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Role of epigenetic changes in hematological malignancies

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Abstract

Inactivation of tumor suppressor genes is an important event contributing to the development of neoplasia. In addition to the classic genetic mechanisms of deletion or inactivating point mutations, growth regulatory genes can be functionally inactivated without alterations of the primary sequence by methylation of cytosine residues in the promoter regions of the genes. After introducing epigenetic phenomena in general and the molecular basis of DNA methylation in more detail, this review will present the broad spectrum of alterations in DNA methylation patterns found in hematopoietic malignancies. In addition, the implications for therapy and prognosis will be discussed.

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References

  1. Adorjan P, Distler J, Lipscher E, Model F, Muller J, Pelet C, Braun A, Florl AR, Gutig D, Grabs G, Howe A, Kursar M, Lesche R, Leu E, Lewin A, Maier S, Muller V, Otto T, Scholz C, Schulz WA, Seifert HH, Schwope I, Ziebarth H, Berlin K, Piepenbrock C, Olek A (2002) Tumour class prediction and discovery by microarray-based DNA methylation analysis. Nucleic Acids Res 30:e21

    Article  PubMed  Google Scholar 

  2. Aggerholm A, Guldberg P, Hokland M, Hokland P (1999) Extensive intra- and interindividual heterogeneity of p15INK4B methylation in acute myeloid leukemia. Cancer Res 59:436–441

    CAS  PubMed  Google Scholar 

  3. Aggerholm A, Hokland P (2000) DAP-kinase CpG island methylation in acute myeloid leukemia: methodology versus biology? Blood 95:2997–2999

    CAS  PubMed  Google Scholar 

  4. Agirre X, Vizmanos JL, Calasanz MJ, Garcia-Delgado M, Larrayoz MJ, Novo FJ (2003) Methylation of CpG dinucleotides and/or CCWGG motifs at the promoter of TP53 correlates with decreased gene expression in a subset of acute lymphoblastic leukemia patients. Oncogene 22:1070–1072

    Article  CAS  PubMed  Google Scholar 

  5. Anderson AE, Haines TR, Robinson DP, Butcher DT, Sadikovic B, Rodenhiser DI (2001) Sodium bisulfite analysis of the methylation status of DNA from small portions of paraffin slides. Biotechniques 31:1004, 1006, 1008

    CAS  PubMed  Google Scholar 

  6. Antequera F, Boyes J, Bird A (1990) High levels of de novo methylation and altered chromatin structure at CpG islands in cell lines. Cell 62:503–514

    CAS  PubMed  Google Scholar 

  7. Aoki E, Uchida T, Ohashi H, Nagai H, Murase T, Ichikawa A, Yamao K, Hotta T, Kinoshita T, Saito H, Murate T (2000) Methylation status of the p15INK4B gene in hematopoietic progenitors and peripheral blood cells in myelodysplastic syndromes. Leukemia 14:586–593

    Article  CAS  PubMed  Google Scholar 

  8. Asimakopoulos FA, Shteper PJ, Fibach E, Rachmilewitz E, Ben-Neriah Y, Ben-Yehuda D (1999) Prognostic significance of c-ABL methylation in chronic myelogenous leukemia: still an open question. Blood 94:1141

    CAS  PubMed  Google Scholar 

  9. Asimakopoulos FA, Shteper PJ, Krichevsky S, Fibach E, Polliack A, Rachmilewitz E, Ben-Neriah Y, Ben-Yehuda D (1999) ABL1 methylation is a distinct molecular event associated with clonal evolution of chronic myeloid leukemia. Blood 94:2452–2460

    CAS  PubMed  Google Scholar 

  10. Attwood JT, Yung RL, Richardson BC (2002) DNA methylation and the regulation of gene transcription. Cell Mol Life Sci 59:241–257

    Article  Google Scholar 

  11. Au WY, Fung A, Man C, Ma SK, Wan TS, Liang R, Kwong YL (2003) Aberrant p15 gene promoter methylation in therapy-related myelodysplastic syndrome and acute myeloid leukaemia: clinicopathological and karyotypic associations. Br J Haematol 120:1062–1065

    CAS  PubMed  Google Scholar 

  12. Aviram A, Witenberg B, Shaklai M, Blickstein D (2003) Detection of methylated ABL1 promoter in Philadelphia-negative myeloproliferative disorders. Blood Cells Mol Dis 30:100–106

    Article  CAS  PubMed  Google Scholar 

  13. Balog RP, de Souza YE, Tang HM, DeMasellis GM, Gao B, Avila A, Gaban DJ, Mittelman D, Minna JD, Luebke KJ, Garner HR (2002) Parallel assessment of CpG methylation by two-color hybridization with oligonucleotide arrays. Anal Biochem 309:301–310

    Article  CAS  PubMed  Google Scholar 

  14. Batova A, Diccianni MB, Yu JC, Nobori T, Link MP, Pullen J, Yu AL (1997) Frequent and selective methylation of p15 and deletion of both p15 and p16 in T-cell acute lymphoblastic leukemia. Cancer Res 57:832–836

    CAS  PubMed  Google Scholar 

  15. Baur AS, Shaw P, Burri N, Delacretaz F, Bosman FT, Chaubert P (1999) Frequent methylation silencing of p15(INK4b) (MTS2) and p16(INK4a) (MTS1) in B-cell and T-cell lymphomas. Blood 94:1773–1781

    CAS  PubMed  Google Scholar 

  16. Baylin SB, Fearon ER, Vogelstein B, de Bustros A, Sharkis SJ, Burke PJ, Staal SP, Nelkin BD (1987) Hypermethylation of the 5’ region of the calcitonin gene is a property of human lymphoid and acute myeloid malignancies. Blood 70:412–417

    CAS  PubMed  Google Scholar 

  17. Baylin SB, Herman JG, Graff JR, Vertino PM, Issa JP (1998) Alterations in DNA methylation: a fundamental aspect of neoplasia. Adv Cancer Res 72:141–196

    PubMed  Google Scholar 

  18. Belinsky SA, Nikula KJ, Baylin SB, Issa JP (1996) Increased cytosine DNA-methyltransferase activity is target-cell-specific and an early event in lung cancer. Proc Natl Acad Sci U S A 93:4045–4050

    Article  CAS  PubMed  Google Scholar 

  19. Bhattacharya SK, Ramchandani S, Cervoni N, Szyf M (1999) A mammalian protein with specific demethylase activity for mCpG DNA. Nature 397:579–583

    Article  CAS  PubMed  Google Scholar 

  20. Bird A (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16:6–21

    Article  CAS  PubMed  Google Scholar 

  21. Bird AP (1986) CpG-rich islands and the function of DNA methylation. Nature 321:209–213

    CAS  PubMed  Google Scholar 

  22. Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB (1999) Synergy of demethylation and histone deacetylase inhibition in the re- expression of genes silenced in cancer. Nat Genet 21:103–107

    Article  PubMed  Google Scholar 

  23. Cameron EE, Baylin SB, Herman JG (1999) p15(INK4B) CpG island methylation in primary acute leukemia is heterogeneous and suggests density as a critical factor for transcriptional silencing. Blood 94:2445–2451

    CAS  PubMed  Google Scholar 

  24. Cervoni N, Bhattacharya S, Szyf M (1999) DNA demethylase is a processive enzyme. J Biol Chem 274:8363–8366

    Article  CAS  PubMed  Google Scholar 

  25. Chen B, He L, Savell VH, Jenkins JJ, Parham DM (2000) Inhibition of the interferon-gamma/signal transducers and activators of transcription (STAT) pathway by hypermethylation at a STAT-binding site in the p21WAF1 promoter region. Cancer Res 60:3290–3298

    CAS  PubMed  Google Scholar 

  26. Chen CY, Tsay W, Tang JL, Shen HL, Lin SW, Huang SY, Yao M, Chen YC, Shen MC, Wang CH, Tien HF (2003) SOCS1 methylation in patients with newly diagnosed acute myeloid leukemia. Genes Chromosomes Cancer 37:300–305

    Article  CAS  PubMed  Google Scholar 

  27. Chen WY, Zeng X, Carter MG, Morrell CN, Chiu Yen RW, Esteller M, Watkins DN, Herman JG, Mankowski JL, Baylin SB (2003) Heterozygous disruption of Hic1 predisposes mice to a gender-dependent spectrum of malignant tumors. Nat Genet 33:197–202

    Article  CAS  PubMed  Google Scholar 

  28. Chim CS, Liang R, Tam CY, Kwong YL (2001) Methylation of p15 and p16 genes in acute promyelocytic leukemia: potential diagnostic and prognostic significance. J Clin Oncol 19:2033–2040

    CAS  PubMed  Google Scholar 

  29. Clark SJ, Harrison J, Paul CL, Frommer M (1994) High sensitivity mapping of methylated cytosines. Nucleic Acids Res 22:2990–2997

    PubMed  Google Scholar 

  30. Clark SJ, Melki J (2002) DNA methylation and gene silencing in cancer: which is the guilty party? Oncogene 21:5380–5387

    Article  CAS  PubMed  Google Scholar 

  31. Corn PG, Kuerbitz SJ, van Noesel MM, Esteller M, Compitello N, Baylin SB, Herman JG (1999) Transcriptional silencing of the p73 gene in acute lymphoblastic leukemia and Burkitt’s lymphoma is associated with 5’ CpG island methylation. Cancer Res 59:3352–3356

    PubMed  Google Scholar 

  32. Corn PG, Smith BD, Ruckdeschel ES, Douglas D, Baylin SB, Herman JG (2000) E-cadherin expression is silenced by 5’ CpG island methylation in acute leukemia. Clin Cancer Res 6:4243–4248

    CAS  PubMed  Google Scholar 

  33. Dante R, Dante-Paire J, Rigal D, Roizes G (1992) Methylation patterns of long interspersed repeated DNA and alphoid repetitive DNA from human cell lines and tumors. Anticancer Res 12:559–563

    CAS  PubMed  Google Scholar 

  34. Das-Gupta EP, Russell NH (2000) Anticorresponding p15 promoter methylation and microsatellite instability in acute myeloblastic leukemia. Blood 96:2002

    CAS  Google Scholar 

  35. Daskalakis M, Nguyen TT, Nguyen C, Guldberg P, Kohler G, Wijermans P, Jones PA, Lubbert M (2002) Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2’-deoxycytidine (decitabine) treatment. Blood 100:2957–2964

    Article  CAS  PubMed  Google Scholar 

  36. Deiss LP, Feinstein E, Berissi H, Cohen O, Kimchi A (1995) Identification of a novel serine/threonine kinase and a novel 15-kD protein as potential mediators of the gamma interferon-induced cell death. Genes Dev 9:15–30

    CAS  PubMed  Google Scholar 

  37. Dhodapkar M, Grill J, Lust JA (1995) Abnormal regional hypermethylation of the calcitonin gene in myelodysplastic syndromes. Leuk Res 19:719–726

    Article  CAS  PubMed  Google Scholar 

  38. Dodge JE, List AF, Futscher BW (1998) Selective variegated methylation of the p15 CpG island in acute myeloid leukemia. Int J Cancer 78:561–567

    Article  CAS  PubMed  Google Scholar 

  39. Dodge JE, Munson C, List AF (2001) KG-1 and KG-1a model the p15 CpG island methylation observed in acute myeloid leukemia patients. Leuk Res 25:917–925

    Article  CAS  PubMed  Google Scholar 

  40. Dottori M, Down M, Huttmann A, Fitzpatrick DR, Boyd AW (1999) Cloning and characterization of EphA3 (Hek) gene promoter: DNA methylation regulates expression in hematopoietic tumor cells. Blood 94:2477–2486

    CAS  PubMed  Google Scholar 

  41. Eads CA, Danenberg KD, Kawakami K, Saltz LB, Blake C, Shibata D, Danenberg PV, Laird PW (2000a) MethyLight: a high-throughput assay to measure DNA methylation. Nucleic Acids Res 28:E32

    Article  CAS  PubMed  Google Scholar 

  42. Eads CA, Danenberg KD, Kawakami K, Saltz LB, Danenberg PV, Laird PW (1999) CpG island hypermethylation in human colorectal tumors is not associated with DNA methyltransferase overexpression. Cancer Res 59:2302–2306

    CAS  PubMed  Google Scholar 

  43. Ehrlich M (2002) DNA methylation in cancer: too much, but also too little. Oncogene 21:5400–5413

    Article  CAS  PubMed  Google Scholar 

  44. el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B (1993) WAF1, a potential mediator of p53 tumor suppression. Cell 75:817–825

    CAS  PubMed  Google Scholar 

  45. Esteller M, Corn PG, Urena JM, Gabrielson E, Baylin SB, Herman JG (1998) Inactivation of glutathione S-transferase P1 gene by promoter hypermethylation in human neoplasia. Cancer Res 58:4515–4518

    CAS  PubMed  Google Scholar 

  46. Esteller M, Gaidano G, Goodman SN, Zagonel V, Capello D, Botto B, Rossi D, Gloghini A, Vitolo U, Carbone A, Baylin SB, Herman JG (2002) Hypermethylation of the DNA repair gene O(6)-methylguanine DNA methyltransferase and survival of patients with diffuse large B-cell lymphoma. J Natl Cancer Inst 94:26–32

    CAS  PubMed  Google Scholar 

  47. Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG (1999) Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res 59:793–797

    PubMed  Google Scholar 

  48. Fajkusova L, Fajkus J, Polackova K, Fulnecek J, Dvorakova D, Krahulcova E (2000) Detailed mapping of methylcytosine positions at the CpG island surrounding the Pa promoter at the bcr-abl locus in CML patients and in two cell lines, K562 and BV173. Blood Cells Mol Dis 26:193–204

    Article  CAS  PubMed  Google Scholar 

  49. Feinberg AP (1999) Imprinting of a genomic domain of 11p15 and loss of imprinting in cancer: an introduction. Cancer Res 59:1743s–1746s

    CAS  PubMed  Google Scholar 

  50. Feinberg AP, Vogelstein B (1983) Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301:89–92

    CAS  PubMed  Google Scholar 

  51. Felgner J, Kreipe H, Heidorn K, Jaquet K, Heuss R, Zschunke F, Radzun HJ, Parwaresch MR (1992) Lineage-specific methylation of the c-fms gene in blood cells and macrophages. Leukemia 6:420–425

    CAS  PubMed  Google Scholar 

  52. Fraga MF, Esteller M (2002) DNA methylation: a profile of methods and applications. Biotechniques 33:632, 634, 636–649

    CAS  PubMed  Google Scholar 

  53. Franchina M, Kay PH (2000) Evidence that cytosine residues within 5’-CCTGG-3’ pentanucleotides can be methylated in human DNA independently of the methylating system that modifies 5’-CG-3’ dinucleotides. DNA Cell Biol 19:521–526

    Article  CAS  PubMed  Google Scholar 

  54. Fryxell KB, McGee SB, Simoneaux DK, Willman CL, Cornwell MM (1999) Methylation analysis of the human multidrug resistance 1 gene in normal and leukemic hematopoietic cells. Leukemia 13:910–917

    Article  CAS  PubMed  Google Scholar 

  55. Fujii H, Biel MA, Zhou W, Weitzman SA, Baylin SB, Gabrielson E (1998) Methylation of the HIC-1 candidate tumor suppressor gene in human breast cancer. Oncogene 16:2159–2164

    Article  CAS  PubMed  Google Scholar 

  56. Gama-Sosa MA, Slagel VA, Trewyn RW, Oxenhandler R, Kuo KC, Gehrke CW, Ehrlich M (1983) The 5-methylcytosine content of DNA from human tumors. Nucleic Acids Res 11:6883–6894

    CAS  PubMed  Google Scholar 

  57. Garcia-Manero G (2003) Prognostic implications of epigenetic silencing of p15INK4B in acute promyelocytic leukemia. Leukemia 17:839–840

    Article  CAS  PubMed  Google Scholar 

  58. Garcia-Manero G, Bueso-Ramos C, Daniel J, Williamson J, Kantarjian HM, Issa JP (2002) DNA methylation patterns at relapse in adult acute lymphocytic leukemia. Clin Cancer Res 8:1897–1903

    CAS  PubMed  Google Scholar 

  59. Garcia-Manero G, Daniel J, Smith TL, Kornblau SM, Lee MS, Kantarjian HM, Issa JP (2002) DNA methylation of multiple promoter-associated CpG islands in adult acute lymphocytic leukemia. Clin Cancer Res 8:2217–2224

    CAS  PubMed  Google Scholar 

  60. Garcia-Manero G, Jeha S, Daniel J, Williamson J, Albitar M, Kantarjian HM, Issa JP (2003) Aberrant DNA methylation in pediatric patients with acute lymphocytic leukemia. Cancer 97:695–702

    Article  CAS  PubMed  Google Scholar 

  61. Gardiner-Garden M, Frommer M (1987) CpG islands in vertebrate genomes. J Mol Biol 196:261–282

    PubMed  Google Scholar 

  62. Gaudet F, Hodgson JG, Eden A, Jackson-Grusby L, Dausman J, Gray JW, Leonhardt H, Jaenisch R (2003) Induction of tumors in mice by genomic hypomethylation. Science 300:489–492

    Article  CAS  PubMed  Google Scholar 

  63. Gitan RS, Shi H, Chen CM, Yan PS, Huang TH (2002) Methylation-specific oligonucleotide microarray: a new potential for high-throughput methylation analysis. Genome Res 12:158–164

    CAS  PubMed  Google Scholar 

  64. Gonzalez M, Mateos MV, Garcia-Sanz R, Balanzategui A, Lopez-Perez R, Chillon MC, Gonzalez D, Alaejos I, San Miguel JF (2000) De novo methylation of tumor suppressor gene p16/INK4a is a frequent finding in multiple myeloma patients at diagnosis. Leukemia 14:183–187

    Article  CAS  PubMed  Google Scholar 

  65. Gonzalgo ML, Jones PA (1997) Rapid quantitation of methylation differences at specific sites using methylation-sensitive single nucleotide primer extension (Ms-SNuPE). Nucleic Acids Res 25:2529–2531

    Article  CAS  PubMed  Google Scholar 

  66. Goodman PA, Burkhardt N, Juran B, Tibbles HE, Uckun FM (2003) Hypermethylation of the spleen tyrosine kinase promoter in T-lineage acute lymphoblastic leukemia. Oncogene 22:2504–2514

    Article  CAS  PubMed  Google Scholar 

  67. Guo SX, Taki T, Ohnishi H, Piao HY, Tabuchi K, Bessho F, Hanada R, Yanagisawa M, Hayashi Y (2000) Hypermethylation of p16 and p15 genes and RB protein expression in acute leukemia. Leuk Res 24:39–46

    Article  CAS  PubMed  Google Scholar 

  68. Hanada M, Delia D, Aiello A, Stadtmauer E, Reed JC (1993) bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia. Blood 82:1820–1828

    CAS  PubMed  Google Scholar 

  69. Hannon GJ, Beach D (1994) p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature 371:257–261

    CAS  PubMed  Google Scholar 

  70. Hatada I, Mukai T (1995) Genomic imprinting of p57KIP2, a cyclin-dependent kinase inhibitor, in mouse. Nat Genet 11:204–206

    CAS  PubMed  Google Scholar 

  71. Henikoff S, Matzke MA (1997) Exploring and explaining epigenetic effects. Trends Genet 13:293–295

    Article  CAS  PubMed  Google Scholar 

  72. Herman JG, Civin CI, Issa JP, Collector MI, Sharkis SJ, Baylin SB (1997) Distinct patterns of inactivation of p15INK4B and p16INK4A characterize the major types of hematological malignancies. Cancer Res 57:837–841

    CAS  PubMed  Google Scholar 

  73. Hou P, Ji M, Liu Z, Shen J, Cheng L, He N, Lu Z (2003) A microarray to analyze methylation patterns of p16(Ink4a) gene 5’-CpG islands. Clin Biochem 36:197–202

    Article  CAS  PubMed  Google Scholar 

  74. Ihalainen J, Pakkala S, Savolainen ER, Jansson SE, Palotie A (1993) Hypermethylation of the calcitonin gene in the myelodysplastic syndromes. Leukemia 7:263–267

    CAS  PubMed  Google Scholar 

  75. Iravani M, Dhat R, Price CM (1997) Methylation of the multi tumor suppressor gene-2 (MTS2, CDKN1, p15INK4B) in childhood acute lymphoblastic leukemia. Oncogene 15:2609–2614

    Article  CAS  PubMed  Google Scholar 

  76. Issa JP, Kantarjian H, Mohan A, O’Brien S, Cortes J, Pierce S, Talpaz M (1999) Methylation of the ABL1 promoter in chronic myelogenous leukemia: lack of prognostic significance. Blood 93:2075–2080

    CAS  PubMed  Google Scholar 

  77. Issa JP, Zehnbauer BA, Civin CI, Collector MI, Sharkis SJ, Davidson NE, Kaufmann SH, Baylin SB (1996) The estrogen receptor CpG island is methylated in most hematopoietic neoplasms. Cancer Res 56:973–977

    CAS  PubMed  Google Scholar 

  78. Issa JP, Zehnbauer BA, Kaufmann SH, Biel MA, Baylin SB (1997) HIC1 hypermethylation is a late event in hematopoietic neoplasms. Cancer Res 57:1678–1681

    CAS  PubMed  Google Scholar 

  79. Jacobs JJ, van Lohuizen M (2002) Polycomb repression: from cellular memory to cellular proliferation and cancer. Biochim Biophys Acta 1602:151–161

    Article  CAS  PubMed  Google Scholar 

  80. Katzenellenbogen RA, Baylin SB, Herman JG (1999) Hypermethylation of the DAP-kinase CpG island is a common alteration in B-cell malignancies. Blood 93:4347–4353

    PubMed  Google Scholar 

  81. Kerjean A, Vieillefond A, Thiounn N, Sibony M, Jeanpierre M, Jouannet P (2001) Bisulfite genomic sequencing of microdissected cells. Nucleic Acids Res 29:E106–106

    Article  CAS  PubMed  Google Scholar 

  82. Kikuchi T, Toyota M, Itoh F, Suzuki H, Obata T, Yamamoto H, Kakiuchi H, Kusano M, Issa JP, Tokino T, Imai K (2002) Inactivation of p57KIP2 by regional promoter hypermethylation and histone deacetylation in human tumors. Oncogene 21:2741–2749

    Article  CAS  PubMed  Google Scholar 

  83. Kitazawa S, Kitazawa R, Maeda S (2000) Identification of methylated cytosine from archival formalin-fixed paraffin-embedded specimens. Lab Invest 80:275–276

    CAS  PubMed  Google Scholar 

  84. Kress C, Thomassin H, Grange T (2001) Local DNA demethylation in vertebrates: how could it be performed and targeted? FEBS Lett 494:135–140

    Article  CAS  PubMed  Google Scholar 

  85. Kusy S, Cividin M, Sorel N, Brizard F, Guilhot F, Brizard A, Larsen C, Roche J (2003) p14ARF, p15INK4b, and p16INK4a methylation status in chronic myelogenous leukemia. Blood 101:374–375

    Article  CAS  PubMed  Google Scholar 

  86. Lane DP (1992) Cancer. p53, guardian of the genome. Nature 358:15–16

    CAS  PubMed  Google Scholar 

  87. Lederberg J (2001) The meaning of epigenetics. The Scientist 15:6

    Google Scholar 

  88. Lee PJ, Washer LL, Law DJ, Boland CR, Horon IL, Feinberg AP (1996) Limited up-regulation of DNA methyltransferase in human colon cancer reflecting increased cell proliferation. Proc Natl Acad Sci U S A 93:10366–10370

    Article  CAS  PubMed  Google Scholar 

  89. Lee SW (1996) H-cadherin, a novel cadherin with growth inhibitory functions and diminished expression in human breast cancer. Nat Med 2:776–782

    CAS  PubMed  Google Scholar 

  90. Leegwater PA, Lambooy LH, De Abreu RA, Bokkerink JP, van den Heuvel LP (1997) DNA methylation patterns in the calcitonin gene region at first diagnosis and at relapse of acute lymphoblastic leukemia (ALL). Leukemia 11:971–978

    Article  CAS  PubMed  Google Scholar 

  91. Lehmann U, Hasemeier B, Lilischkis R, Kreipe H (2001) Quantitative analysis of promoter hypermethylation in laser-microdissected archival specimens. Lab Invest 81:635–638

    CAS  PubMed  Google Scholar 

  92. Lengauer C (2003) Cancer. An unstable liaison. Science 300:442–443

    Article  CAS  PubMed  Google Scholar 

  93. Leone G, Teofili L, Voso MT, Lubbert M (2002) DNA methylation and demethylating drugs in myelodysplastic syndromes and secondary leukemias. Haematologica 87:1324–1341

    CAS  PubMed  Google Scholar 

  94. Li Q, Kopecky KJ, Mohan A, Willman CL, Appelbaum FR, Weick JK, Issa JP (1999) Estrogen receptor methylation is associated with improved survival in adult acute myeloid leukemia. Clin Cancer Res 5:1077–1084

    CAS  PubMed  Google Scholar 

  95. Li Y, Nagai H, Ohno T, Yuge M, Hatano S, Ito E, Mori N, Saito H, Kinoshita T (2002) Aberrant DNA methylation of p57(KIP2) gene in the promoter region in lymphoid malignancies of B-cell phenotype. Blood 100:2572–2577

    Article  CAS  PubMed  Google Scholar 

  96. Lipsanen V, Leinonen P, Alhonen L, Janne J (1988) Hypomethylation of ornithine decarboxylase gene and erb-A1 oncogene in human chronic lymphatic leukemia. Blood 72:2042–2044

    CAS  PubMed  Google Scholar 

  97. Lo YM, Wong IH, Zhang J, Tein MS, Ng MH, Hjelm NM (1999) Quantitative analysis of aberrant p16 methylation using real-time quantitative methylation-specific polymerase chain reaction. Cancer Res 59:3899–3903

    CAS  PubMed  Google Scholar 

  98. Lorincz MC, Groudine M (2001) C(m)C(a/t)GG methylation: a new epigenetic mark in mammalian DNA? Proc Natl Acad Sci U S A 98:10034–10036

    Article  CAS  PubMed  Google Scholar 

  99. Lorincz MC, Schubeler D, Goeke SC, Walters M, Groudine M, Martin DI (2000) Dynamic analysis of proviral induction and De Novo methylation: implications for a histone deacetylase-independent, methylation density-dependent mechanism of transcriptional repression. Mol Cell Biol 20:842–850

    Article  CAS  PubMed  Google Scholar 

  100. Lubbert M (2000) DNA methylation inhibitors in the treatment of leukemias, myelodysplastic syndromes and hemoglobinopathies: clinical results and possible mechanisms of action. Curr Top Microbiol Immunol 249:135–164

    Google Scholar 

  101. Lubbert M (2003) Gene silencing of the p15/INK4B cell-cycle inhibitor by hypermethylation: an early or later epigenetic alteration in myelodysplastic syndromes? Leukemia 17:1762–1764

    Article  CAS  PubMed  Google Scholar 

  102. Lubbert M, Mertelsmann R, Herrmann F (1997) Cytosine methylation changes during normal hematopoiesis and in acute myeloid leukemia. Leukemia 11 [Suppl 1]:S12–S18

  103. Lubbert M, Oster W, Ludwig WD, Ganser A, Mertelsmann R, Herrmann F (1992) A switch toward demethylation is associated with the expression of myeloperoxidase in acute myeloblastic and promyelocytic leukemias. Blood 80:2066–2073

    CAS  PubMed  Google Scholar 

  104. Lubbert M, Wijermans P, Kunzmann R, Verhoef G, Bosly A, Ravoet C, Andre M, Ferrant A (2001) Cytogenetic responses in high-risk myelodysplastic syndrome following low-dose treatment with the DNA methylation inhibitor 5-aza-2’-deoxycytidine. Br J Haematol 114:349–357

    Article  CAS  PubMed  Google Scholar 

  105. Mahmoudi T, Verrijzer CP (2001) Chromatin silencing and activation by Polycomb and trithorax group proteins. Oncogene 20:3055–3066

    Article  CAS  PubMed  Google Scholar 

  106. Makos M, Nelkin BD, Lerman MI, Latif F, Zbar B, Baylin SB (1992) Distinct hypermethylation patterns occur at altered chromosome loci in human lung and colon cancer. Proc Natl Acad Sci U S A 89:1929–1933

    CAS  PubMed  Google Scholar 

  107. Malinen T, Palotie A, Pakkala S, Peltonen L, Ruutu T, Jansson SE (1991) Acceleration of chronic myeloid leukemia correlates with calcitonin gene hypermethylation. Blood 77:2435–2440

    CAS  PubMed  Google Scholar 

  108. Malone CS, Miner MD, Doerr JR, Jackson JP, Jacobsen SE, Wall R, Teitell M (2001) CmC(A/T)GG DNA methylation in mature B cell lymphoma gene silencing. Proc Natl Acad Sci U S A 98:10404–10409

    Article  CAS  PubMed  Google Scholar 

  109. Martinez-Delgado B, Fernandez-Piqueras J, Garcia MJ, Arranz E, Gallego J, Rivas C, Robledo M, Benitez J (1997) Hypermethylation of a 5’ CpG island of p16 is a frequent event in non-Hodgkin’s lymphoma. Leukemia 11:425–428

    Article  CAS  PubMed  Google Scholar 

  110. Martinez-Delgado B, Melendez B, Cuadros M, Jose Garcia M, Nomdedeu J, Rivas C, Fernandez-Piqueras J, Benitez J (2002) Frequent inactivation of the p73 gene by abnormal methylation or LOH in non-Hodgkin’s lymphomas. Int J Cancer 102:15–19

    Article  CAS  PubMed  Google Scholar 

  111. Martinez-Delgado B, Richart A, Garcia MJ, Robledo M, Osorio A, Cebrian A, Rivas C, Benitez J (2000) Hypermethylation of P16ink4a and P15ink4b genes as a marker of disease in the follow-up of non-Hodgkin’s lymphomas. Br J Haematol 109:97–103

    Article  CAS  PubMed  Google Scholar 

  112. Martinez-Delgado B, Robledo M, Arranz E, Osorio A, Garcia MJ, Echezarreta G, Rivas C, Benitez J (1998) Hypermethylation of p15/ink4b/MTS2 gene is differentially implicated among non-Hodgkin’s lymphomas. Leukemia 12:937–941

    Article  CAS  PubMed  Google Scholar 

  113. McDonald LE, Kay GF (1997) Methylation analysis using bisulfite genomic sequencing: application to small numbers of intact cells. Biotechniques 22:272–274

    PubMed  Google Scholar 

  114. Melino G, De Laurenzi V, Vousden KH (2002) p73: Friend or foe in tumorigenesis. Nat Rev Cancer 2:605–615

    Article  CAS  PubMed  Google Scholar 

  115. Melki JR, Clark SJ (2002) DNA methylation changes in leukaemia. Semin Cancer Biol 12:347–357

    Article  CAS  PubMed  Google Scholar 

  116. Melki JR, Vincent PC, Brown RD, Clark SJ (2000) Hypermethylation of E-cadherin in leukemia. Blood 95:3208–3213

    CAS  PubMed  Google Scholar 

  117. Melki JR, Vincent PC, Clark SJ (1999) Cancer-specific region of hypermethylation identified within the HIC1 putative tumour suppressor gene in acute myeloid leukaemia. Leukemia 13:877–883

    Article  CAS  PubMed  Google Scholar 

  118. Melki JR, Vincent PC, Clark SJ (1999) Concurrent DNA hypermethylation of multiple genes in acute myeloid leukemia. Cancer Res 59:3730–3740

    PubMed  Google Scholar 

  119. Melki JR, Warnecke P, Vincent PC, Clark SJ (1998) Increased DNA methyltransferase expression in leukaemia. Leukemia 12:311–316

    Article  CAS  PubMed  Google Scholar 

  120. Mizuno S, Chijiwa T, Okamura T, Akashi K, Fukumaki Y, Niho Y, Sasaki H (2001) Expression of DNA methyltransferases DNMT1, 3A, and 3B in normal hematopoiesis and in acute and chronic myelogenous leukemia. Blood 97:1172–1179

    Article  CAS  PubMed  Google Scholar 

  121. Muller-Tidow C, Bornemann C, Diederichs S, Westermann A, Klumpen S, Zuo P, Wang W, Berdel WE, Serve H (2001) Analyses of the genomic methylation status of the human cyclin A1 promoter by a novel real-time PCR-based methodology. FEBS Lett 490:75–78

    Article  CAS  PubMed  Google Scholar 

  122. Nakamura M, Sakaki T, Hashimoto H, Nakase H, Ishida E, Shimada K, Konishi N (2001) Frequent alterations of the p14(ARF) and p16(INK4a) genes in primary central nervous system lymphomas. Cancer Res 61:6335–6339

    CAS  PubMed  Google Scholar 

  123. Nakatsuka S, Liu A, Yao M, Takakuwa T, Tomita Y, Hoshida Y, Nishiu M, Aozasa K (2003) Methylation of promoter region in p27 gene plays a role in the development of lymphoid malignancies. Int J Oncol 22:561–568

    CAS  PubMed  Google Scholar 

  124. Nakayama M, Wada M, Harada T, Nagayama J, Kusaba H, Ohshima K, Kozuru M, Komatsu H, Ueda R, Kuwano M (1998) Hypomethylation status of CpG sites at the promoter region and overexpression of the human MDR1 gene in acute myeloid leukemias. Blood 92:4296–4307

    CAS  PubMed  Google Scholar 

  125. Nelkin BD, Przepiorka D, Burke PJ, Thomas ED, Baylin SB (1991) Abnormal methylation of the calcitonin gene marks progression of chronic myelogenous leukemia. Blood 77:2431–2434

    CAS  PubMed  Google Scholar 

  126. Ng MH (2002) Death associated protein kinase: from regulation of apoptosis to tumor suppressive functions and B cell malignancies. Apoptosis 7:261–270

    Article  CAS  PubMed  Google Scholar 

  127. Ng MH, Chung YF, Lo KW, Wickham NW, Lee JC, Huang DP (1997) Frequent hypermethylation of p16 and p15 genes in multiple myeloma. Blood 89:2500–2506

    CAS  PubMed  Google Scholar 

  128. Ng MH, To KW, Lo KW, Chan S, Tsang KS, Cheng SH, Ng HK (2001) Frequent death-associated protein kinase promoter hypermethylation in multiple myeloma. Clin Cancer Res 7:1724–1729

    CAS  PubMed  Google Scholar 

  129. Nguyen TT, Mohrbacher AF, Tsai YC, Groffen J, Heisterkamp N, Nichols PW, Yu MC, Lubbert M, Jones PA (2000) Quantitative measure of c-abl and p15 methylation in chronic myelogenous leukemia: biological implications. Blood 95:2990–2992

    CAS  PubMed  Google Scholar 

  130. Nosaka K, Maeda M, Tamiya S, Sakai T, Mitsuya H, Matsuoka M (2000) Increasing methylation of the CDKN2A gene is associated with the progression of adult T-cell leukemia. Cancer Res 60:1043–1048

    CAS  PubMed  Google Scholar 

  131. Obaya AJ, Sedivy JM (2002) Regulation of cyclin-Cdk activity in mammalian cells. Cell Mol Life Sci 59:126–142

    Article  Google Scholar 

  132. Ohashi H, Tsushita K, Utsumi M, Shimoyama M, Murate T, Uchida T, Aoki E, Saito H, Kinoshita T (2001) Relationship between methylation of the p15 gene and ectopic expression of the EVI-1 gene in myelodysplastic syndromes (MDS). Leukemia 15:990–991

    Article  CAS  PubMed  Google Scholar 

  133. Oka T, Ouchida M, Koyama M, Ogama Y, Takada S, Nakatani Y, Tanaka T, Yoshino T, Hayashi K, Ohara N, Kondo E, Takahashi K, Tsuchiyama J, Tanimoto M, Shimizu K, Akagi T (2002) Gene silencing of the tyrosine phosphatase SHP1 gene by aberrant methylation in leukemias/lymphomas. Cancer Res 62:6390–6394

    CAS  PubMed  Google Scholar 

  134. Omura-Minamisawa M, Diccianni MB, Batova A, Chang RC, Bridgeman LJ, Yu J, Pullen J, Bowman WP, Yu AL (2000) Universal inactivation of both p16 and p15 but not downstream components is an essential event in the pathogenesis of T-cell acute lymphoblastic leukemia. Clin Cancer Res 6:1219–1228

    CAS  PubMed  Google Scholar 

  135. Paz MF, Fraga MF, Avila S, Guo M, Pollan M, Herman JG, Esteller M (2003) A systematic profile of DNA methylation in human cancer cell lines. Cancer Res 63:1114–1121

    CAS  PubMed  Google Scholar 

  136. Pinyol M, Cobo F, Bea S, Jares P, Nayach I, Fernandez PL, Montserrat E, Cardesa A, Campo E (1998) p16(INK4a) gene inactivation by deletions, mutations, and hypermethylation is associated with transformed and aggressive variants of non-Hodgkin’s lymphomas. Blood 91:2977–2984

    CAS  PubMed  Google Scholar 

  137. Plass C, Yu F, Yu L, Strout MP, El-Rifai W, Elonen E, Knuutila S, Marcucci G, Young DC, Held WA, Bloomfield CD, Caligiuri MA (1999) Restriction landmark genome scanning for aberrant methylation in primary refractory and relapsed acute myeloid leukemia; involvement of the WIT-1 gene. Oncogene 18:3159–3165

    Article  CAS  PubMed  Google Scholar 

  138. Preisler HD, Li B, Chen H, Fisher L, Nayini J, Raza A, Creech S, Venugopal P (2001) P15INK4B gene methylation and expression in normal, myelodysplastic, and acute myelogenous leukemia cells and in the marrow cells of cured lymphoma patients. Leukemia 15:1589–1595

    Article  CAS  PubMed  Google Scholar 

  139. Quesnel B, Fenaux P (1999) P15INK4b gene methylation and myelodysplastic syndromes. Leuk Lymphoma 35:437–443

    CAS  PubMed  Google Scholar 

  140. Ramchandani S, Bhattacharya SK, Cervoni N, Szyf M (1999) DNA methylation is a reversible biological signal. Proc Natl Acad Sci U S A 96:6107–6112

    Article  CAS  PubMed  Google Scholar 

  141. Reik W, Maher ER (1997) Imprinting in clusters: lessons from Beckwith-Wiedemann syndrome. Trends Genet 13:330–334

    CAS  PubMed  Google Scholar 

  142. Reik W, Walter J (2001) Genomic imprinting: parental influence on the genome. Nat Rev Genet 2:21–32

    Article  CAS  PubMed  Google Scholar 

  143. Robertson KD, Uzvolgyi E, Liang G, Talmadge C, Sumegi J, Gonzales FA, Jones PA (1999) The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors. Nucleic Acids Res 27:2291–2298

    CAS  PubMed  Google Scholar 

  144. Roman J, Castillejo JA, Jimenez A, Bornstein R, Gonzalez MG, del Carmen Rodriguez M, Barrios M, Maldonado J, Torres A (2001) Hypermethylation of the calcitonin gene in acute lymphoblastic leukaemia is associated with unfavourable clinical outcome. Br J Haematol 113:329–338

    Article  CAS  PubMed  Google Scholar 

  145. Roman-Gomez J, Castillejo JA, Jimenez A, Cervantes F, Boque C, Hermosin L, Leon A, Granena A, Colomer D, Heiniger A, Torres A (2003) Cadherin-13, a mediator of calcium-dependent cell-cell adhesion, is silenced by methylation in chronic myeloid leukemia and correlates with pretreatment risk profile and cytogenetic response to interferon alfa. J Clin Oncol 21:1472–1479

    Article  PubMed  Google Scholar 

  146. Roman-Gomez J, Castillejo JA, Jimenez A, Gonzalez MG, Moreno F, Rodriguez Mdel C, Barrios M, Maldonado J, Torres A (2002) 5’ CpG island hypermethylation is associated with transcriptional silencing of the p21(CIP1/WAF1/SDI1) gene and confers poor prognosis in acute lymphoblastic leukemia. Blood 99:2291–2296

    Article  CAS  PubMed  Google Scholar 

  147. Sacchi S, Kantarjian HM, O’Brien S, Cortes J, Rios MB, Giles FJ, Beran M, Koller CA, Keating MJ, Talpaz M (1999) Chronic myelogenous leukemia in nonlymphoid blastic phase: analysis of the results of first salvage therapy with three different treatment approaches for 162 patients. Cancer 86:2632–2641

    Article  CAS  PubMed  Google Scholar 

  148. Sanchez-Beato M, Saez AI, Navas IC, Algara P, Sol Mateo M, Villuendas R, Camacho F, Sanchez-Aguilera A, Sanchez E, Piris MA (2001) Overall survival in aggressive B-cell lymphomas is dependent on the accumulation of alterations in p53, p16, and p27. Am J Pathol 159:205–213

    CAS  PubMed  Google Scholar 

  149. Sanchez-Beato M, Sanchez-Aguilera A, Piris MA (2003) Cell cycle deregulation in B-cell lymphomas. Blood 101:1220–1235

    Article  CAS  PubMed  Google Scholar 

  150. Santini V, Kantarjian HM, Issa JP (2001) Changes in DNA methylation in neoplasia: pathophysiology and therapeutic implications. Ann Intern Med 134:573–586

    CAS  PubMed  Google Scholar 

  151. Seedhouse CH, Das-Gupta EP, Russell NH (2003) Methylation of the hMLH1 promoter and its association with microsatellite instability in acute myeloid leukemia. Leukemia 17:83–88

    Article  CAS  PubMed  Google Scholar 

  152. Shen L, Kondo Y, Issa JP, Garcia-Manero G (2002) Lack of p21(CIP1) DNA methylation in acute lymphocytic leukemia. Blood 100:3432–3433, author reply 3433–3434

    Article  CAS  Google Scholar 

  153. Shen L, Toyota M, Kondo Y, Obata T, Daniel S, Pierce S, Imai K, Kantarjian HM, Issa JP, Garcia-Manero G (2003) Aberrant DNA methylation of p57KIP2 identifies a cell-cycle regulatory pathway with prognostic impact in adult acute lymphocytic leukemia. Blood 101:4131–4136

    Article  CAS  PubMed  Google Scholar 

  154. Silverman LR (2001) Targeting hypomethylation of DNA to achieve cellular differentiation in myelodysplastic syndromes (MDS). Oncologist 6:8–14

    CAS  Google Scholar 

  155. Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R, Stone RM, Nelson D, Powell BL, DeCastro CM, Ellerton J, Larson RA, Schiffer CA, Holland JF (2002) Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 20:2429–2440

    CAS  PubMed  Google Scholar 

  156. Singer-Sam J, Riggs AD. 1993. X chromosome inactivation and DNA methylation. In Jost JP, Saluz HP (eds) DNA methylation: molecular biology and biological significance. Birkhäuser, Basel

  157. Tan LW, Dobrovic A (2001) Methylation analysis of formalin-fixed, paraffin-embedded sections using a nontoxic DNA extraction protocol. Biotechniques 31:1354, 1356–1357

    CAS  PubMed  Google Scholar 

  158. Tasaka T, Asou H, Munker R, Said JW, Berenson J, Vescio RA, Nagai M, Takahara J, Koeffler HP (1998) Methylation of the p16INK4A gene in multiple myeloma. Br J Haematol 101:558–564

    Article  CAS  PubMed  Google Scholar 

  159. Taylor JM, Kay PH, Spagnolo DV (2001) The diagnostic significance of Myf-3 hypermethylation in malignant lymphoproliferative disorders. Leukemia 15:583–589

    Article  CAS  PubMed  Google Scholar 

  160. Teofili L, Martini M, Luongo M, Diverio D, Capelli G, Breccia M, Lo Coco F, Leone G, Larocca LM (2003) Hypermethylation of GpG islands in the promoter region of p15(INK4b) in acute promyelocytic leukemia represses p15(INK4b) expression and correlates with poor prognosis. Leukemia 17:919–924

    Article  CAS  PubMed  Google Scholar 

  161. Tessema M, Langer F, Dingemann J, Ganser A, Kreipe H, Lehmann U (2003) Aberrant methylation and impaired expression of the p15(INK4b) cell cycle regulatory gene in chronic myelomonocytic leukemia (CMML). Leukemia 17:910–918

    Article  CAS  PubMed  Google Scholar 

  162. Thomas X, Teillon MH, Belhabri A, Rimokh R, Fiere D, Magaud JP, Archimbaud E (1999) Hypermethylation of calcitonin gene in adult acute leukemia at diagnosis and during complete remission. Hematol Cell Ther 41:19–26

    CAS  PubMed  Google Scholar 

  163. Tien HF, Tang JH, Tsay W, Liu MC, Lee FY, Wang CH, Chen YC, Shen MC (2001) Methylation of the p15(INK4B) gene in myelodysplastic syndrome: it can be detected early at diagnosis or during disease progression and is highly associated with leukaemic transformation. Br J Haematol 112:148–154

    CAS  PubMed  Google Scholar 

  164. Toyooka KO, Toyooka S, Virmani AK, Sathyanarayana UG, Euhus DM, Gilcrease M, Minna JD, Gazdar AF (2001) Loss of expression and aberrant methylation of the CDH13 (H-cadherin) gene in breast and lung carcinomas. Cancer Res 61:4556–4560

    CAS  PubMed  Google Scholar 

  165. Toyooka S, Toyooka KO, Harada K, Miyajima K, Makarla P, Sathyanarayana UG, Yin J, Sato F, Shivapurkar N, Meltzer SJ, Gazdar AF (2002) Aberrant methylation of the CDH13 (H-cadherin) promoter region in colorectal cancers and adenomas. Cancer Res 62:3382–3386

    CAS  PubMed  Google Scholar 

  166. Toyota M, Kopecky KJ, Toyota MO, Jair KW, Willman CL, Issa JP (2001) Methylation profiling in acute myeloid leukemia. Blood 97:2823–2829

    Article  CAS  PubMed  Google Scholar 

  167. Tsukamoto N, Morita K, Karasawa M, Omine M (1992) Methylation status of c-myc oncogene in leukemic cells: hypomethylation in acute leukemia derived from myelodysplastic syndromes. Exp Hematol 20:1061–1064

    CAS  PubMed  Google Scholar 

  168. Uchida T, Kinoshita T, Nagai H, Nakahara Y, Saito H, Hotta T, Murate T (1997) Hypermethylation of the p15INK4B gene in myelodysplastic syndromes. Blood 90:1403–1409

    CAS  PubMed  Google Scholar 

  169. Urashima M, Teoh G, Ogata A, Chauhan D, Treon SP, Sugimoto Y, Kaihara C, Matsuzaki M, Hoshi Y, DeCaprio JA, Anderson KC (1997) Characterization of p16(INK4A) expression in multiple myeloma and plasma cell leukemia. Clin Cancer Res 3:2173–2179

    CAS  PubMed  Google Scholar 

  170. Von Hoff DD, Slavik M, Muggia FM (1976) 5-Azacytidine. A new anticancer drug with effectiveness in acute myelogenous leukemia. Ann Intern Med 85:237–245

    Google Scholar 

  171. Wahlfors J, Hiltunen H, Heinonen K, Hamalainen E, Alhonen L, Janne J (1992) Genomic hypomethylation in human chronic lymphocytic leukemia. Blood 80:2074–2080

    CAS  PubMed  Google Scholar 

  172. Wales MM, Biel MA, el Deiry W, Nelkin BD, Issa JP, Cavenee WK, Kuerbitz SJ, Baylin SB (1995) p53 activates expression of HIC-1, a new candidate tumour suppressor gene on 17p13.3. Nat Med 1:570–577

    CAS  PubMed  Google Scholar 

  173. Wang JC, Chen W, Nallusamy S, Chen C, Novetsky AD (2002) Hypermethylation of the P15INK4b and P16INK4a in agnogenic myeloid metaplasia (AMM) and AMM in leukaemic transformation. Br J Haematol 116:582–586

    Article  CAS  PubMed  Google Scholar 

  174. Wijermans P, Lubbert M, Verhoef G, Bosly A, Ravoet C, Andre M, Ferrant A (2000) Low-dose 5-aza-2’-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients. J Clin Oncol 18:956–962

    PubMed  Google Scholar 

  175. Willemze R, Archimbaud E, Muus P (1993) Preliminary results with 5-aza-2’-deoxycytidine (DAC)-containing chemotherapy in patients with relapsed or refractory acute leukemia. The EORTC Leukemia Cooperative Group. Leukemia 7 [Suppl 1]:49–50

  176. Willemze R, Suciu S, Archimbaud E, Muus P, Stryckmans P, Louwagie EA, Berneman Z, Tjean M, Wijermans P, Dohner H, Jehn U, Labar B, Jaksic B, Dardenne M, Zittoun R (1997) A randomized phase II study on the effects of 5-Aza-2’-deoxycytidine combined with either amsacrine or idarubicin in patients with relapsed acute leukemia: an EORTC Leukemia Cooperative Group phase II study (06893). Leukemia 11 [Suppl 1]:S24–S27

  177. Wolffe AP, Jones PL, Wade PA (1999) DNA demethylation. Proc Natl Acad Sci U S A 96:5894–5896

    Article  CAS  PubMed  Google Scholar 

  178. Wong IH, Ng MH, Huang DP, Lee JC (2000) Aberrant p15 promoter methylation in adult and childhood acute leukemias of nearly all morphologic subtypes: potential prognostic implications. Blood 95:1942–1949

    CAS  PubMed  Google Scholar 

  179. Wu J, Herman JG, Wilson G, Lee RY, Yen RW, Mabry M, de Bustros A, Nelkin BD, Baylin SB (1996) Expression of prokaryotic HhaI DNA methyltransferase is transforming and lethal to NIH 3T3 cells. Cancer Res 56:616–622

    CAS  PubMed  Google Scholar 

  180. Yan PS, Perry MR, Laux DE, Asare AL, Caldwell CW, Huang TH (2000) CpG island arrays: an application toward deciphering epigenetic signatures of breast cancer. Clin Cancer Res 6:1432–1438

    CAS  PubMed  Google Scholar 

  181. Yang MY, Liu TC, Chang JG, Lin PM, Lin SF (2003) JunB gene expression is inactivated by methylation in chronic myeloid leukemia. Blood 101:3205–3211

    Article  CAS  PubMed  Google Scholar 

  182. Yuille MR, Condie A, Stone EM, Wilsher J, Bradshaw PS, Brooks L, Catovsky D (2001) TCL1 is activated by chromosomal rearrangement or by hypomethylation. Genes Chromosomes Cancer 30:336–341

    Article  CAS  PubMed  Google Scholar 

  183. Zhang SJ, Endo S, Ichikawa T, Washiyama K, Kumanishi T (1998) Frequent deletion and 5’ CpG island methylation of the p16 gene in primary malignant lymphoma of the brain. Cancer Res 58:1231–1237

    CAS  PubMed  Google Scholar 

  184. Zhu WG, Otterson GA (2003) The interaction of histone deacetylase inhibitors and DNA methyltransferase inhibitors in the treatment of human cancer cells. Curr Med Chem Anti-Canc Agents 3:187–199

    Google Scholar 

  185. Zion M, Ben-Yehuda D, Avraham A, Cohen O, Wetzler M, Melloul D, Ben-Neriah Y (1994) Progressive de novo DNA methylation at the bcr-abl locus in the course of chronic myelogenous leukemia. Proc Natl Acad Sci U S A 91:10722–10726

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank Mathewos Tessema for helpful discussions, Britta Hasemeier for art work, Florian Länger and Holly Sundberg for critically reading the manuscript and the anonymous reviewer for constructive criticism.

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  1. Institute of Pathology, Medizinische Hochschule Hannover, Carl-Neuberg-Str.1, 30625, Hannover, Germany

    Ulrich Lehmann, Kai Brakensiek & Hans Kreipe

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  1. Ulrich Lehmann
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Correspondence to Ulrich Lehmann.

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Grant numbers and sources of support: Deutsche Krebshilfe, grant 10-1842-Le I

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Lehmann, U., Brakensiek, K. & Kreipe, H. Role of epigenetic changes in hematological malignancies. Ann Hematol 83, 137–152 (2004). https://doi.org/10.1007/s00277-003-0798-7

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