Blood Reviews
Volume 20, Issue 4 , Pages 227-234 , July 2006

DNA hypomethylation therapy for hemoglobin disorders: Molecular mechanisms and clinical applications

References 

  1. Bunn HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med. 1997;337:762–769
  2. Weatherall DJ. Pathophysiology of thalassaemia. Baillieres Clin Haematol. 1998;11:127–146
  3. DeSimone J, Heller P, Hall L, Zwiers D. 5-Azacytidine stimulates fetal hemoglobin synthesis in anemic baboons. Proc Natl Acad Sci USA. 1982;79:4428–4431
  4. 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
  5. Ley TJ, DeSimone J, Noguchi CT, et al. 5-Azacytidine increases gamma-globin synthesis and reduces the proportion of dense cells in patients with sickle cell anemia. Blood. 1983;62:370–380
  6. Charache S, Dover GJ, Moore RD, et al. Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia. Blood. 1992;79:2555–2565
  7. 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
  8. Rochette J, Craig JE, Thein SL. Fetal hemoglobin levels in adults. Blood Rev. 1994;8:213–224
  9. Bailey K, Morris JS, Thomas P, Serjeant GR. Fetal haemoglobin and early manifestations of homozygous sickle cell disease. Arch Dis Child. 1992;67:517–520
  10. Stevens MC, Hayes RJ, Vaidya S, Serjeant GR. Fetal hemoglobin and clinical severity of homozygous sickle cell disease in early childhood. J Pediatr. 1981;98:37–41
  11. Bollekens JA, Forget BG. Delta beta thalassemia and hereditary persistence of fetal hemoglobin. Hematol Oncol Clin North Am. 1991;5:399–422
  12. Serjeant GR. Natural history and determinants of clinical severity of sickle cell disease. Curr Opin Hematol. 1995;2:103–108
  13. Perrine RP, Pembrey ME, John P, Perrine S, Shoup F. Natural history of sickle cell anemia in Saudi Arabs. A study of 270 subjects. Ann Intern Med. 1978;88:1–6
  14. Kar BC, Satapathy RK, Kulozik AE, et al. Sickle cell disease in Orissa State, India. Lancet. 1986;2:1198–1201
  15. Platt OS, Thorington BD, Brambilla DJ, et al. Pain in sickle cell disease. Rates and risk factors. N Engl J Med. 1991;325:11–16
  16. Castro O, Brambilla DJ, Thorington B, et al. The acute chest syndrome in sickle cell disease: incidence and risk factors. The Cooperative Study of Sickle Cell Disease. Blood. 1994;84:643–649
  17. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med. 1994;330:1639–1644
  18. Bulger M, Sawado T, Schubeler D, Groudine M. ChIPs of the beta-globin locus: unraveling gene regulation within an active domain. Curr Opin Genet Dev. 2002;12:170–177
  19. Forsberg EC, Bresnick EH. Histone acetylation beyond promoters: long-range acetylation patterns in the chromatin world. Bioessays. 2001;23:820–830
  20. Hake SB, Xiao A, Allis CD. Linking the epigenetic ’language’ of covalent histone modifications to cancer. Br J Cancer. 2004;90:761–769
  21. Kouzarides T. Histone methylation in transcriptional control. Curr Opin Genet Dev. 2002;12:198–209
  22. Laybourn PJ, Kadonaga JT. Role of nucleosomal cores and histone H1 in regulation of transcription by RNA polymerase II. Science. 1991;254:238–245
  23. Noma K, Grewal SI. Histone H3 lysine 4 methylation is mediated by Set1 and promotes maintenance of active chromatin states in fission yeast. Proc Natl Acad Sci USA. 2002;99(Suppl 4):16438–16445
  24. Strahl BD, Allis CD. The language of covalent histone modifications. Nature. 2000;403:41–45
  25. Strahl BD, Ohba R, Cook RG, Allis CD. Methylation of histone H3 at lysine 4 is highly conserved and correlates with transcriptionally active nuclei in Tetrahymena. Proc Natl Acad Sci USA. 1999;96:14967–14972
  26. Pradhan S, Bacolla A, Wells RD, Roberts RJ. Recombinant human DNA (cytosine-5) methyltransferase. I. Expression, purification, and comparison of de novo and maintenance methylation. J Biol Chem. 1999;274:33002–33010
  27. Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999;99:247–257
  28. Singal R, Ginder GD. DNA methylation. Blood. 1999;93:4059–4070
  29. Samlowski WE, Leachman SA, Wade M, et al. Evaluation of a 7-day continuous intravenous infusion of decitabine: inhibition of promoter-specific and global genomic DNA methylation. J Clin Oncol. 2005;23:3897–3905
  30. Santi DV, Norment A, Garrett CE. Covalent bond formation between a DNA-cytosine methyltransferase and DNA containing 5-azacytosine. Proc Natl Acad Sci USA. 1984;81:6993–6997
  31. Juttermann R, Li E, Jaenisch R. Toxicity of 5-aza-2’-deoxycytidine to mammalian cells is mediated primarily by covalent trapping of DNA methyltransferase rather than DNA demethylation. Proc Natl Acad Sci USA. 1994;91:11797–11801
  32. Ghoshal K, Datta J, Majumder S, et al. 5-Aza-deoxycytidine induces selective degradation of DNA methyltransferase 1 by a proteasomal pathway that requires the KEN box, bromo-adjacent homology domain, and nuclear localization signal. Mol Cell Biol. 2005;25:4727–4741
  33. Mavilio F, Giampaolo A, Care A, et al. Molecular mechanisms of human hemoglobin switching: selective undermethylation and expression of globin genes in embryonic, fetal, and adult erythroblasts. Proc Natl Acad Sci USA. 1983;80:6907–6911
  34. van der Ploeg LH, Flavell RA. DNA methylation in the human gamma delta beta-globin locus in erythroid and nonerythroid tissues. Cell. 1980;19:947–958
  35. 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 USA. 1983;80:4842–4846
  36. 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
  37. 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
  38. 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
  39. 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
  40. Lavelle DE. The molecular mechanism of fetal hemoglobin reactivation. Semin Hematol. 2004;41:3–10
  41. Letvin NL, Linch DC, Beardsley GP, McIntyre KW, Nathan DG. Augmentation of fetal-hemoglobin production in anemic monkeys by hydroxyurea. N Engl J Med. 1984;310:869–873
  42. Stamatoyannopoulos G. Control of globin gene expression during development and erythroid differentiation. Exp Hematol. 2005;33:259–271
  43. 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
  44. Olivieri NF, Freedman MH, Perrine SP, et al. Trial of recombinant human erythropoietin: three patients with thalassemia intermedia. Blood. 1992;80:3258–3260
  45. Nagel RL, Vichinsky E, Shah M, et al. F reticulocyte response in sickle cell anemia treated with recombinant human erythropoietin: a double-blind study. Blood. 1993;81:9–14
  46. 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
  47. 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
  48. Kaminskas E, Farrell AT, Wang YC, Sridhara R, Pazdur R. FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. Oncologist. 2005;10:176–182
  49. Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002;20:2429–2440
  50. DeSimone J, Heller P, Schimenti JC, Duncan CH. Fetal hemoglobin production in adult baboons by 5-azacytidine or by phenylhydrazine-induced hemolysis is associated with hypomethylation of globin gene DNA. Prog Clin Biol Res. 1983;134:489–500
  51. Lowrey CH, Nienhuis AW. Brief report: treatment with azacitidine of patients with end-stage beta-thalassemia. N Engl J Med. 1993;329:845–848
  52. Carr BI, Rahbar S, Asmeron Y, Riggs A, Winberg CD. Carcinogenicity and haemoglobin synthesis induction by cytidine analogues. Br J Cancer. 1988;57:395–402
  53. Rodgers GP, Dover GJ, Noguchi CT, Schechter AN, Nienhuis AW. Hematologic responses of patients with sickle cell disease to treatment with hydroxyurea. N Engl J Med. 1990;322:1037–1045
  54. Platt OS, Orkin SH, Dover G, Beardsley GP, Miller B, Nathan DG. Hydroxyurea enhances fetal hemoglobin production in sickle cell anemia. J Clin Invest. 1984;74:652–656
  55. 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
  56. Rigano P, Manfre L, La Galla R, et al. Clinical and hematological response to hydroxyurea in a patient with Hb Lepore/beta-thalassemia. Hemoglobin. 1997;21:219–226
  57. Cario H, Wegener M, Debatin KM, Kohne E. Treatment with hydroxyurea in thalassemia intermedia with paravertebral pseudotumors of extramedullary hematopoiesis. Ann Hematol. 2002;81:478–482
  58. de Paula EV, Lima CS, Arruda VR, Alberto FL, Saad ST, Costa FF. Long-term hydroxyurea therapy in beta-thalassaemia patients. Eur J Haematol. 2003;70:151–155
  59. Hajjar FM, Pearson HA. Pharmacologic treatment of thalassemia intermedia with hydroxyurea. J Pediatr. 1994;125:490–492
  60. Bradai M, Abad MT, Pissard S, Lamraoui F, Skopinski L, de Montalembert M. Hydroxyurea can eliminate transfusion requirements in children with severe beta-thalassemia. Blood. 2003;102:1529–1530
  61. 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 USA. 2001;98:1847–1852
  62. 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
  63. Weinberg RS, Ji X, Sutton M, et al. Butyrate increases the efficiency of translation of gamma-globin mRNA. Blood. 2005;105:1807–1809
  64. Perrine SP, Yang Y-M, Piga A, et al. Butyrate + EPO in Beta Thalassemia Intermedia: Interim Findings of a Phase II Trial. Blood. 2002;100:47a
  65. DeSimone J, Koshy M, Dorn L, et al. Maintenance of elevated fetal hemoglobin levels by decitabine during dose interval treatment of sickle cell anemia. Blood. 2002;99:3905–3908
  66. 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
  67. Yang AS, Estecio MR, Garcia-Manero G, Kantarjian HM, Issa JP. Comment on “Chromosomal instability and tumors promoted by DNA hypomethylation” and “Induction of tumors in nice by genomic hypomethylation. Science. 2003;302:1153;author reply 1153
  68. Belinsky SA, Klinge DM, Stidley CA, et al. Inhibition of DNA methylation and histone deacetylation prevents murine lung cancer. Cancer Res. 2003;63:7089–7093
  69. Laird PW, Jackson-Grusby L, Fazeli A, et al. Suppression of intestinal neoplasia by DNA hypomethylation. Cell. 1995;81:197–205
  70. Powars DR, Weiss JN, Chan LS, Schroeder WA. Is there a threshold level of fetal hemoglobin that ameliorates morbidity in sickle cell anemia?. Blood. 1984;63:921–926

PII: S0268-960X(06)00002-6

doi: 10.1016/j.blre.2006.01.002

Blood Reviews
Volume 20, Issue 4 , Pages 227-234 , July 2006

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