Experimental Hematology
Volume 36, Issue 9 , Pages 1057-1072 , September 2008

A cell stress signaling model of fetal hemoglobin induction: what doesn't kill red blood cells may make them stronger

Received 18 May 2008 ,Revised 25 June 2008 ,Accepted 27 June 2008.

References 

  1. Weatherall DJ, JGGL , Warrell DA. In:  Weatherall DJ,  Ledingharm JGG,  Warrell DA editor. Oxford textbook of medicine. 3rd ed. Oxford: Oxford University Press; 1996;
  2. Nagel RL, Roth EF. Malaria and red cell genetic defects. Blood. 1989;74:1213–1221
  3. Aidoo M, Terlouw DJ, Kolczak MS, et al. Protective effects of the sickle cell gene against malaria morbidity and mortality. Lancet. 2002;359:1311–1312
  4. Ingram VM. Gene mutations in human haemoglobin: the chemical difference between normal and sickle cell haemoglobin. Nature. 1957;180:326–328
  5. Frenette PS, Atweh GF. Sickle cell disease: old discoveries, new concepts, and future promise. J Clin Invest. 2007;117:850–858
  6. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sicskle cell disease. Life expectancy and risk factors for early death. N Engl J Med. 1994;330:1639–1644
  7. Sickle-cell anaemia. Report by the Secretariat Fifty-Ninth World Health Assembly. Geneva: World Health Organization; 2006;p. 1–5
  8. Patrinos GP, Giardine B, Riemer C, et al. Improvements in the HbVar database of human hemoglobin variants and thalassemia mutations for population and sequence variation studies. Nucleic Acids Res. 2004;32:D537–D541
  9. Schrier SL. Pathophysiology of thalassemia. Curr Opin Hematol. 2002;9:123–126
  10. 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;109:5027–5035
  11. Delea TE, Edelsberg J, Sofrygin O, et al. Consequences and costs of noncompliance with iron chelation therapy in patients with transfusion-dependent thalassemia: a literature review. Transfusion. 2007;47:1919–1929
  12. Bhatia M, Walters MC. Hematopoietic cell transplantation for thalassemia and sickle cell disease: past, present and future. Bone Marrow Transplant. 2008;41:109–117
  13. Shenoy S. Has stem cell transplantation come of age in the treatment of sickle cell disease?. Bone Marrow Transplant. 2007;40:813–821
  14. Lucarelli G, Gaziev J. Advances in the allogeneic transplantation for thalassemia. Blood Rev. 2008;22:53–63
  15. Vermylen C, Cornu G, Ferster A, et al. Haematopoietic stem cell transplantation for sickle cell anaemia: the first 50 patients transplanted in Belgium. Bone Marrow Transplant. 1998;22:1–6
  16. Bernaudin F, Socie G, Kuentz M, et al. Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease. Blood. 2007;110:2749–2756
  17. Walters MC, Storb R, Patience M, et al. Impact of bone marrow transplantation for symptomatic sickle cell disease: an interim report. Multicenter investigation of bone marrow transplantation for sickle cell disease. Blood. 2000;95:1918–1924
  18. Walters MC, Patience M, Leisenring W, et al. Barriers to bone marrow transplantation for sickle cell anemia. Biol Blood Marrow Transplant. 1996;2:100–104
  19. Sadelain M. Recent advances in globin gene transfer for the treatment of beta-thalassemia and sickle cell anemia. Curr Opin Hematol. 2006;13:142–148
  20. Bank A, Dorazio R, Leboulch P. A phase I/II clinical trial of beta-globin gene therapy for beta-thalassemia. Ann N Y Acad Sci. 2005;1054:308–316
  21. Dunbar CE. The yin and yang of stem cell gene therapy: insights into hematopoiesis, leukemogenesis, and gene therapy safety. Hematology Am Soc Hematol Educ Program. 2007;2007:460–465
  22. Hargrove PW, Kepes S, Hanawa H, et al. Globin lentiviral vector insertions can perturb the expression of endogenous genes in beta-thalassemic hematopoietic cells. Mol Ther. 2008;16:525–533
  23. Wood WG. Haemoglobin synthesis during human fetal development. Br Med Bull. 1976;32:282–287
  24. 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
  25. Edington GM, Lehmann H. Expression of the sickle-cell gene in Africa. Br Med J. 1955;1:1308–1311
  26. Goldberg MA, Husson MA, Bunn HF. Participation of hemoglobins A and F in polymerization of sickle hemoglobin. J Biol Chem. 1977;252:3414–3421
  27. Nathan DG, Gunn RB. Thalassemia: the consequences of unbalanced hemoglobin synthesis. Am J Med. 1966;41:815–830
  28. Papayannopoulou TH, Brice M, Stamatoyannopoulos G. Stimulation of fetal hemoglobin synthesis in bone marrow cultures from adult individuals. Proc Natl Acad Sci U S A. 1976;73:2033–2037
  29. DeSimone J, Heller P, Hall L, Zwiers D. 5-Azacytidine stimulates fetal hemoglobin synthesis in anemic baboons. Proc Natl Acad Sci U S A. 1982;79:4428–4431
  30. Ley TJ, DeSimone J, Anagnou NP, et al. 5-azacytidine selectively increases gamma-globin synthesis in a patient with beta+ thalassemia. N Engl J Med. 1982;307:1469–1475
  31. Ley TJ, Anagnou NP, Noguchi CT, et al. DNA methylation and globin gene expression in patients treated with 5-azacytidine. Prog Clin Biol Res. 1983;134:457–474
  32. Dover GJ, Charache SH, Boyer SH, Talbot CC, Smith KD. 5-Azacytidine increases fetal hemoglobin production in a patient with sickle cell disease. Prog Clin Biol Res. 1983;134:475–488
  33. Koshy M, Dorn L, Bressler L, et al. 2-deoxy 5-azacytidine and fetal hemoglobin induction in sickle cell anemia. Blood. 2000;96:2379–2384
  34. Saunthararajah Y, Molokie R, Saraf S, et al. Clinical effectiveness of decitabine in severe sickle cell disease. Br J Haematol. 2008;141:126–129
  35. Lowrey CH, Nienhuis AW. Brief report: treatment with azacitidine of patients with end-stage beta-thalassemia. [see comments] N Engl J Med. 1993;329:845–848
  36. Saunthararajah Y, Lavelle D, DeSimone J. DNA hypo-methylating agents and sickle cell disease. Br J Haematol. 2004;126:629–636
  37. Fathallah H, Atweh GF. Induction of fetal hemoglobin in the treatment of sickle cell disease. Hematolpgy Am Soc Hematol Educ Program. 2006;58–62
  38. Steinberg MH, Lu ZH, Barton FB, Terrin ML, Charache S, Dover GJ. Fetal hemoglobin in sickle cell anemia: determinants of response to hydroxyurea. Multicenter Study of Hydroxyurea. Blood. 1997;89:1078–1088
  39. Fucharoen S, Siritanaratkul N, Winichagoon P, et al. Hydroxyurea increases hemoglobin F levels and improves the effectiveness of erythropoiesis in beta-thalassemia/hemoglobin E disease. Blood. 1996;87:887–892
  40. Zeng YT, Huang SZ, Ren ZR, et al. Hydroxyurea therapy in beta-thalassaemia intermedia: improvement in haematological parameters due to enhanced beta-globin synthesis. Br J Haematol. 1995;90:557–563
  41. Hajjar FM, Pearson HA. Pharmacologic treatment of thalassemia intermedia with hydroxyurea. J Pediatr. 1994;125:490–492
  42. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med. 1995;332:1317–1322
  43. Schultz WH, Ware RE. Malignancy in patients with sickle cell disease. Am J Hematol. 2003;74:249–253
  44. Steinberg MH, Barton F, Castro O, et al. Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment. JAMA. 2003;289:1645–1651
  45. Debaun MR, Field JJ. Limitations of clinical trials in sickle cell disease: a case study of the Multi-Center Study of Hydroxyurea (MSH) Trial and the Stroke Prevention (STOP) trial. Hematology Am Soc Hematol Educ Program. 2007;2007:482–488
  46. Lanzkron S, Haywood C, Segal JB, Dover GJ. Hospitalization rates and costs of care of patients with sickle-cell anemia in the state of Maryland in the era of hydroxyurea. Am J Hematol. 2006;81:927–932
  47. Ritho JN, Mayhew DY, Hartzema AG, Liu H, Lottenberg R. Hydroxyurea use in sickle cell disease patients in a Florida Medicaid population. [abstract] Blood. 2007;110:Abstract 79
  48. Aliyu ZY, Babadok A. Hydroxyurea utilization in Nigeria, a lesson in public health. [abstract] Blood. 2007;110:Abstract 80
  49. Chaulk CP, Kazandjian VA. Directly observed therapy for treatment completion of pulmonary tuberculosis: Consensus Statement of the Public Health Tuberculosis Guidelines Panel. JAMA. 1998;279:943–948
  50. Laurent C, Diakhate N, Gueye NF, et al. The Senegalese government's highly active antiretroviral therapy initiative: an 18-month follow-up study. AIDS. 2002;16:1363–1370
  51. Wood WG, Stamatoyannopoulos G, Lim G, Nute PE. F-cells in the adult: normal values and levels in individuals with hereditary and acquired elevations of Hb F. Blood. 1975;46:671–682
  52. Papayannopoulou T, Kalmantis T, Stamatoyannopoulos G. 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. 1979;76:6420–6424
  53. Farquhar MN, Turner PA, Papayannopoulou T, Brice M, Nienhuis AW, Stamatoyannopoulos G. The asynchrony of gamma- and beta-chain synthesis during human erythroid cell maturation. III. gamma- and beta-mRNA in immature and mature erythroid clones. Dev Biol. 1981;85:403–408
  54. Mabaera R, Greene MR, Richardson CA, Conine SJ, Kozul CD, Lowrey CH. Neither DNA hypomethylation nor changes in the kinetics of erythroid differentiation explain 5-azacytidine's ability to induce human fetal hemoglobin. Blood. 2008;111:411–420
  55. Weinberg RS, Ji X, Sutton M, et al. Butyrate increases the efficiency of translation of gamma-globin mRNA. Blood. 2005;105:1807–1809
  56. Dover GJ, Boyer SH. Fetal hemoglobin-containing cells have the same mean corpuscular hemoglobin as cells without fetal hemoglobin: a reciprocal relationship between gamma- and beta-globin gene expression in normal subjects and in those with high fetal hemoglobin production. Blood. 1987;69:1109–1113
  57. Chakalova L, Osborne CS, Dai YF, et al. The Corfu deltabeta thalassemia deletion disrupts gamma-globin gene silencing and reveals post-transcriptional regulation of HbF expression. Blood. 2005;105:2154–2160
  58. Clegg JB, Weatherall DJ, Bodmer WF. 5-azacytidine for beta-thalassemia?. Lancet. 1983;1:536
  59. Stamatoyannopoulos G. Control of globin gene expression during development and erythroid differentiation. Exp Hematol. 2005;33:259–271
  60. Jane SM, Gumucio DL, Ney PA, Cunningham JM, Nienhuis AW. Methylation-enhanced binding of Sp1 to the stage selector element of the human gamma-globin gene promoter may regulate development specificity of expression. Mol Cell Biol. 1993;13:3272–3281
  61. Sengupta PK, Lavelle D, DeSimone J. Increased binding of Sp1 to the gamma-globin gene promoter upon site-specific cytosine methylation. Am J Hematol. 1994;46:169–172
  62. Stamatoyannopoulos G, Veith R, Galanello R, Papayannopoulou T. Hb F production in stressed erythropoiesis: observations and kinetic models. Ann N Y Acad Sci. 1985;445:188–197
  63. Veith R, Galanello R, Papayannopoulou T, Stamatoyannopoulos G. Stimulation of F-cell production in patients with sickle-cell anemia treated with cytarabine or hydroxyurea. N Engl J Med. 1985;313:1571–1575
  64. Charache S, Dover G, Smith K, Talbot CC, Moyer M, Boyer S. Treatment of sickle cell anemia with 5-azacytidine results in increased fetal hemoglobin production and is associated with nonrandom hypomethylation of DNA around the gamma-delta-beta-globin gene complex. Proc Natl Acad Sci U S A. 1983;80:4842–4846
  65. Ley TJ, Chiang YL, Haidaris D, Anagnou NP, Wilson VL, Anderson WF. 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. 1984;81:6618–6622
  66. Humphries RK, Dover G, Young NS, et al. 5-Azacytidine acts directly on both erythroid precursors and progenitors to increase production of fetal hemoglobin. J Clin Invest. 1985;75:547–557
  67. Bard H, Prosmanne J. Relative rates of fetal hemoglobin and adult hemoglobin synthesis in cord blood of infants of insulin-dependent diabetic mothers. Pediatrics. 1985;75:1143–1147
  68. Perrine SP, Greene MF, Faller DV. Delay in the fetal globin switch in infants of diabetic mothers. N Engl J Med. 1985;312:334–338
  69. Perrine SP, Rudolph A, Faller DV, et al. Butyrate infusions in the ovine fetus delay the biologic clock for globin gene switching. Proc Natl Acad Sci U S A. 1988;85:8540–8542
  70. Constantoulakis P, Papayannopoulou T, Stamatoyannopoulos G. Alpha-amino-N-butyric acid stimulates fetal hemoglobin in the adult. Blood. 1988;72:1961–1967
  71. Atweh GF, Sutton M, Nassif I, et al. Sustained induction of fetal hemoglobin by pulse butyrate therapy in sickle cell disease. Blood. 1999;93:1790–1797
  72. Perrine SP, Ginder GD, Faller DV, et al. A short-term trial of butyrate to stimulate fetal-globin-gene expression in the beta-globin disorders. N Engl J Med. 1993;328:81–86
  73. Collins AF, Pearson HA, Giardina P, McDonagh KT, Brusilow SW, Dover GJ. Oral sodium phenylbutyrate therapy in homozygous beta thalassemia: a clinical trial. Blood. 1995;85:43–49
  74. Dover GJ, Brusilow S, Charache S. Induction of fetal hemoglobin production in subjects with sickle cell anemia by oral sodium phenylbutyrate. Blood. 1994;84:339–343
  75. Fibach E, Prasanna P, Rodgers GP, Samid D. Enhanced fetal hemoglobin production by phenylacetate and 4-phenylbutyrate in erythroid precursors derived from normal donors and patients with sickle cell anemia and beta-thalassemia. Blood. 1993;82:2203–2209
  76. Sher GD, Ginder GD, Little J, Yang S, Dover GJ, Olivieri NF. Extended therapy with intravenous arginine butyrate in patients with beta-hemoglobinopathies. N Engl J Med. 1995;332:1606–1610
  77. Reich S, Buhrer C, Henze G, et al. Oral isobutyramide reduces transfusion requirements in some patients with homozygous beta-thalassemia. Blood. 2000;96:3357–3363
  78. Domenica Cappellini M, Graziadei G, Ciceri L, et al. Oral isobutyramide therapy in patients with thalassemia intermedia: results of a phase II open study. Blood Cells Mol Dis. 2000;26:105–111
  79. Kieslich M, Schwabe D, Cinatl J, Driever PH. Increase of fetal hemoglobin synthesis indicating differentiation induction in children receiving valproic acid. Pediatr Hematol Oncol. 2003;20:15–22
  80. Collins AF, Dover GJ, Luban NL. Increased fetal hemoglobin production in patients receiving valproic acid for epilepsy. Blood. 1994;84:1690–1691
  81. Simpson RT. Structure of chromatin containing extensively acetylated H3 and H4. Cell. 1978;13:691–699
  82. Candido EP, Reeves R, Davie JR. Sodium butyrate inhibits histone deacetylation in cultured cells. Cell. 1978;14:105–113
  83. Sealy L, Chalkley R. The effect of sodium butyrate on histone modification. Cell. 1978;14:115–121
  84. McCaffrey PG, Newsome DA, Fibach E, Yoshida M, Su MS. Induction of gamma-globin by histone deacetylase inhibitors. Blood. 1997;90:2075–2083
  85. Boosalis MS, Bandyopadhyay R, Bresnick EH, et al. Short-chain fatty acid derivatives stimulate cell proliferation and induce STAT-5 activation. Blood. 2001;97:3259–3267
  86. Fathallah H, Weinberg RS, Galperin Y, Sutton M, Atweh GF. Role of epigenetic modifications in normal globin gene regulation and butyrate-mediated induction of fetal hemoglobin. Blood. 2007;110:3391–3397
  87. Skarpidi E, Cao H, Heltweg B, et al. Hydroxamide derivatives of short-chain fatty acids are potent inducers of human fetal globin gene expression. Exp Hematol. 2003;31:197–203
  88. Wei GH, Zhao GW, Song W, et al. Mechanisms of human gamma-globin transcriptional induction by apicidin involves p38 signaling to chromatin. Biochem Biophys Res Commun. 2007;363:889–894
  89. Witt O, Monkemeyer S, Ronndahl G, et al. Induction of fetal hemoglobin expression by the histone deacetylase inhibitor apicidin. Blood. 2003;101:2001–2007
  90. Cao H, Stamatoyannopoulos G, Jung M. Induction of human gamma globin gene expression by histone deacetylase inhibitors. Blood. 2004;103:701–709
  91. Pan LN, Lu J, Huang B. HDAC inhibitors: a potential new category of anti-tumor agents. Cell Mol Immunol. 2007;4:337–343
  92. Moutouh-de Parseval LA, Verhelle D, Glezer E, et al. Pomalidomide and lenalidomide regulate erythropoiesis and fetal hemoglobin production in human CD34+ cells. J Clin Invest. 2008;118:248–258
  93. Aerbajinai W, Zhu J, Gao Z, Chin K, Rodgers GP. Thalidomide induces gamma-globin gene expression through increased reactive oxygen species-mediated p38 MAPK signaling and histone H4 acetylation in adult erythropoiesis. Blood. 2007;110:2864–2871
  94. Nascimento Mde L, Ladipo OA, Coutinho EM. Nomegestrol acetate contraceptive implant use by women with sickle cell disease. Clin Pharmacol Ther. 1998;64:433–438
  95. da Silva Santos Duarte A, Sales TS, Mengel JO, Costa FF, Saad ST. Progesterone upregulates GATA-1 on erythroid progenitors cells in liquid culture. Blood Cells Mol Dis. 2002;29:213–224
  96. Stamatoyannopoulos G, Veith R, al-Khatti A, Papayannopoulou T. Induction of fetal hemoglobin by cell-cycle-specific drugs and recombinant erythropoietin. Am J Pediatr Hematol Oncol. 1990;12:21–26
  97. Miller BA, Perrine SP, Bernstein A, et al. Influence of steel factor on hemoglobin synthesis in sickle cell disease. Blood. 1992;79:1861–1868
  98. Wojda U, Leigh KR, Njoroge JM, et al. Fetal hemoglobin modulation during human erythropoiesis: stem cell factor has “late” effects related to the expression pattern of CD117. Blood. 2003;101:492–497
  99. Gabbianelli M, Morsilli O, Massa A, et al. Effective erythropoiesis and HbF reactivation induced by kit ligand in beta-thalassemia. Blood. 2008;111:421–429
  100. Bohmer RM. Reactivation of fetal hemoglobin in adult stem cell erythropoiesis by transforming growth factor-beta. J Hematother Stem Cell Res. 2003;12:499–504
  101. Witt O, Sand K, Pekrun A. Butyrate-induced erythroid differentiation of human K562 leukemia cells involves inhibition of ERK and activation of p38 MAP kinase pathways. Blood. 2000;95:2391–2396
  102. Witt O, Monkemeyer S, Kanbach K, Pekrun A. Induction of fetal hemoglobin synthesis by valproate: modulation of MAP kinase pathways. Am J Hematol. 2002;71:45–46
  103. Pace BS, Zein S. Understanding mechanisms of gamma-globin gene regulation to develop strategies for pharmacological fetal hemoglobin induction. Dev Dyn. 2006;235:1727–1737
  104. Hsiao CH, Li W, Lou TF, Baliga BS, Pace BS. Fetal hemoglobin induction by histone deacetylase inhibitors involves generation of reactive oxygen species. Exp Hematol. 2006;34:264–273
  105. Pace BS, Qian XH, Sangerman J, et al. p38 MAP kinase activation mediates gamma-globin gene induction in erythroid progenitors. Exp Hematol. 2003;31:1089–1096
  106. Sangerman J, Lee MS, Yao X, et al. Mechanism for fetal hemoglobin induction by histone deacetylase inhibitors involves gamma-globin activation by CREB1 and ATF-2. Blood. 2006;108:3590–3599
  107. Ikuta T, Ausenda S, Cappellini MD. Mechanism for fetal globin gene expression: role of the soluble guanylate cyclase-cGMP-dependent protein kinase pathway. Proc Natl Acad Sci U S A. 2001;98:1847–1852
  108. Inoue A, Kuroyanagi Y, Terui K, Moi P, Ikuta T. Negative regulation of gamma-globin gene expression by cyclic AMP-dependent pathway in erythroid cells. Exp Hematol. 2004;32:244–253
  109. Keefer JR, Schneidereith TA, Mays A, Purvis SH, Dover GJ, Smith KD. Role of cyclic nucleotides in fetal hemoglobin induction in cultured CD34+ cells. Exp Hematol. 2006;34:1151–1161
  110. Kuroyanagi Y, Kaneko Y, Muta K, et al. cAMP differentially regulates gamma-globin gene expression in erythroleukemic cells and primary erythroblasts through c-Myb expression. Biochem Biophys Res Commun. 2006;344:1038–1047
  111. Bailey L, Kuroyanagi Y, Franco-Penteado CF, et al. Expression of the gamma-globin gene is sustained by the cAMP-dependent pathway in beta-thalassaemia. Br J Haematol. 2007;138:382–395
  112. Cokic VP, Andric SA, Stojilkovic SS, Noguchi CT, Schechter AN. Hydroxyurea nitrosylates and activates soluble guanylyl cyclase in human erythroid cells. Blood. 2008;111:1117–1123
  113. Cokic VP, Smith RD, Beleslin-Cokic BB, et al. Hydroxyurea induces fetal hemoglobin by the nitric oxide-dependent activation of soluble guanylyl cyclase. J Clin Invest. 2003;111:231–239
  114. Gladwin MT, Shelhamer JH, Ognibene FP, et al. Nitric oxide donor properties of hydroxyurea in patients with sickle cell disease. Br J Haematol. 2002;116:436–444
  115. Park JI, Choi HS, Jeong JS, Han JY, Kim IH. Involvement of p38 kinase in hydroxyurea-induced differentiation of K562 cells. Cell Growth Differ. 2001;12:481–486
  116. Bhanu NV, Trice TA, Lee YT, et al. A sustained and pancellular reversal of gamma-globin gene silencing in adult human erythroid precursor cells. Blood. 2005;105:387–393
  117. Fibach E, Bianchi N, Borgatti M, et al. Effects of rapamycin on accumulation of alpha-, beta- and gamma-globin mRNAs in erythroid precursor cells from beta-thalassaemia patients. Eur J Haematol. 2006;77:437–441
  118. Mischiati C, Sereni A, Lampronti I, et al. Rapamycin-mediated induction of gamma-globin mRNA accumulation in human erythroid cells. Br J Haematol. 2004;126:612–621
  119. Zuccato C, Bianchi N, Borgatti M, et al. Everolimus is a potent inducer of erythroid differentiation and gamma-globin gene expression in human erythroid cells. Acta Haematol. 2007;117:168–176
  120. Obata T, Brown GE, Yaffe MB. MAP kinase pathways activated by stress: the p38 MAPK pathway. Crit Care Med. 2000;28:N67–N77
  121. Kyriakis JM, Avruch J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev. 2001;81:807–869
  122. Tang DC, Zhu J, Liu W, et al. The hydroxyurea-induced small GTP-binding protein SAR modulates gamma-globin gene expression in human erythroid cells. Blood. 2005;106:3256–3263
  123. McElveen RL, Lou TF, Reese K, Xia S, Baliga BS, Pace BS. Erk pathway inhibitor U0126 induces gamma-globin expression in erythroid cells. Cell Mol Biol (Noisy-le-grand). 2005;51:215–227
  124. Probin V, Wang Y, Zhou D. Busulfan-induced senescence is dependent on ROS production upstream of the MAPK pathway. Free Radic Biol Med. 2007;42:1858–1865
  125. Sanchez-Arevalo Lobo VJ, Aceves Luquero CI, Alvarez-Vallina L, et al. Modulation of the p38 MAPK (mitogen-activated protein kinase) pathway through Bcr/Abl: implications in the cellular response to Ara-C. Biochem J. 2005;387:231–238
  126. Raman M, Earnest S, Zhang K, Zhao Y, Cobb MH. TAO kinases mediate activation of p38 in response to DNA damage. EMBO J. 2007;26:2005–2014
  127. Persengiev SP, Green MR. The role of ATF/CREB family members in cell growth, survival and apoptosis. Apoptosis. 2003;8:225–228
  128. Maurice DH. Cyclic nucleotide phosphodiesterase-mediated integration of cGMP and cAMP signaling in cells of the cardiovascular system. Front Biosci. 2005;10:1221–1228
  129. Zaccolo M, Movsesian MA. cAMP and cGMP signaling cross-talk: role of phosphodiesterases and implications for cardiac pathophysiology. Circ Res. 2007;100:1569–1578
  130. Chen JJ. Regulation of protein synthesis by the heme-regulated eIF2alpha kinase: relevance to anemias. Blood. 2007;109:2693–2699
  131. Wek RC, Jiang HY, Anthony TG. Coping with stress: eIF2 kinases and translational control. Biochem Soc Trans. 2006;34:7–11
  132. Masuoka HC, Townes TM. Targeted disruption of the activating transcription factor 4 gene results in severe fetal anemia in mice. Blood. 2002;99:736–745
  133. Patterson AD, Hollander MC, Miller GF, Fornace AJ. Gadd34 requirement for normal hemoglobin synthesis. Mol Cell Biol. 2006;26:1644–1653
  134. Mankidy R, Faller DV, Mabaera R, et al. Short-chain fatty acids induce gamma-globin gene expression by displacement of a HDAC3-NCoR repressor complex. Blood. 2006;108:3179–3186
  135. Bain J, Plater L, Elliott M, et al. The selectivity of protein kinase inhibitors: a further update. Biochem J. 2007;408:297–315
  136. Saunthararajah Y, Hillery CA, Lavelle D, et al. Effects of 5-aza-2'-deoxycytidine on fetal hemoglobin levels, red cell adhesion, and hematopoietic differentiation in patients with sickle cell disease. Blood. 2003;102:3865–3870
  137. Carr BI, Rahbar S, Doroshow JH, et al. Fetal hemoglobin gene activation in a phase II study of 5,6-dihydro-5-azacytidine for bronchogenic carcinoma. Cancer Res. 1987;47:4199–4201
  138. Lavelle D, Vaitkus K, Banzon V, et al. Fetal hemoglobin induction in baboons (P. Anubis) following administration of a novel decitabine dinucleotide (S110) compound. [abstract] Blood. 2007;110:Abstract 571
  139. Liu DP, Liang CC, Ao ZH, et al. Treatment of severe beta-thalassemia (patients) with Myleran. Am J Hematol. 1990;33:50–55
  140. Bianchi N, Ongaro F, Chiarabelli C, et al. Induction of erythroid differentiation of human K562 cells by cisplatin analogs. Biochem Pharmacol. 2000;60:31–40
  141. Iyamu WE, Adunyah SE, Fasold H, et al. Enhancement of hemoglobin and F-cell production by targeting growth inhibition and differentiation of K562 cells with ribonucleotide reductase inhibitors (Didox and Trimidox) in combination with streptozotocin. Am J Hematol. 2000;63:176–183
  142. Yu J, Lemas V, Page T, Connor JD, Yu AL. Induction of erythroid differentiation in K562 cells by inhibitors of inosine monophosphate dehydrogenase. Cancer Res. 1989;49:5555–5560
  143. Pace BS, Elford HL, Stamatoyannopoulos G. Transgenic mouse model of pharmacologic induction of fetal hemoglobin: studies using a new ribonucleotide reductase inhibitor. Didox. Am J Hematol. 1994;45:136–141
  144. Rodrigue CM, Arous N, Bachir D, et al. Resveratrol, a natural dietary phytoalexin, possesses similar properties to hydroxyurea towards erythroid differentiation. Br J Haematol. 2001;113:500–507
  145. Delgado-Canedo A, Chies JA, Nardi NB. Induction of fetal haemoglobin expression in erythroid cells—a model based on iron availability signalling. Med Hypotheses. 2005;65:932–936
  146. Bianchi N, Osti F, Rutigliano C, et al. The DNA-binding drugs mithramycin and chromomycin are powerful inducers of erythroid differentiation of human K562 cells. Br J Haematol. 1999;104:258–265
  147. Bianchi N, Chiarabelli C, Borgatti M, Mischiati C, Fibach E, Gambari R. Accumulation of gamma-globin mRNA and induction of erythroid differentiation after treatment of human leukaemic K562 cells with tallimustine. Br J Haematol. 2001;113:951–961
  148. Lampronti I, Bianchi N, Borgatti M, Fibach E, Prus E, Gambari R. Accumulation of gamma-globin mRNA in human erythroid cells treated with angelicin. Eur J Haematol. 2003;71:189–195
  149. Viola G, Vedaldi D, Dall'Acqua F, et al. Induction of gamma-globin mRNA, erythroid differentiation and apoptosis in UVA-irradiated human erythroid cells in the presence of furocumarin derivatives. Biochem Pharmacol. 2008;75:810–825
  150. Veith R, Dautenhahn AG, Roth RC. Methotrexate stimulates fetal hemoglobin production in anemic baboons. Prog Clin Biol Res. 1989;316B:363–370
  151. Veith R, Papayannopoulou T, Kurachi S, Stamatoyannopoulos G. Treatment of baboon with vinblastine: insights into the mechanisms of pharmacologic stimulation of Hb F in the adult. Blood. 1985;66:456–459
  152. Letvin NL, Linch DC, Beardsley GP, McIntyre KW, Miller BA, Nathan DG. Influence of cell cycle phase-specific agents on simian fetal hemoglobin synthesis. J Clin Invest. 1985;75:1999–2005
  153. Pace BS, White GL, Dover GJ, Boosalis MS, Faller DV, Perrine SP. Short-chain fatty acid derivatives induce fetal globin expression and erythropoiesis in vivo. Blood. 2002;100:4640–4648
  154. Witt O, Schmejkal S, Pekrun A. Tributyrin plus all-trans-retinoic acid efficiently induces fetal hemoglobin expression in human erythroleukemia cells. Am J Hematol. 2000;64:319–321
  155. Stamatoyannopoulos G, Blau CA, Nakamoto B, et al. Fetal hemoglobin induction by acetate, a product of butyrate catabolism. Blood. 1994;84:3198–3204
  156. Torkelson S, White B, Faller DV, Phipps K, Pantazis C, Perrine SP. Erythroid progenitor proliferation is stimulated by phenoxyacetic and phenylalkyl acids. Blood Cells Mol Dis. 1996;22:150–158
  157. Cao H, Jung M, Stamatoyannopoulos G. Hydroxamide derivatives of short-chain fatty acid have erythropoietic activity and induce gamma gene expression in vivo. Exp Hematol. 2005;33:1443–1449
  158. Safaya S, Ibrahim A, Rieder RF. Augmentation of gamma-globin gene promoter activity by carboxylic acids and components of the human beta-globin locus control region. Blood. 1994;84:3929–3935
  159. Liakopoulou E, Blau CA, Li Q, et al. Stimulation of fetal hemoglobin production by short chain fatty acids. Blood. 1995;86:3227–3235
  160. Bohacek R, Boosalis MS, McMartin C, Faller DV, Perrine SP. Identification of novel small-molecule inducers of fetal hemoglobin using pharmacophore and ‘PSEUDO’ receptor models. Chem Biol Drug Des. 2006;67:318–328
  161. Mai A, Jelicic K, Rotili D, et al. Identification of two new synthetic histone deacetylase inhibitors that modulate globin gene expression in erythroid cells from healthy donors and patients with thalassemia. Mol Pharmacol. 2007;72:1111–1123
  162. Cao H, Stamatoyannopoulos G. Histone deacetylase inhibitor FK228 is a potent inducer of human fetal hemoglobin. Am J Hematol. 2006;81:981–983
  163. Johnson J, Hunter R, McElveen R, Qian XH, Baliga BS, Pace BS. Fetal hemoglobin induction by the histone deacetylase inhibitor, scriptaid. Cell Mol Biol (Noisy-le-grand). 2005;51:229–238
  164. Smith RD, Li J, Noguchi CT, Schechter AN. Quantitative PCR analysis of HbF inducers in primary human adult erythroid cells. Blood. 2000;95:863–869
  165. Haynes J, Baliga BS, Obiako B, Ofori-Acquah S, Pace B. Zileuton induces hemoglobin F synthesis in erythroid progenitors: role of the L-arginine-nitric oxide signaling pathway. Blood. 2004;103:3945–3950
  166. Amoyal I, Prus E, Fibach E. Vanadate elevates fetal hemoglobin in human erythroid precursors by inhibiting cell maturation. Exp Biol Med (Maywood). 2007;232:654–661
  167. Hsieh MM, Linde NS, Wynter A, et al. HIF prolyl hydroxylase inhibition results in endogenous erythropoietin induction, erythrocytosis, and modest fetal hemoglobin expression in rhesus macaques. Blood. 2007;110:2140–2147

PII: S0301-472X(08)00332-9

doi: 10.1016/j.exphem.2008.06.014

Experimental Hematology
Volume 36, Issue 9 , Pages 1057-1072 , September 2008

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