Reawakening fetal hemoglobin: prospects for new therapies for the β-globin disorders

Blood - Tập 120 Số 15 - Trang 2945-2953 - 2012
Daniel E. Bauer1,2,3, Sophia C. Kamran3,4, Stuart H. Orkin1,2,3,4
1Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA
2Division of Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, MA
3Harvard Medical School, Boston, MA; and
4Howard Hughes Medical Institute, Boston, MA

Tóm tắt

AbstractThe level of fetal hemoglobin (HbF) modifies the severity of the common β-globin disorders. Knowledge of the normal mechanisms that repress HbF in the adult stage has remained limited until recently despite nearly 3 decades of molecular investigation, in part because of imperfect model systems. Recent studies have provided new insights into the developmental regulation of globin genes and identified specific transcription factors and epigenetic regulators responsible for physiologic silencing of HbF. Most prominent among these regulators is BCL11A, a transcriptional repressor that inhibits adult-stage HbF expression. KLF1 and c-Myb are additional critical HbF-regulating erythroid transcription factors more broadly involved in erythroid gene expression programs. Chromatin modifiers, including histone deacetylases and DNA methyltransferases, also play key roles in orchestrating appropriate globin gene expression. Taken together, these discoveries present novel therapeutic targets for further consideration. Although substantial hurdles remain, opportunities are now rich for the rational design of HbF inducers.

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Tài liệu tham khảo

Weatherall, 2010, The inherited diseases of hemoglobin are an emerging global health burden., Blood, 115, 4331, 10.1182/blood-2010-01-251348

Modell, 2008, Global epidemiology of haemoglobin disorders and derived service indicators., Bull World Health Organ, 86, 480, 10.2471/BLT.06.036673

Kauf, 2009, The cost of health care for children and adults with sickle cell disease., Am J Hematol, 84, 323, 10.1002/ajh.21408

World urbanization prospects, the 2011 revision 2012 Accessed May 15, 2012 http://esa.un.org/unup/documentation/highlights.htm

Pauling, 1949, Sickle cell anemia a molecular disease., Science, 110, 543, 10.1126/science.110.2865.543

Weatherall, 2001, Towards molecular medicine; reminiscences of the haemoglobin field, 1960-2000., Br J Haematol, 115, 729, 10.1046/j.1365-2141.2001.03227.x

Stamatoyannopoulos, 2005, Control of globin gene expression during development and erythroid differentiation., Exp Hematol, 33, 259, 10.1016/j.exphem.2004.11.007

Bank, 2006, Regulation of human fetal hemoglobin: New players, new complexities., Blood, 107, 435, 10.1182/blood-2005-05-2113

Sunshine, 1978, Requirement for therapeutic inhibition of sickle haemoglobin gelation., Nature, 275, 238, 10.1038/275238a0

Dover, 1978, Individual variation in the production and survival of F cells in sickle-cell disease., N Engl J Med, 299, 1428, 10.1056/NEJM197812282992603

Andreani, 2011, Quantitatively different red cell/nucleated cell chimerism in patients with long-term, persistent hematopoietic mixed chimerism after bone marrow transplantation for thalassemia major or sickle cell disease., Haematologica, 96, 128, 10.3324/haematol.2010.031013

Platt, 1994, Mortality in sickle cell disease. life expectancy and risk factors for early death., N Engl J Med, 330, 1639, 10.1056/NEJM199406093302303

DeSimone, 1982, 5-azacytidine stimulates fetal hemoglobin synthesis in anemic baboons., Proc Natl Acad Sci U S A, 79, 4428, 10.1073/pnas.79.14.4428

Ley, 1982, 5-azacytidine selectively increases gamma-globin synthesis in a patient with beta+ thalassemia., N Engl J Med, 307, 1469, 10.1056/NEJM198212093072401

Ley, 1984, DNA methylation and regulation of the human beta-globin-like genes in mouse erythroleukemia cells containing human chromosome 11., Proc Natl Acad Sci U S A, 81, 6618, 10.1073/pnas.81.21.6618

Letvin, 1984, Augmentation of fetal-hemoglobin production in anemic monkeys by hydroxyurea., N Engl J Med, 310, 869, 10.1056/NEJM198404053101401

Platt, 1984, Hydroxyurea enhances fetal hemoglobin production in sickle cell anemia., J Clin Invest, 74, 652, 10.1172/JCI111464

Platt, 2008, Hydroxyurea for the treatment of sickle cell anemia., N Engl J Med, 358, 1362, 10.1056/NEJMct0708272

Taher, 2010, Overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: The OPTIMAL CARE study., Blood, 115, 1886, 10.1182/blood-2009-09-243154

Noordermeer, 2008, Joining the loops: beta-globin gene regulation., IUBMB Life, 60, 824, 10.1002/iub.129

Behringer, 1990, Human gamma- to beta-globin gene switching in transgenic mice., Genes Dev, 4, 380, 10.1101/gad.4.3.380

Enver, 1990, Developmental regulation of human fetal-to-adult globin gene switching in transgenic mice., Nature, 344, 309, 10.1038/344309a0

Chakalova, 2005, The corfu deltabeta thalassemia deletion disrupts gamma-globin gene silencing and reveals post-transcriptional regulation of HbF expression., Blood, 105, 2154, 10.1182/blood-2003-11-4069

Sankaran, 2011, A functional element necessary for fetal hemoglobin silencing., N Engl J Med, 365, 807, 10.1056/NEJMoa1103070

Thein, 2007, Intergenic variants of HBS1L-MYB are responsible for a major quantitative trait locus on chromosome 6q23 influencing fetal hemoglobin levels in adults., Proc Natl Acad Sci U S A, 104, 11346, 10.1073/pnas.0611393104

Menzel, 2007, A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome 2p15., Nat Genet, 39, 1197, 10.1038/ng2108

Uda, 2008, Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia., Proc Natl Acad Sci U S A, 105, 1620, 10.1073/pnas.0711566105

Sedgewick, 2008, BCL11A is a major HbF quantitative trait locus in three different populations with beta-hemoglobinopathies., Blood Cells Mol Dis, 41, 255, 10.1016/j.bcmd.2008.06.007

Lettre, 2008, DNA polymorphisms at the BCL11A, HBS1L-MYB, and beta-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease., Proc Natl Acad Sci U S A, 105, 11869, 10.1073/pnas.0804799105

Nuinoon, 2010, A genome-wide association identified the common genetic variants influence disease severity in beta0-thalassemia/hemoglobin E., Hum Genet, 127, 303, 10.1007/s00439-009-0770-2

Sankaran, 2008, Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A., Science, 322, 1839, 10.1126/science.1165409

Sankaran, 2009, Developmental and species-divergent globin switching are driven by BCL11A., Nature, 460, 1093, 10.1038/nature08243

Xu, 2010, Transcriptional silencing of {gamma}-globin by BCL11A involves long-range interactions and cooperation with SOX6., Genes Dev, 24, 783, 10.1101/gad.1897310

Borg, 2010, Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin., Nat Genet, 42, 801, 10.1038/ng.630

Siatecka, 2010, Severe anemia in the nan mutant mouse caused by sequence-selective disruption of erythroid kruppel-like factor., Proc Natl Acad Sci U S A, 107, 15151, 10.1073/pnas.1004996107

Perkins, 1995, Lethal beta-thalassaemia in mice lacking the erythroid CACCC-transcription factor EKLF., Nature, 375, 318, 10.1038/375318a0

Nuez, 1995, Defective haematopoiesis in fetal liver resulting from inactivation of the EKLF gene., Nature, 375, 316, 10.1038/375316a0

Guy, 1998, Erythroid kruppel-like factor is essential for beta-globin gene expression even in absence of gene competition, but is not sufficient to induce the switch from gamma-globin to beta-globin gene expression., Blood, 91, 2259, 10.1182/blood.V91.7.2259

Miller, 1993, A novel, erythroid cell-specific murine transcription factor that binds to the CACCC element and is related to the kruppel family of nuclear proteins., Mol Cell Biol, 13, 2776, 10.1128/MCB.13.5.2776

Feng, 1994, Analyses of beta-thalassemia mutant DNA interactions with erythroid kruppel-like factor (EKLF), an erythroid cell-specific transcription factor., J Biol Chem, 269, 1493, 10.1016/S0021-9258(17)42283-6

Zhou, 2010, KLF1 regulates BCL11A expression and gamma- to beta-globin gene switching., Nat Genet, 42, 742, 10.1038/ng.637

Perkins, 1996, Silencing of human fetal globin expression is impaired in the absence of the adult beta-globin gene activator protein EKLF., Proc Natl Acad Sci U S A, 93, 12267, 10.1073/pnas.93.22.12267

Satta, 2011, Compound heterozygosity for KLF1 mutations associated with remarkable increase of fetal hemoglobin and red cell protoporphyrin., Haematologica, 96, 767, 10.3324/haematol.2010.037333

Singleton, 2008, Mutations in EKLF/KLF1 form the molecular basis of the rare blood group in(lu) phenotype., Blood, 112, 2081, 10.1182/blood-2008-03-145672

Arnaud, 2010, A dominant mutation in the gene encoding the erythroid transcription factor KLF1 causes a congenital dyserythropoietic anemia., Am J Hum Genet, 87, 721, 10.1016/j.ajhg.2010.10.010

Perseu, 2011, KLF1 gene mutations cause borderline HbA(2)., Blood, 118, 4454, 10.1182/blood-2011-04-345736

Drissen, 2005, The erythroid phenotype of EKLF-null mice: Defects in hemoglobin metabolism and membrane stability., Mol Cell Biol, 25, 5205, 10.1128/MCB.25.12.5205-5214.2005

Hodge, 2006, A global role for EKLF in definitive and primitive erythropoiesis., Blood, 107, 3359, 10.1182/blood-2005-07-2888

Tallack, 2010, A global role for KLF1 in erythropoiesis revealed by ChIP-seq in primary erythroid cells., Genome Res, 20, 1052, 10.1101/gr.106575.110

Pilon, 2011, Genome-wide ChIP-seq reveals a dramatic shift in the binding of the transcription factor erythroid kruppel-like factor during erythrocyte differentiation., Blood, 118, e139, 10.1182/blood-2011-05-355107

Mucenski, 1991, A functional c-myb gene is required for normal murine fetal hepatic hematopoiesis., Cell, 65, 677, 10.1016/0092-8674(91)90099-K

Jiang, 2006, cMYB is involved in the regulation of fetal hemoglobin production in adults., Blood, 108, 1077, 10.1182/blood-2006-01-008912

Sankaran, 2011, MicroRNA-15a and -16-1 act via MYB to elevate fetal hemoglobin expression in human trisomy 13., Proc Natl Acad Sci U S A, 108, 1519, 10.1073/pnas.1018384108

Bianchi, 2010, c-myb supports erythropoiesis through the transactivation of KLF1 and LMO2 expression., Blood, 116, e99, 10.1182/blood-2009-08-238311

Aerbajinai, 2009, SCF induces gamma-globin gene expression by regulating downstream transcription factor COUP-TFII., Blood, 114, 187, 10.1182/blood-2008-07-170712

van Dijk, 2010, Fetal globin expression is regulated by friend of Prmt1., Blood, 116, 4349, 10.1182/blood-2010-03-274399

Lopez, 2002, Multiple hematopoietic defects and delayed globin switching in ikaros null mice., Proc Natl Acad Sci U S A, 99, 602, 10.1073/pnas.022412699

Rupon, 2006, Methyl binding domain protein 2 mediates gamma-globin gene silencing in adult human betaYAC transgenic mice., Proc Natl Acad Sci U S A, 103, 6617, 10.1073/pnas.0509322103

Zhou, 2004, The role of p22 NF-E4 in human globin gene switching., J Biol Chem, 279, 26227, 10.1074/jbc.M402191200

Macari, 2011, Induction of human fetal hemoglobin via the NRF2 antioxidant response signaling pathway., Blood, 117, 5987, 10.1182/blood-2010-10-314096

Tanabe, 2007, Embryonic and fetal beta-globin gene repression by the orphan nuclear receptors, TR2 and TR4., EMBO J, 26, 2295, 10.1038/sj.emboj.7601676

Forsberg, 2000, Developmentally dynamic histone acetylation pattern of a tissue-specific chromatin domain., Proc Natl Acad Sci U S A, 97, 14494, 10.1073/pnas.97.26.14494

Yin, 2007, Histone acetylation at the human beta-globin locus changes with developmental age., Blood, 110, 4101, 10.1182/blood-2007-05-091256

Perrine, 2010, Fetal globin gene inducers: novel agents and new potential., Ann N Y Acad Sci, 1202, 158, 10.1111/j.1749-6632.2010.05593.x

Cao, 2004, Induction of human gamma globin gene expression by histone deacetylase inhibitors., Blood, 103, 701, 10.1182/blood-2003-02-0478

Bradner, 2010, Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease., Proc Natl Acad Sci U S A, 107, 12617, 10.1073/pnas.1006774107

Zhao, 2009, PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, coupling histone and DNA methylation in gene silencing., Nat Struct Mol Biol, 16, 304, 10.1038/nsmb.1568

Rank, 2010, Identification of a PRMT5-dependent repressor complex linked to silencing of human fetal globin gene expression., Blood, 116, 1585, 10.1182/blood-2009-10-251116

van der Ploeg, 1980, DNA methylation in the human gamma delta beta-globin locus in erythroid and nonerythroid tissues., Cell, 19, 947, 10.1016/0092-8674(80)90086-0

Goren, 2006, Fine tuning of globin gene expression by DNA methylation., PLoS One, 1, e46, 10.1371/journal.pone.0000046

Cioe, 1981, Differential expression of the globin genes in human leukemia K562(S) cells induced to differentiate by hemin or butyric acid., Cancer Res, 41, 237

Zein, 2010, Identification of fetal hemoglobin-inducing agents using the human leukemia KU812 cell line., Exp Biol Med (Maywood), 235, 1385, 10.1258/ebm.2010.010129

Ma, 2008, Generation of functional erythrocytes from human embryonic stem cell-derived definitive hematopoiesis., Proc Natl Acad Sci U S A, 105, 13087, 10.1073/pnas.0802220105

Lapillonne, 2010, Red blood cell generation from human induced pluripotent stem cells: Perspectives for transfusion medicine., Haematologica, 95, 1651, 10.3324/haematol.2010.023556

Zou, 2011, Site-specific gene correction of a point mutation in human iPS cells derived from an adult patient with sickle cell disease., Blood, 118, 4599, 10.1182/blood-2011-02-335554

Papapetrou, 2011, Genomic safe harbors permit high beta-globin transgene expression in thalassemia induced pluripotent stem cells., Nat Biotechnol, 29, 73, 10.1038/nbt.1717

Chang, 2010, Globin phenotype of erythroid cells derived from human induced pluripotent stem cells., Blood, 115, 2553, 10.1182/blood-2009-11-252650

Fibach, 1993, The two-step liquid culture: A novel procedure for studying maturation of human normal and pathological erythroid precursors., Stem Cells, 11, 36, 10.1002/stem.5530110608

Giarratana, 2005, Ex vivo generation of fully mature human red blood cells from hematopoietic stem cells., Nat Biotechnol, 23, 69, 10.1038/nbt1047

van den Akker, 2010, The majority of the in vitro erythroid expansion potential resides in CD34(-) cells, outweighing the contribution of CD34(+) cells and significantly increasing the erythroblast yield from peripheral blood samples., Haematologica, 95, 1594, 10.3324/haematol.2009.019828

Giarratana, 2011, Proof of principle for transfusion of in vitro-generated red blood cells., Blood, 118, 5071, 10.1182/blood-2011-06-362038

Li, 2012, Characterization of the transcriptome profiles related to globin gene switching during in vitro erythroid maturation., BMC Genomics, 13, 153, 10.1186/1471-2164-13-153

Sripichai, 2009, Cytokine-mediated increases in fetal hemoglobin are associated with globin gene histone modification and transcription factor reprogramming., Blood, 114, 2299, 10.1182/blood-2009-05-219386

Chan, 2012, Generation of a genomic reporter assay system for analysis of gamma- and beta-globin gene regulation., FASEB J, 26, 1736, 10.1096/fj.11-199356

Blau, 2005, {Gamma}-globin gene expression in chemical inducer of dimerization (CID)-dependent multipotential cells established from human {beta}-globin locus yeast artificial chromosome ({beta}-YAC) transgenic mice., J Biol Chem, 280, 36642, 10.1074/jbc.M504402200

Hardison, 1998, Hemoglobins from bacteria to man: evolution of different patterns of gene expression., J Exp Biol, 201, 1099, 10.1242/jeb.201.8.1099

Peterson, 1993, Transgenic mice containing a 248-kb yeast artificial chromosome carrying the human beta-globin locus display proper developmental control of human globin genes., Proc Natl Acad Sci U S A, 90, 7593, 10.1073/pnas.90.16.7593

Porcu, 1997, The human beta globin locus introduced by YAC transfer exhibits a specific and reproducible pattern of developmental regulation in transgenic mice., Blood, 90, 4602, 10.1182/blood.V90.11.4602

Xu, 2011, Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing., Science, 334, 993, 10.1126/science.1211053

Pászty, 1997, Transgenic knockout mice with exclusively human sickle hemoglobin and sickle cell disease., Science, 278, 876, 10.1126/science.278.5339.876

Kingsley, 2006, “Maturational” globin switching in primary primitive erythroid cells., Blood, 107, 1665, 10.1182/blood-2005-08-3097

McGrath, 2011, A transient definitive erythroid lineage with unique regulation of the beta-globin locus in the mammalian embryo., Blood, 117, 4600, 10.1182/blood-2010-12-325357

Chada, 1986, An embryonic pattern of expression of a human fetal globin gene in transgenic mice., Nature, 319, 685, 10.1038/319685a0

Papayannopoulou, 1979, Cellular regulation of hemoglobin switching: Evidence for inverse relationship between fetal hemoglobin synthesis and degree of maturity of human erythroid cells., Proc Natl Acad Sci U S A, 76, 6420, 10.1073/pnas.76.12.6420

Ganis, 2012, Zebrafish globin switching occurs in two developmental stages and is controlled by the LCR., Dev Biol, 366, 185, 10.1016/j.ydbio.2012.03.021

Jing, 2011, Zebrafish as a model for normal and malignant hematopoiesis., Dis Model Mech, 4, 433, 10.1242/dmm.006791

Lavelle, 1986, On the mechanism of hb F elevations in the baboon by erythropoietic stress and pharmacologic manipulation., Blood, 67, 1083, 10.1182/blood.V67.4.1083.1083

Chin, 2009, Transcriptional activation of the gamma-globin gene in baboons treated with decitabine and in cultured erythroid progenitor cells involves different mechanisms., Exp Hematol, 37, 1131, 10.1016/j.exphem.2009.06.007

Papayannopoulou, 1981, Asynchronous synthesis of HbF and HbA during erythroblast maturation. II. studies of G gamma, A gamma, and beta chain synthesis in individual erythroid clones from neonatal and adult BFU-E cultures., Blood, 57, 531, 10.1182/blood.V57.3.531.bloodjournal573531

Perkins, 2000, Fetal expression of a human agamma globin transgene rescues globin chain imbalance but not hemolysis in EKLF null mouse embryos., Blood, 95, 1827, 10.1182/blood.V95.5.1827.004k10_1827_1833

Liu, 2003, Bcl11a is essential for normal lymphoid development., Nat Immunol, 4, 525, 10.1038/ni925

Leid, 2004, CTIP1 and CTIP2 are differentially expressed during mouse embryogenesis., Gene Expr Patterns, 4, 733, 10.1016/j.modgep.2004.03.009

Kuo, 2010, Bcl11A/CTIP1 mediates the effect of the glutamate receptor on axon branching and dendrite outgrowth., J Neurochem, 114, 1381, 10.1111/j.1471-4159.2010.06852.x

John, 2012, Bcl11a is required for neuronal morphogenesis and sensory circuit formation in dorsal spinal cord development., Development, 139, 1831, 10.1242/dev.072850

Zeggini, 2008, Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes., Nat Genet, 40, 638, 10.1038/ng.120

Langberg, 2012, Single nucleotide polymorphisms in JAZF1 and BCL11A gene are nominally associated with type 2 diabetes in african-american families from the GENNID study., J Hum Genet, 57, 57, 10.1038/jhg.2011.133

Koehler, 2010, A complex task? Direct modulation of transcription factors with small molecules., Curr Opin Chem Biol, 14, 331, 10.1016/j.cbpa.2010.03.022

Filippakopoulos, 2010, Selective inhibition of BET bromodomains., Nature, 468, 1067, 10.1038/nature09504

Nicodeme, 2010, Suppression of inflammation by a synthetic histone mimic., Nature, 468, 1119, 10.1038/nature09589

Dawson, 2011, Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia., Nature, 478, 529, 10.1038/nature10509

Saunthararajah, 2003, Effects of 5-aza-2′-deoxycytidine on fetal hemoglobin levels, red cell adhesion, and hematopoietic differentiation in patients with sickle cell disease., Blood, 102, 3865, 10.1182/blood-2003-05-1738

Olivieri, 2011, A pilot study of subcutaneous decitabine in beta-thalassemia intermedia., Blood, 118, 2708, 10.1182/blood-2011-03-341909

Moutouh-de Parseval, 2008, Pomalidomide and lenalidomide regulate erythropoiesis and fetal hemoglobin production in human CD34+ cells., J Clin Invest, 118, 248, 10.1172/JCI32322

Meiler, 2011, Pomalidomide augments fetal hemoglobin production without the myelosuppressive effects of hydroxyurea in transgenic sickle cell mice., Blood, 118, 1109, 10.1182/blood-2010-11-319137

Ito, 2010, Identification of a primary target of thalidomide teratogenicity., Science, 327, 1345, 10.1126/science.1177319

Moellering, 2009, Direct inhibition of the NOTCH transcription factor complex., Nature, 462, 182, 10.1038/nature08543

Lanford, 2010, Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection., Science, 327, 198, 10.1126/science.1178178

Wilber, 2011, Therapeutic levels of fetal hemoglobin in erythroid progeny of beta-thalassemic CD34+ cells after lentiviral vector-mediated gene transfer., Blood, 117, 2817, 10.1182/blood-2010-08-300723

Cheng, 2012, Genome editing in induced pluripotent stem cells., Genes Cells, 17, 431, 10.1111/j.1365-2443.2012.01599.x