Seminars in Oncology
Volume 35, Issue 4 , Pages 378-387 , August 2008

Epigenetics in Acute Myeloid Leukemia

  • Christoph Plass

      Affiliations

    • German Cancer Research Center, Division of Toxicology and Cancer Risk Factors, Heidelberg, Germany.
    • Corresponding Author InformationAddress correspondence to Christoph Plass, PhD, German Cancer Research Center (DKFZ), Division C010, Toxicology and Cancer Risk Factors, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
    • ,
  • Christopher Oakes

      Affiliations

    • German Cancer Research Center, Division of Toxicology and Cancer Risk Factors, Heidelberg, Germany.
    • ,
  • William Blum

      Affiliations

    • Department of Internal Medicine, Division of Hematology and Oncology, The Comprehensive Cancer Center, The Ohio State University, Columbus, OH.
    • ,
  • Guido Marcucci

      Affiliations

    • Department of Internal Medicine, Division of Hematology and Oncology, The Comprehensive Cancer Center, The Ohio State University, Columbus, OH.

References 

  1. Mrozek K, Heerema NA, Bloomfield CD. Cytogenetics in acute leukemia. Blood Rev. 2004;18:115–136
  2. Caligiuri MA, Strout MP, Lawrence D, Arthur DC, Baer MR, Yu F, et al. Rearrangement of ALL1 (MLL) in acute myeloid leukemia with normal cytogenetics. Cancer Res. 1998;58:55–59
  3. Gilliland DG, Griffin JD. Role of FLT3 in leukemia. Curr Opin Hematol. 2002;9:274–281
  4. Dohner K, Schlenk RF, Habdank M, Scholl C, Rucker FG, Corbacioglu A, et al. Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood. 2005;106:3740–3746
  5. Baldus CD, Liyanarachchi S, Mrozek K, Auer H, Tanner SM, Guimond M, et al. Acute myeloid leukemia with complex karyotypes and abnormal chromosome 21: Amplification discloses overexpression of APP, ETS2, and ERG genes. Proc Natl Acad Sci U S A. 2004;101:3915–3920
  6. Heuser M, Beutel G, Krauter J, Dohner K, von Neuhoff N, Schlegelberger B, et al. High meningioma 1 (MN1) expression as a predictor for poor outcome in acute myeloid leukemia with normal cytogenetics. Blood. 2006;108:3898–3905
  7. Baldus CD, Tanner SM, Ruppert AS, Whitman SP, Archer KJ, Marcucci G, et al. BAALC expression predicts clinical outcome of de novo acute myeloid leukemia patients with normal cytogenetics: a Cancer and Leukemia Group B Study. Blood. 2003;102:1613–1618
  8. Chong S, Whitelaw E. Epigenetic germline inheritance. Curr Opin Genet Dev. 2004;14:692–696
  9. Li E, Bestor TH, Jaenisch R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell. 1992;69:915–926
  10. 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
  11. Hansen RS, Wijmenga C, Luo P, Stanek AM, Canfield TK, Weemaes CM, et al. The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc Natl Acad Sci U S A. 1999;96:14412–14417
  12. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999;23:185–188
  13. Morgan HD, Santos F, Green K, Dean W, Reik W. Epigenetic reprogramming in mammals. Hum Mol Genet. 2005;14:R47–R58
  14. Barreto G, Schafer A, Marhold J, Stach D, Swaminathan SK, Handa V, et al. Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. Nature. 2007;445:671–675
  15. Jost JP, Oakeley EJ, Zhu B, Benjamin D, Thiry S, Siegmann M, et al. 5-Methylcytosine DNA glycosylase participates in the genome-wide loss of DNA methylation occurring during mouse myoblast differentiation. Nucleic Acids Res. 2001;29:4452–4461
  16. Hoffmann MJ, Schulz WA. Causes and consequences of DNA hypomethylation in human cancer. Biochem Cell Biol. 2005;83:296–321
  17. Bestor TH, Tycko B. Creation of genomic methylation patterns. Nat Genet. 1996;12:363–367
  18. Recillas-Targa F, De La Rosa-Velazquez IA, Soto-Reyes E, Benitez-Bribiesca L. Epigenetic boundaries of tumour suppressor gene promoters: the CTCF connection and its role in carcinogenesis. J Cell Mol Med. 2006;10:554–568
  19. Klose RJ, Bird AP. Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci. 2006;31:89–97
  20. Kouzarides T. Chromatin modifications and their function. Cell. 2007;128:693–705
  21. Valencia-Sanchez MA, Liu J, Hannon GJ, Parker R. Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev. 2006;20:515–524
  22. Fabbri M, Garzon R, Cimmino A, Liu Z, Zanesi N, Callegari E, et al. MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci U S A. 2007;104:15805–15810
  23. Bayne EH, Allshire RC. RNA-directed transcriptional gene silencing in mammals. Trends Genet. 2005;21:370–373
  24. Heard E, Disteche CM. Dosage compensation in mammals: fine-tuning the expression of the X chromosome. Genes Dev. 2006;20:1848–1867
  25. Fuks F, Burgers WA, Brehm A, Hughes-Davies L, Kouzarides T. DNA methyltransferase Dnmt1 associates with histone deacetylase activity. Nat Genet. 2000;24:88–91
  26. Rountree MR, Bachman KE, Baylin SB. DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nat Genet. 2000;25:269–277
  27. D'Alessio AC, Szyf M. Epigenetic tete-a-tete: the bilateral relationship between chromatin modifications and DNA methylation. Biochem Cell Biol. 2006;84:463–476
  28. Fuks F, Hurd PJ, Deplus R, Kouzarides T. The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase. Nucleic Acids Res. 2003;31:2305–2312
  29. Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature. 2006;439:871–874
  30. Lehnertz B, Ueda Y, Derijck AA, Braunschweig U, Perez-Burgos L, Kubicek S, et al. Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin. Curr Biol. 2003;13:1192–1200
  31. Gibbons RJ, McDowell TL, Raman S, O'Rourke DM, Garrick D, Ayyub H, et al. Mutations in ATRX, encoding a SWI/SNF-like protein, cause diverse changes in the pattern of DNA methylation. Nat Genet. 2000;24:368–371
  32. Dennis K, Fan T, Geiman T, Yan Q, Muegge K. Lsh, a member of the SNF2 family, is required for genome-wide methylation. Genes Dev. 2001;15:2940–2944
  33. Zhu H, Geiman TM, Xi S, Jiang Q, Schmidtmann A, Chen T, et al. Lsh is involved in de novo methylation of DNA. EMBO J. 2006;25:335–345
  34. Ooi SK, Qiu C, Bernstein E, Li K, Jia D, Yang Z, et al. DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature. 2007;448:714–717
  35. Jia D, Jurkowska RZ, Zhang X, Jeltsch A, Cheng X. Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylation. Nature. 2007;449:248–251
  36. D'Alessio AC, Weaver IC, Szyf M. Acetylation-induced transcription is required for active DNA demethylation in methylation-silenced genes. Mol Cell Biol. 2007;27:7462–7474
  37. Workman JL. Nucleosome displacement in transcription. Genes Dev. 2006;20:2009–2017
  38. Oakes CC, Smiraglia DJ, Plass C, Trasler JM, Robaire B. Aging results in hypermethylation of ribosomal DNA in sperm and liver of male rats. Proc Natl Acad Sci U S A. 2003;100:1775–1780
  39. Eckhardt F, Lewin J, Cortese R, Rakyan VK, Attwood J, Burger M, et al. DNA methylation profiling of human chromosomes 6, 20 and 22. Nat Genet. 2006;38:1378–1385
  40. Robertson K. DNA methylation and human disease. Nat Rev Genet. 2005;6:597–610
  41. Spivakov M, Fisher AG. Epigenetic signatures of stem-cell identity. Nat Rev Genet. 2007;8:263–271
  42. Song F, Smith JF, Kimura MT, Morrow AD, Matsuyama T, Nagase H, et al. Association of tissue-specific differentially methylated regions (TDMs) with differential gene expression. Proc Natl Acad Sci U S A. 2005;102:3336–3341
  43. Klose RJ, Sarraf SA, Schmiedeberg L, McDermott SM, Stancheva I, Bird AP. DNA binding selectivity of MeCP2 due to a requirement for A/T sequences adjacent to methyl-CpG. Mol Cell. 2005;19:667–678
  44. Stratling WH, Yu F. Origin and roles of nuclear matrix proteins (Specific functions of the MAR-binding protein MeCP2/ARBP). Crit Rev Eukaryot Gene Expr. 1999;9:311–318
  45. Ehrlich M. Cancer-linked DNA hypomethylation and its relationship to hypermethylation. Curr Top Microbiol Immunol. 2006;310:251–274
  46. Costello JF, Fruhwald MC, Smiraglia DJ, Rush LJ, Robertson GP, Gao X, et al. Aberrant CpG-island methylation has non-random and tumour-type-specific patterns. Nat Genet. 2000;24:132–138
  47. Smith LT, Otterson GA, Plass C. Unraveling the epigenetic code of cancer for therapy. Trends Genet. 2007;23:449–456
  48. Baylin SB, Fearon ER, Vogelstein B, de Bustros A, Sharkis SJ, Burke PJ, et al. Hypermethylation of the 5′ region of the calcitonin gene is a property of human lymphoid and acute myeloid malignancies. Blood. 1987;70:412–417
  49. Pfeifer GP, Steigerwald S, Boehm TL, Drahovsky D. DNA methylation levels in acute human leukemia. Cancer Lett. 1988;39:185–192
  50. Costello JF, Plass C. Methylation matters. J Med Genet. 2001;38:285–303
  51. Issa JP, Zehnbauer BA, Civin CI, Collector MI, Sharkis SJ, Davidson NE, et al. The estrogen receptor CpG island is methylated in most hematopoietic neoplasms. Cancer Res. 1996;56:973–977
  52. Herman JG, Civin CI, Issa JP, Collector MI, Sharkis SJ, Baylin SB. Distinct patterns of inactivation of p15INK4B and p16INK4A characterize the major types of hematological malignancies. Cancer Res. 1997;57:837–841
  53. Voso MT, Scardocci A, Guidi F, Zini G, Di Mario A, Pagano L, et al. Aberrant methylation of DAP-kinase in therapy-related acute myeloid leukemia and myelodysplastic syndromes. Blood. 2004;103:698–700
  54. Seedhouse CH, Das-Gupta EP, Russell NH. Methylation of the hMLH1 promoter and its association with microsatellite instability in acute myeloid leukemia. Leukemia. 2003;17:83–88
  55. Melki JR, Vincent PC, Brown RD, Clark SJ. Hypermethylation of E-cadherin in leukemia. Blood. 2000;95:3208–3213
  56. Issa JP, Zehnbauer BA, Kaufmann SH, Biel MA, Baylin SB. HIC1 hypermethylation is a late event in hematopoietic neoplasms. Cancer Res. 1997;57:1678–1681
  57. Plass C, Yu F, Yu L, Strout MP, El-Rifai W, Elonen E, et al. Restriction landmark genome scanning for aberrant methylation in primary refractory and relapsed acute myeloid leukemia; involvement of the WIT-1 gene. Oncogene. 1999;18:3159–3165
  58. Agrawal S, Hofmann WK, Tidow N, Ehrich M, van den Boom D, Koschmieder S, et al. The C/EBPdelta tumor suppressor is silenced by hypermethylation in acute myeloid leukemia. Blood. 2007;109:3895–3905
  59. Esteller M. Profiling aberrant DNA methylation in hematologic neoplasms: a view from the tip of the iceberg. Clin Immunol. 2003;109:80–88
  60. Melki JR, Vincent PC, Clark SJ. Concurrent DNA hypermethylation of multiple genes in acute myeloid leukemia. Cancer Res. 1999;59:3730–3740
  61. Toyota M, Kopecky KJ, Toyota MO, Jair KW, Willman CL, Issa JP. Methylation profiling in acute myeloid leukemia. Blood. 2001;97:2823–2829
  62. Rush LJ, Dai Z, Smiraglia DJ, Gao X, Wright FA, Fruhwald M, et al. Novel methylation targets in de novo acute myeloid leukemia with prevalence of chromosome 11 loci. Blood. 2001;97:3226–3233
  63. International-Human-Genome-Sequencing-Consortium. Finishing the euchromatic sequence of the human genome. Nature. 2004;431:931–945
  64. Di Croce L, Raker VA, Corsaro M, Fazi F, Fanelli M, Faretta M, et al. Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science. 2002;295:1079–1082
  65. Liu S, Shen T, Huynh L, Klisovic MI, Rush LJ, Ford JL, et al. Interplay of RUNX1/MTG8 and DNA methyltransferase 1 in acute myeloid leukemia. Cancer Res. 2005;65:1277–1284
  66. Villa R, Pasini D, Gutierrez A, Morey L, Occhionorelli M, Vire E, et al. Role of the polycomb repressive complex 2 in acute promyelocytic leukemia. Cancer Cell. 2007;11:513–525
  67. Villa R, Morey L, Raker VA, Buschbeck M, Gutierrez A, De Santis F, et al. The methyl-CpG binding protein MBD1 is required for PML-RARalpha function. Proc Natl Acad Sci U S A. 2006;103:1400–1405
  68. Tabe Y, Konopleva M, Kondo Y, Contractor R, Jin L, Ruvolo V, et al. PML-RARalpha and AML1-ETO translocations are rarely associated with methylation of the RARbeta2 promoter. Ann Hematol. 2006;85:689–704
  69. Ohm JE, Baylin SB. Stem cell chromatin patterns: an instructive mechanism for DNA hypermethylation?. Cell Cycle. 2007;6:1040–1043
  70. Ohm JE, McGarvey KM, Yu X, Cheng L, Schuebel KE, et al. A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet. 2007;39:237–242
  71. Schlesinger Y, Straussman R, Keshet I, Farkash S, Hecht M, Zimmerman J, et al. Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat Genet. 2007;39:232–236
  72. Widschwendter M, Fiegl H, Egle D, Mueller-Holzner E, Spizzo G, Marth C, et al. Epigenetic stem cell signature in cancer. Nat Genet. 2007;39:157–158
  73. Opavsky R, Wang SH, Trikha P, Raval A, Huang Y, Wu YZ, et al. CpG island methylation in a mouse model of lymphoma is driven by the genetic configuration of tumor cells. PLoS Genet. 2007;3:1757–1769
  74. Krivtsov AV, Armstrong SA. MLL translocations, histone modifications and leukaemia stem-cell development. Nat Rev Cancer. 2007;7:823–833
  75. Whitman SP, Ruppert AS, Marcucci G, Mrózek K, Paschka P, Langer C, et al. Long-term disease-free survivors with cytogenetically normal acute myeloid leukemia and MLL partial tandem duplication: a Cancer and Leukemia Group B study. Blood. 2007;109:5164–5167
  76. Dorrance AM, Liu S, Yuan W, Becknell B, Arnoczky KJ, Guimond M, et al. Mll partial tandem duplication induces aberrant Hox expression in vivo via specific epigenetic alterations. J Clin Invest. 2006;116:2707–2716
  77. Whitman SP, Liu S, Vukosavljevic T, Rush LJ, Yu L, Liu C, et al. The MLL partial tandem duplication: evidence for recessive gain-of-function in acute myeloid leukemia identifies a novel patient subgroup for molecular-targeted therapy. Blood. 2005;106:345–352
  78. Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R, 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
  79. Kaminskas E, Farrell A, Abraham S, Baird A, Hsieh LS, Lee SL, et al. Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes. Clin Cancer Res. 2005;11:3604–3608
  80. Fenaux P, Mufti G, Santini V, Finelli C, Giagounidis A, Schoch R, et al. Azacitidine (AZA) treatment prolongs overall survival (OS) in higher-risk MDS patients compared with conventional care regimens (CCR): results of the AZA-001 phase III study. [abstract] Blood (ASH Annual Meeting Abstracts). 2007;110:817
  81. Fabre C, Gardin C, Mbida R-M, Quesnel Q, Dreyfus F, et al. Treatment of AML with azacytidine (AZA): current results of the French ATU program. [abstract] Blood (ASH Annual Meeting Abstracts). 2007;110:1849
  82. Kantarjian H, Issa JP, Rosenfeld CS, Bennett JM, Albitar M, DiPersio J, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006;106:1794–1803
  83. Kantarjian H, Oki Y, Garcia-Manero G, Huang X, O'Brien S, Cortes J, et al. Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood. 2007;109:52–57
  84. Issa JP, Garcia-Manero G, Giles FJ, Mannari R, Thomas D, et al. Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2′-deoxycytidine (decitabine) in hematopoietic malignancies. Blood. 2004;103:1635–1640
  85. Yang AS, Doshi KD, Choi SW, Mason JB, Mannari RK, Gharybian V, et al. DNA methylation changes after 5-aza-2′-deoxycytidine therapy in patients with leukemia. Cancer Res. 2006;66:5495–5503
  86. Cashen A, Schiller G, Larsen J, Cullen M, DiPersio J. Phase II study of low-dose decitabine for the front-line treatment of older patients with acute myeloid leukemia (AML). [abstract] Blood (ASH Annual Meeting Abstracts). 2006;108:1984
  87. Warrell RP, He LZ, Richon V, Calleja E, Pandolfi PP. Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. J Natl Cancer Inst. 1998;90:1621–1625
  88. Warrell RP. Arsenicals and inhibitors of histone deacetylase as anticancer therapy. Haematologica. 1999;84:75–77Suppl EHA-4
  89. Gore SD, Weng LJ, Figg WD, Zhai S, Donehower RC, Dover G, et al. Impact of prolonged infusions of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia. Clin Cancer Res. 2002;8:963–970
  90. Byrd JC, Marcucci G, Parthun MR, Xiao JJ, Klisovic RB, Moran M, et al. A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia. Blood. 2005;105:959–967
  91. Garcia-Manero G, Yang H, Bueso-Ramos C, Ferrajoli A, Cortes J, Wierda WG, et al. Phase I study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) in patients with advanced leukemias and myelodysplastic syndromes. Blood. 2008;111:1060–1066
  92. Kuendgen A, Strupp C, Aivado M, Bernhardt A, Hildebrandt B, Haas R, et al. Treatment of myelodysplastic syndromes with valproic acid alone or in combination with all-trans retinoic acid. Blood. 2004;104:1266–1269
  93. Gojo I, Jiemjit A, Trepel JB, Sparreboom A, Figg WD, Rollins S, et al. Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias. Blood. 2007;109:2781–2790
  94. Gore SD, Baylin S, Sugar E, Carraway H, Miller CB, Carducci M, et al. Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res. 2006;66:6361–6369
  95. Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, Yang H, Rosner G, Verstovsek S, et al. Phase 1/2 study of the combination of 5-aza-2′-deoxycytidine with valproic acid in patients with leukemia. Blood. 2006;108:3271–3279
  96. Soriano AO, Yang H, Faderl S, Estrov Z, Giles F, Ravandi F, et al. Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood. 2007;110:2302–2308
  97. Blum W, Klisovic RB, Hackanson B, Liu Z, Liu S, Devine H, et al. Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. J Clin Oncol. 2007;25:3884–3891
  98. Ravandi F, Faderl S, Deborah Thomas D, Burger J, Koller C, Garcia-Manero G, et al. Phase I study of suberoylanilide hydroxamic acid (SAHA) and decitabine in patients with relapsed, refractory or poor prognosis leukemia. [abstract] Blood (ASH Annual Meeting Abstracts). 2007;110:897
  99. Garcia-Manero G, Yang A, Klimek V, Cortes J, Ravandi F, Newsome W, et al. Phase I/II study of MGCD0103, an oral isotype-selective histone deacetylase (HDAC) inhibitor, in combination with 5-azacitidine in higher-risk myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). [abstract] Blood (ASH Annual Meeting Abstracts). 2007;110:444

 This work was supported by grants from the Leukemia Lymphoma Society (C.P.) and in part by NCI P30CA16058 (C.P.), CA93548 (C.P.) CA101956 (C.P.), CA102031 (G.M.). C.P. is a Leukemia Lymphoma Society Scholar.

PII: S0093-7754(08)00118-8

doi: 10.1053/j.seminoncol.2008.04.008

Seminars in Oncology
Volume 35, Issue 4 , Pages 378-387 , August 2008

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