 2013;17(2):282-290.
79. Camaschella C. Iron and hepcidin: a story of recycling and balance. Hematology Am Soc Hematol Educ Program. 2013;2013:1-8.
80. Ramos P, Guy E, Chen N, et al. Enhanced erythropoiesis in Hfe-KO mice indicates a role for Hfe in the modulation of erythroid iron homeostasis. Blood. 2011;117(4):1379-1389.
81. Nai A, Lidonnici MR, Rausa M, et al. The second transferrin receptor regulates red blood cell production in mice. Blood. 2015;125(7):1170-1179.
82. Goodell MA, Porpiglia E, Hidalgo D, Koulnis M, Tzafriri AR, Socolovsky M. Stat5 Signaling Specifies Basal versus Stress Erythropoietic Responses through Distinct Binary and Graded Dynamic Modalities. PLoS Biol. 2012;10(8):e1001383.
83. Peslak SA, Wenger J, Bemis JC, et al. EPOmediated expansion of late-stage erythroid progenitors in the bone marrow initiates recovery from sublethal radiation stress. Blood. 2012;120(12):2501-2511.
84. Perry JM, Harandi OF, Paulson RF. BMP4, SCF, and hypoxia cooperatively regulate the expansion of murine stress erythroid progenitors. Blood. 2007;109(10):4494-4502.
85. Perry JM, Harandi OF, Porayette P, Hegde S, Kannan AK, Paulson RF. Maintenance of the BMP4-dependent stress erythropoiesis pathway in the murine spleen requires hedgehog signaling. Blood. 2009;113(4):911-918.
86. Harandi OF, Hedge S, Wu DC, McKeone D, Paulson RF. Murine erythroid short-term radioprotection requires a BMP4-dependent, self-renewing population of stress erythroid progenitors. J Clin Invest. 2010;120 (12):4507-4519.
87. Chow A, Huggins M, Ahmed J, et al. CD169(+) macrophages provide a niche promoting erythropoiesis under homeostasis and stress. Nat Med. 2013;19(4):429-436.
88. Lenox LE, Perry JM, Paulson RF. BMP4 and Madh5 regulate the erythroid response to acute anemia. Blood. 2005;105(7):2741-2748.
89. Ramos P, Casu C, Gardenghi S, et al. Macrophages support pathological erythropoiesis in polycythemia vera and beta-thalassemia. Nat Med. 2013;19(4):437-445.
90. Chasis JA. Erythroblastic islands: specialized microenvironmental niches for erythropoiesis. Curr Opin Hematol. 2006;13(3):137-141.
91. Chasis JA, Mohandas N. Erythroblastic islands: niches for erythropoiesis. Blood. 2008;112(3):470-478.
92. Mohandas N, Chasis JA. The erythroid niche: molecular processes occurring within erythroblastic islands. Transfus Clin Biol. 2010;17(3):110-111.
93. Ripich T, Jessberger R. SWAP-70 regulates erythropoiesis by controlling alpha4 integrin. Haematologica. 2011;96(12):1743-1752.
94. Kovach NL, Lin N, Yednock T, Harlan JM, Broudy VC. Stem cell factor modulates avidity of alpha 4 beta 1 and alpha 5 beta 1 integrins expressed on hematopoietic cell lines. Blood. 1995;85(1):159-167.
95. Eshghi S, Vogelezang MG, Hynes RO, Griffith LG, Lodish HF. Alpha4beta1 integrin and erythropoietin mediate temporally distinct steps in erythropoiesis: integrins in red cell development. J Cell Biol. 2007;177(5):871-880.
96. Paulson RF, Shi L, Wu DC. Stress erythropoiesis: new signals and new stress progenitor cells. Curr Opin Hematol. 2011;18(3):139-145.
97. Ulyanova T, Jiang Y, Padilla S, Nakamoto B, Papayannopoulou T. Combinatorial and distinct roles of alpha and alpha integrins in stress erythropoiesis in mice. Blood. 2011;117(3):975-985.
98. Kapur R, Cooper R, Zhang L, Williams DA. Cross-talk between alpha(4)beta(1)/alpha(5)beta(1) and c-Kit results in opposing effect on growth and survival of hematopoietic cells via the activation of focal adhesion kinase, mitogen-activated protein kinase, and Akt signaling pathways. Blood. 2001;97(7):1975-1981.
99. Vemula S, Ramdas B, Hanneman P, Martin J, Beggs HE, Kapur R. Essential role for focal adhesion kinase in regulating stress hematopoiesis. Blood. 2010;116(20):4103-4115.
100. Varricchio L, Tirelli V, Masselli E, et al. The Expression of the Glucocorticoid Receptor in Human Erythroblasts is Uniquely Regulated by KIT Ligand: Implications for Stress Erythropoiesis. Stem Cells Dev. 2012;21(15):2852-2865.
101. Zhang L, Prak L, Rayon-Estrada V, et al. ZFP36L2 is required for self-renewal of early burst-forming unit erythroid progenitors. Nature. 2013;499(7456):92-96.
102. Oh P, Lobry C, Gao J, et al. In Vivo Mapping of Notch Pathway Activity in Normal and Stress Hematopoiesis. Cell Stem Cell. 2013;13(2):190-204.
103. Coulon S, Dussiot M, Grapton D, et al. Polymeric IgA1 controls erythroblast proliferation and accelerates erythropoiesis recovery in anemia. Nat Med. 2011;17(11):1456-1465.
104. Stellacci E, Di Noia A, Di Baldassarre A, Migliaccio G, Battistini A, Migliaccio AR. Interaction between the glucocorticoid and erythropoietin receptors in human erythroid cells. Exp Hematol. 2009;37(5):559-572.
105. Falchi M, Varricchio L, Martelli F, et al. Dexamethasone targeted directly to macrophages induces macrophage niches that promote erythroid expansion. Haematologica. 2015;100(2):178-187.
106. 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.
107. Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. 2001;276(11):7806-7810.
108. Nicolas G, Bennoun M, Devaux I, et al. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci USA. 2001;98(15):8780-8785.
109. 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.
110. Ganz T. Systemic iron homeostasis. Physiol Rev. 2013;93(4):1721-1741.
111. Wilkinson N, Pantopoulos K. The IRP/IRE system in vivo: insights from mouse models. Front Pharmacol. 2014;5:176.
112. Anderson ER, Taylor M, Xue X, et al. Intestinal HIF2alpha promotes tissue-iron accumulation in disorders of iron overload with anemia. Proc Natl Acad Sci USA. 2013;110(50):E4922-4930.
113. Anderson SA, Nizzi CP, Chang YI, et al. The IRP1-HIF-2alpha axis coordinates iron and oxygen sensing with erythropoiesis and iron absorption. Cell Metab. 2013;17(2):282-290.
114. Ghosh MC, Zhang DL, Jeong SY, et al. Deletion of iron regulatory protein 1 causes polycythemia and pulmonary hypertension in mice through translational derepression of HIF2alpha. Cell Metab. 2013;17(2):271-281.
115. Wilkinson N, Pantopoulos K. IRP1 regulates erythropoiesis and systemic iron homeostasis by controlling HIF2alpha mRNA translation. Blood. 2013;122(9):1658-1668.
116. 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.
117. 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.
118. Kautz L, Jung G, Valore EV, Rivella S, Nemeth E, Ganz T. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat Genet. 2014;46(7):678-684.
119. 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 USA. 1995;92(20):9259-9263.
120. Yang B, Kirby S, Lewis J, Detloff PJ, Maeda N, Smithies O. A mouse model for beta 0-thalassemia. Proc Natl Acad Sci USA. 1995;92(25):11608-11612.
121. Skow LC, Burkhart BA, Johnson FM, et al. A mouse model for beta-thalassemia. Cell. 1983;34(3):1043-1052.
122. Li H, Rybicki AC, Suzuka SM, et al. Transferrin therapy ameliorates disease in beta-thalassemic mice. Nat Med. 2010;16(2):177-182.
123. 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.
124. 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.
125. Rivella S, May C, Chadburn A, Riviere I, Sadelain M. A novel murine model of Cooley anemia and its rescue by lentiviralmediated human beta-globin gene transfer. Blood. 2003;101(8):2932-2939.
126. Breda L, Rivella S. Modulators of erythropoiesis: emerging therapies for hemoglobinopathies and disorders of red cell production. Hematol Oncol Clin North Am. 2014;28(2):375-386.
127. Adamsky K, Weizer O, Amariglio N, et al. Decreased hepcidin mRNA expression in thalassemic mice. Br J Haematol. 2004; 124(1):123-124.
128. Weizer-Stern O, Adamsky K, Amariglio N, et al. mRNA expression of iron regulatory genes in beta-thalassemia intermedia and beta-thalassemia major mouse models. Am J Hematol. 2006;81(7):479-483.
129. Musallam KM, Taher AT, Cappellini MD, Sankaran VG. Clinical experience with fetal hemoglobin induction therapy in patients with beta-thalassemia. Blood. 2013; 121(12):2199-2212; quiz 372.
130. Thein SL. The emerging role of fetal hemoglobin induction in non-transfusion-dependent thalassemia. Blood Rev. 2012;26 Suppl 1:S35-39.
131. Melchiori L, Gardenghi S, Rivella S. beta-Thalassemia: HiJAKing Ineffective Erythropoiesis and Iron Overload. Adv Hematol. 2010;2010:938640.
132. Savona MR. Are we altering the natural history of primary myelofibrosis? Leukemia Res. 2014;38(9):1004-1012.
133. Pasquier F, Cabagnols X, Secardin L, Plo I, Vainchenker W. Myeloproliferative Neoplasms: JAK2 Signaling Pathway as a Central Target for Therapy. Clin Lymphoma Myeloma Leuk. 2014;14 Suppl:S23-S35.
134. Meyer SC, Keller MD, Woods BA, et al. Genetic studies reveal an unexpected negative regulatory role for Jak2 in thrombopoiesis. Blood. 2014;124(14):2280-2284.
135. Oh SP, Yeo CY, Lee Y, Schrewe H, Whitman M, Li E. Activin type IIA and IIB receptors mediate Gdf11 signaling in axial vertebral patterning. Genes Dev. 2002;16(21):2749-2754.
136. Zhou L, Nguyen AN, Sohal D, et al. Inhibition of the TGF-beta receptor I kinase promotes hematopoiesis in MDS. Blood. 2008;112(8):3434-3443.
137. Sinha M, Jang YC, Oh J, et al. Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science. 2014;344(6184):649-652.
138. Andersen RE, Lim DA. An ingredient for the elixir of youth. Cell Res. 2014;24(12):1381-1382.
139. Szumska D, Pieles G, Essalmani R, et al. VACTERL/caudal regression/Currarino syndrome-like malformations in mice with mutation in the proprotein convertase Pcsk5. Genes Dev. 2008;22(11):1465-1477.
140. Lotinun S, Pearsall RS, Horne WC, Baron R. Activin receptor signaling: a potential therapeutic target for osteoporosis. Curr Mol Pharmacol. 2012;5(2):195-204.
141. Raje N, Vallet S. Sotatercept, a soluble activin receptor type 2A IgG-Fc fusion protein for the treatment of anemia and bone loss. Curr Opin Mol Ther. 2010;12(5):586-597.
142. Suragani RN, Cawley SM, Li R, et al. Modified activin receptor IIB ligand trap mitigates ineffective erythropoiesis and disease complications in murine beta-thalassemia. Blood. 2014;123(25):3864-3872.
143. Dussiot M, Maciel TT, Fricot A, et al. An activin receptor IIA ligand trap corrects ineffective erythropoiesis in beta-thalassemia. Nat Med. 2014;20(4):398-407.
144. Suragani RN, Cadena SM, Cawley SM, et al. Transforming growth factor-beta superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis. Nat Med. 2014;20(4):408-414.
145. Piga AG, Perrotta S, Melpignano A, et al. ACE-536 Increases Hemoglobin and Decreases Transfusion Burden and Serum Ferritin in Adults with Beta-Thalassemia: Preliminary Results from a Phase 2 Study. Blood. 2014;124(21):abs. 53.
146. Origa R, Galanello R. Pathophysiology of beta thalassaemia. Pediatr Endocrinol Rev. 2011;8 Suppl 2:263-270.
147. Origa R, Galanello R, Ganz T, et al. Liver iron concentrations and urinary hepcidin in beta-thalassemia. Haematologica. 2007;92(5):583-588.
148. 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.
149. Ramos E, Ruchala P, Goodnough JB, et al. Minihepcidins prevent iron overload in a hepcidin-deficient mouse model of severe hemochromatosis. Blood. 2012;120(18): 3829-3836.
150. Preza GC, Ruchala P, Pinon R, et al. Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload. J Clin Invest. 2011;121(12): 4880-4888.
151. Casu C, Oikonomidau R, Nemeth E, Ganz T, MacDonald B, Rivella S. Use of Minihepcidins As a “Medical Phlebotomy” in the Treatment of Polycythemia Vera. Blood. 2014;124(21):abs. 3231.
152. Du X, She E, Gelbart T, et al. The serine protease TMPRSS6 is required to sense iron deficiency. Science. 2008;320(5879):1088-1092.
153. 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.
154. 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.
155. Maxson JE, Chen J, Enns CA, Zhang AS. Matriptase-2-and proprotein convertasecleaved forms of hemojuvelin have different roles in the down-regulation of hepcidin expression. J Biol Chem. 2010;285(50): 39021-39028.
156. Finberg KE, Whittlesey RL, Fleming MD, Andrews NC. Down-regulation of Bmp/Smad signaling by Tmprss6 is required for maintenance of systemic iron homeostasis. Blood. 2010;115(18):3817-3826.
157. Huang FW, Pinkus JL, Pinkus GS, Fleming MD, Andrews NC. A mouse model of juvenile hemochromatosis. J Clin Invest. 2005;115(8):2187-2191.
158. Nai A, Pagani A, Mandelli G, et al. Deletion of TMPRSS6 attenuates the phenotype in a mouse model of beta-thalassemia. Blood. 2012;119(21):5021-5029.
159. Guo S, Casu C, Gardenghi S, et al. Reducing TMPRSS6 ameliorates hemochromatosis and beta-thalassemia in mice. J Clin Invest. 2013;123(4):1531-1541.
160. Schmidt PJ, Toudjarska I, Sendamarai AK, et al. An RNAi therapeutic targeting Tmprss6 decreases iron overload in Hfe(-/-) mice and ameliorates anemia and iron overload in murine beta-thalassemia intermedia. Blood. 2013;121(7):1200-1208.
161. Taylor M, Qu A, Anderson ER, et al. Hypoxia-inducible factor-2alpha mediates the adaptive increase of intestinal ferroportin during iron deficiency in mice. Gastroenterology. 2011;140(7):2044-2055.
162. Mastrogiannaki M, Matak P, Peyssonnaux C. The gut in iron homeostasis: role of HIF-2 under normal and pathological conditions. Blood. 2013;122(6):885-892.
163. Dong A, Rivella S, Breda L. Gene therapy for hemoglobinopathies: progress and challenges. Transl Res. 2013;161(4):293-306.
164. Breda L, Casu C, Gardenghi S, et al. Therapeutic hemoglobin levels after gene transfer in beta-thalassemia mice and in hematopoietic cells of beta-thalassemia and sickle cells disease patients. PloS One. 2012;7(3):e32345.
165. Payen E, Leboulch P. Advances in stem cell transplantation and gene therapy in the betahemoglobinopathies. Hematology Am Soc Hematol Educ Program. 2012;2012:276-283.
166. 166.Cavazzana-Calvo M, Payen E, Negre O, et al. Transfusion independence and HMGA2 activation after gene therapy of human betathalassaemia. Nature. 2010; 467(7313):318-322.
167. 167.Boulad F, Wang X, Qu J, et al. Safe mobilization of CD34+ cells in adults with beta-thalassemia and validation of effective globin gene transfer for clinical investigation. Blood. 2014;123(10):1483-1486.
168. 168.Liu M, Maurano MT, Wang H, et al. Genomic discovery of potent chromatin insulators for human gene therapy. Nat Biotechnol. 2015;33(2):198-203.
169. Bauer DE, Kamran SC, Lessard S, et al. An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level. Science. 2013;342(6155):253-257.
170. Schmidt PJ, Racie T, Westerman M, Fitzgerald K, Butler JS, Fleming MD. Combination therapy with a Tmprss6 RNAi-therapeutic and the oral iron chelator deferiprone additively diminishes secondary iron overload in a mouse model of beta-thalassemia intermedia. Am J Hematol. 2015 Jan 2. [Epub ahead of print]
171. 171.Casu C, Aghajan M, Oikonomidau R, Guo S, Monia BP, Rivella S. Combination of Tmprss6-ASO and the Iron Chelator Deferiprone Improves Erythropoiesis and Reduces Iron Overload in a Mouse Model of Beta-Thalassemia. Blood. 2014; 124(21):abs. 4024.
172. Breda L, Rivella S, Zuccato C, Gambari R. Combining gene therapy and fetal hemoglobin induction for treatment of beta-thalassemia. Exp Rev Hematol. 2013;6(3):255-264.
173. Zuccato C, Breda L, Salvatori F, et al. A combined approach for beta-thalassemia based on gene therapy-mediated adult hemoglobin (HbA) production and fetal hemoglobin (HbF) induction. Ann Hematol. 2012;91(8): 1201-1213.