title: β-thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies.
abstract: β-thalassemias are monogenic disorders characterized by defective synthesis of the β-globin chain, one of the major components of adult hemoglobin. A large number of mutations in the β-globin gene or its regulatory elements have been associated with β-thalassemias. Due to the complexity of the regulation of the β-globin gene and the role of red cells in many physiological processes, patients can manifest a large spectrum of phenotypes, and clinical requirements vary from patient to patient. It is important to consider the major differences in the light of potential novel therapeutics. This review summarizes the main discoveries and mechanisms associated with the synthesis of β-globin and abnormal erythropoiesis, as well as current and novel therapies.
authors.affiliation: Department of Pediatrics Hematology-Oncology Department of Cell and Developmental Biology Weill Cornell Medical College New York, NY, USA str2010@med.cornell.edu.
authors.forename: Stefano
authors.initials: S
authors.lastname: Rivella
mesh_terms: D000818:Animals; D004920:Erythropoiesis / Q000235:genetics; D006801:Humans; D007501:Iron / Q000378:metabolism; D010641:Phenotype; D035703:Therapies, Investigational; D055544:beta-Globins / Q000235:genetics* / Q000378:metabolism; D017086:beta-Thalassemia / Q000175:diagnosis / Q000209:etiology* / Q000628:therapy*
chemical_list: D055544:beta-Globins; D007501:Iron
references.citation: Genes Dev. 2002 Nov 1;16(21):2749-54
references.pmid: 12414726
references.citation: Proc Natl Acad Sci U S A. 2009 Oct 13;106(41):17413-8
references.pmid: 19805084
references.citation: Blood. 2012 Nov 1;120(18):3829-36
references.pmid: 22990014
references.citation: Genes Dev. 1990 Oct;4(10):1637-49
references.pmid: 2249769
references.citation: Blood. 2014 Jul 31;124(5):803-11
references.pmid: 24829204
references.citation: Nature. 2010 Sep 16;467(7313):318-22
references.pmid: 20844535
references.citation: Haematologica. 2007 May;92(5):583-8
references.pmid: 17488680
references.citation: Curr Opin Hematol. 2011 May;18(3):139-45
references.pmid: 21372709
references.citation: Cell. 1987 Dec 24;51(6):975-85
references.pmid: 3690667
references.citation: Cell Metab. 2008 Dec;8(6):502-11
references.pmid: 18976966
references.citation: Hematology Am Soc Hematol Educ Program. 2013;2013:1-8
references.pmid: 24319154
references.citation: J Clin Invest. 2010 Dec;120(12):4466-77
references.pmid: 21099112
references.citation: J Cell Biol. 2007 Jun 4;177(5):871-80
references.pmid: 17548514
references.citation: Nat Biotechnol. 2015 Feb;33(2):198-203
references.pmid: 25580597
references.citation: Blood. 2011 Oct 20;118(16):4321-30
references.pmid: 21768301
references.citation: Blood. 2003 Apr 15;101(8):2932-9
references.pmid: 12480689
references.citation: Science. 2014 May 9;344(6184):649-52
references.pmid: 24797481
references.citation: Proc Natl Acad Sci U S A. 1971 Oct;68(10):2514-8
references.pmid: 5289885
references.citation: J Clin Invest. 1985 Oct;76(4):1554-8
references.pmid: 2997283
references.citation: Blood. 2009 Jul 2;114(1):181-6
references.pmid: 19414861
references.citation: Blood. 2010 May 6;115(18):3817-26
references.pmid: 20200349
references.citation: Blood. 2013 Feb 14;121(7):1200-8
references.pmid: 23223430
references.citation: Nature. 1980 Feb 14;283(5748):637-42
references.pmid: 6153459
references.citation: Curr Opin Mol Ther. 2010 Oct;12(5):586-97
references.pmid: 20886391
references.citation: Front Pharmacol. 2014 Jul 28;5:176
references.pmid: 25120486
references.citation: Blood. 2013 Mar 21;121(12):2199-212; quiz 2372
references.pmid: 23315167
references.citation: Blood. 2013 May 30;121(22):4575-85
references.pmid: 23610375
references.citation: Haematologica. 2011 Dec;96(12):1743-52
references.pmid: 21880631
references.citation: Blood. 2012 Feb 2;119(5):1228-39
references.pmid: 22086418
references.citation: Mol Cell. 2005 Feb 4;17(3):453-62
references.pmid: 15694345
references.citation: Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11608-12
references.pmid: 8524813
references.citation: Blood Rev. 2013 Jan;27(1):41-53
references.pmid: 23291219
references.citation: Blood. 2010 Sep 30;116(13):2356-64
references.pmid: 20570862
references.citation: Mol Cell Biol. 1993 May;13(5):2776-86
references.pmid: 7682653
references.citation: EMBO J. 2001 Feb 1;20(3):532-40
references.pmid: 11157759
references.citation: Thromb Res. 2012 Nov;130(5):695-702
references.pmid: 22857801
references.citation: Curr Mol Pharmacol. 2012 Jun;5(2):195-204
references.pmid: 21787285
references.citation: Mol Cell Biol. 2003 Nov;23(21):7585-99
references.pmid: 14560005
references.citation: Cell. 1976 Jun;8(2):163-82
references.pmid: 61066
references.citation: Blood. 2008 Aug 1;112(3):875-85
references.pmid: 18480424
references.citation: Science. 2013 Oct 11;342(6155):253-7
references.pmid: 24115442
references.citation: Stem Cells Dev. 2012 Oct 10;21(15):2852-65
references.pmid: 22533504
references.citation: Haematologica. 2013 Jun;98(6):833-44
references.pmid: 23729725
references.citation: Nature. 1995 Sep 21;377(6546):209-13
references.pmid: 7675106
references.citation: Blood. 2002 Nov 1;100(9):3077-86
references.pmid: 12384402
references.citation: Mol Cells. 2012 Jul;34(1):1-5
references.pmid: 22610406
references.citation: Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1626-30
references.pmid: 2000371
references.citation: Blood. 2010 Nov 18;116(20):4103-15
references.pmid: 20664055
references.citation: Hematology Am Soc Hematol Educ Program. 2012;2012:276-83
references.pmid: 23233592
references.citation: Science. 2008 Dec 19;322(5909):1839-42
references.pmid: 19056937
references.citation: Curr Opin Hematol. 2006 May;13(3):137-41
references.pmid: 16567955
references.citation: Physiol Rev. 2013 Oct;93(4):1721-41
references.pmid: 24137020
references.citation: Hematol Oncol Clin North Am. 2010 Dec;24(6):1021-31
references.pmid: 21075278
references.citation: PLoS Biol. 2007 Oct;5(10):e252
references.pmid: 17896863
references.citation: Ann Hematol. 2012 Aug;91(8):1201-13
references.pmid: 22460946
references.citation: Blood. 2008 Aug 1;112(3):470-8
references.pmid: 18650462
references.citation: Nucleic Acids Res. 2014 Jan;42(Database issue):D1063-9
references.pmid: 24137000
references.citation: Hematol Oncol Clin North Am. 2014 Apr;28(2):375-86
references.pmid: 24589272
references.citation: Blood. 1963 Mar;21:261-81
references.pmid: 14022587
references.citation: Fed Proc. 1980 Feb;39(2):226-35
references.pmid: 6986293
references.citation: J Biol Chem. 2010 Dec 10;285(50):39021-8
references.pmid: 20937842
references.citation: Cell. 1983 Oct;34(3):1043-52
references.pmid: 6313205
references.citation: Nat Med. 2014 Apr;20(4):408-14
references.pmid: 24658078
references.citation: Nat Med. 2011;17(11):1456-65
references.pmid: 22019886
references.citation: Blood. 2014 Dec 4;124(24):3636-45
references.pmid: 25339359
references.citation: Gastroenterology. 2011 Jun;140(7):2044-55
references.pmid: 21419768
references.citation: Proc Natl Acad Sci U S A. 1978 Mar;75(3):1456-60
references.pmid: 274732
references.citation: EMBO J. 2011 Nov 2;30(21):4345-55
references.pmid: 21952046
references.citation: Cell. 2014 Aug 14;158(4):849-60
references.pmid: 25126789
references.citation: Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9259-63
references.pmid: 7568113
references.citation: J Vis Exp. 2011;(54). pii: 2809. doi: 10.3791/2809
references.pmid: 21847081
references.citation: Cell Stem Cell. 2013 Aug 1;13(2):190-204
references.pmid: 23791481
references.citation: Blood. 2014 Oct 2;124(14):2280-4
references.pmid: 25115888
references.citation: Am J Hematol. 2015 Apr;90(4):310-3
references.pmid: 25557851
references.citation: J Clin Invest. 2010 Dec;120(12):4507-19
references.pmid: 21060151
references.citation: Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8780-5
references.pmid: 11447267
references.citation: Haematologica. 2011 May;96(5):767-70
references.pmid: 21273267
references.citation: Br J Haematol. 2010 Apr;149(2):181-94
references.pmid: 20201948
references.citation: Science. 2011 Nov 18;334(6058):993-6
references.pmid: 21998251
references.citation: PLoS One. 2011;6(7):e21192
references.pmid: 21760888
references.citation: Hematol Oncol Clin North Am. 2014 Apr;28(2):233-48
references.pmid: 24589264
references.citation: Nat Med. 2013 Apr;19(4):437-45
references.pmid: 23502961
references.citation: Blood. 2011 Jan 20;117(3):975-85
references.pmid: 20956802
references.citation: J Biol Chem. 1998 Feb 6;273(6):3152-7
references.pmid: 9452425
references.citation: J Mol Biol. 2010 May 28;399(1):133-44
references.pmid: 20382157
references.citation: Cell Res. 2014 Dec;24(12):1381-2
references.pmid: 25112712
references.citation: Blood. 2008 Oct 15;112(8):3434-43
references.pmid: 18474728
references.citation: Nat Genet. 2010 Sep;42(9):801-5
references.pmid: 20676099
references.citation: Blood. 2005 Apr 1;105(7):2741-8
references.pmid: 15591122
references.citation: Exp Hematol. 1975 Jan;3(1):32-43
references.pmid: 1157835
references.citation: Cell Metab. 2013 Feb 5;17(2):282-90
references.pmid: 23395174
references.citation: J Biol Chem. 1998 Feb 20;273(8):4712-7
references.pmid: 9468533
references.citation: Hematology Am Soc Hematol Educ Program. 2011;2011:459-65
references.pmid: 22160074
references.citation: Semin Hematol. 1990 Jan;27(1):70-82
references.pmid: 2405497
references.citation: Blood. 1976 May;47(5):777-92
references.pmid: 1260134
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1620-5
references.pmid: 18245381
references.citation: Am J Hematol. 2006 Jul;81(7):479-83
references.pmid: 16755567
references.citation: Blood. 2015 Feb 12;125(7):1170-9
references.pmid: 25499454
references.citation: Blood. 2009 Jan 22;113(4):911-8
references.pmid: 18927434
references.citation: Blood. 2013 Aug 29;122(9):1658-68
references.pmid: 23777768
references.citation: Mol Cell. 2009 Nov 25;36(4):682-95
references.pmid: 19941827
references.citation: Proc Natl Acad Sci U S A. 1971 Jul;68(7):1542-6
references.pmid: 4104431
references.citation: PLoS Biol. 2012 Aug;10(8):e1001383
references.pmid: 22969412
references.citation: Exp Hematol. 2009 May;37(5):559-72
references.pmid: 19375647
references.citation: Proc Natl Acad Sci U S A. 1980 Jul;77(7):4287-91
references.pmid: 6933479
references.citation: Nat Genet. 2007 Oct;39(10):1197-9
references.pmid: 17767159
references.citation: Blood. 2007 Jun 1;109(11):5027-35
references.pmid: 17299088
references.citation: J Clin Invest. 2011 Dec;121(12):4880-8
references.pmid: 22045566
references.citation: Blood. 1992 Jun 1;79(11):3007-13
references.pmid: 1586745
references.citation: Adv Hematol. 2010;2010:938640
references.pmid: 20508726
references.citation: Blood. 2011 Jan 27;117(4):1379-89
references.pmid: 21059897
references.citation: Genes Dev. 2010 Feb 1;24(3):277-89
references.pmid: 20123907
references.citation: Blood Rev. 2012 Apr;26 Suppl 1:S35-9
references.pmid: 22631042
references.citation: Blood. 1995 Jan 1;85(1):159-67
references.pmid: 7528564
references.citation: Nature. 1995 May 25;375(6529):316-8
references.pmid: 7753194
references.citation: Genes Dev. 1999 Jan 1;13(1):112-24
references.pmid: 9887104
references.citation: Science. 2008 Mar 28;319(5871):1793-4
references.pmid: 18369139
references.citation: Genes Dev. 1993 Jan;7(1):106-13
references.pmid: 8422981
references.citation: Nature. 2013 Jul 4;499(7456):92-6
references.pmid: 23748442
references.citation: Blood. 2014 Mar 6;123(10):1483-6
references.pmid: 24429337
references.citation: Blood. 2007 May 15;109(10):4494-502
references.pmid: 17284534
references.citation: Blood. 2014 Oct 23;124(17):2730-4
references.pmid: 25170120
references.citation: Blood. 2012 May 24;119(21):5021-9
references.pmid: 22490684
references.citation: Nat Med. 2014 Apr;20(4):398-407
references.pmid: 24658077
references.citation: Transl Res. 2013 Apr;161(4):293-306
references.pmid: 23337292
references.citation: Blood. 2001 Apr 1;97(7):1975-81
references.pmid: 11264161
references.citation: Clin Lymphoma Myeloma Leuk. 2014 Sep;14 Suppl:S23-35
references.pmid: 25486952
references.citation: Genes Dev. 1990 Mar;4(3):380-9
references.pmid: 1692558
references.citation: Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):E4922-30
references.pmid: 24282296
references.citation: Nat Genet. 2014 Jul;46(7):678-84
references.pmid: 24880340
references.citation: Curr Opin Genet Dev. 2014 Apr;25:1-7
references.pmid: 24584091
references.citation: Blood. 2009 Mar 5;113(10):2191-201
references.pmid: 19011221
references.citation: Blood. 2013 Aug 8;122(6):885-92
references.pmid: 23678007
references.citation: PLoS One. 2012;7(3):e32345
references.pmid: 22479321
references.citation: Blood. 2013 Apr 18;121(16):3246-53
references.pmid: 23422750
references.citation: Expert Rev Hematol. 2013 Jun;6(3):255-64
references.pmid: 23782080
references.citation: Nat Genet. 2008 May;40(5):569-71
references.pmid: 18408718
references.citation: Mol Cell Biol. 1992 Apr;12(4):1561-7
references.pmid: 1549112
references.citation: EMBO J. 1997 Jun 2;16(11):3145-57
references.pmid: 9214632
references.citation: Mol Cell. 2009 Nov 25;36(4):667-81
references.pmid: 19941826
references.citation: Blood Rev. 2012 Apr;26 Suppl 1:S16-9
references.pmid: 22631036
references.citation: Cell. 2012 Jun 8;149(6):1233-44
references.pmid: 22682246
references.citation: J Clin Invest. 2013 Apr;123(4):1531-41
references.pmid: 23524968
references.citation: J Biol Chem. 2001 Mar 16;276(11):7806-10
references.pmid: 11113131
references.citation: Cell Metab. 2013 Feb 5;17(2):271-81
references.pmid: 23395173
references.citation: Haematologica. 2015 Feb;100(2):178-87
references.pmid: 25533803
references.citation: Blood. 2012 Sep 20;120(12):2501-11
references.pmid: 22889760
references.citation: Blood. 2014 Jun 19;123(25):3864-72
references.pmid: 24795345
references.citation: Transfus Sci. 2000 Dec;23(3):185-92
references.pmid: 11099894
references.citation: Nature. 1983 Dec 15-21;306(5944):662-6
references.pmid: 6318113
references.citation: Biochim Biophys Acta. 2012 Mar;1820(3):403-10
references.pmid: 21855608
references.citation: J Clin Invest. 2005 Aug;115(8):2187-91
references.pmid: 16075059
references.citation: Br J Haematol. 1978 Oct;40(2):255-63
references.pmid: 708645
references.citation: Nat Med. 2007 Sep;13(9):1096-101
references.pmid: 17721544
references.citation: Genes Dev. 2008 Jun 1;22(11):1465-77
references.pmid: 18519639
references.citation: Br J Haematol. 2009 May;145(4):455-67
references.pmid: 19344402
references.citation: Science. 2008 May 23;320(5879):1088-92
references.pmid: 18451267
references.citation: Pediatr Endocrinol Rev. 2011 Mar;8 Suppl 2:263-70
references.pmid: 21705976
references.citation: Transfus Clin Biol. 2010 Sep;17(3):110-1
references.pmid: 20655267
references.citation: Expert Rev Hematol. 2012 Oct;5(5):505-11; quiz 512
references.pmid: 23146054
references.citation: Blood. 2008 Nov 1;112(9):3878-88
references.pmid: 18694996
references.citation: Proc Natl Acad Sci U S A. 1989 Oct;86(19):7470-4
references.pmid: 2798417
references.citation: Blood. 2001 Dec 1;98(12):3261-73
references.pmid: 11719363
references.citation: Genes Dev. 2004 Oct 15;18(20):2485-90
references.pmid: 15489291
references.citation: Leuk Res. 2014 Sep;38(9):1004-12
references.pmid: 24931396
references.citation: Nat Med. 2010 Feb;16(2):177-82
references.pmid: 20098432
references.citation: Nat Med. 2013 Apr;19(4):429-36
references.pmid: 23502962
references.citation: Science. 2004 Dec 17;306(5704):2090-3
references.pmid: 15514116
references.citation: Br J Haematol. 2004 Jan;124(1):123-4
references.pmid: 14675418
references.citation: Haematologica. 2016 Jan;101(1):e8-e11
references.pmid: 26405152