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Distinction of acute lymphoblastic leukemia from acute myeloid leukemia through microarray-based DNA methylation analysis

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Abstract

Patterns of DNA methylation are substantially altered in malignancies compared to normal tissue, with both genome-wide hypomethylation and regional increase of cytosine methylation at dinucleotides of cytosine and guanine, i.e., CpG dinucleotides. While genome-wide hypomethylation renders chromosomes instable, hypermethylation of CpGs in promoter regions is generally associated with transcriptional silencing, e.g., of tumor suppressor genes. To investigate whether disease-specific methylation profiles exist for different entities of acute leukemia, a microarray-based DNA methylation analysis simultaneously assessing 249 CpG dinucleotides originating from 57 genes was employed. Hereby, samples from precursor B-cell acute lymphoblastic leukemia (ALL) could be distinguished from cases of acute myeloid leukemia by virtue of N33, EGR4, CDC2, CCND2, or MOS hypermethylation in ALL.

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References

  1. 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 

  2. Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415–428

    Article  CAS  PubMed  Google Scholar 

  3. Razin A, Cedar H (1991) DNA methylation and gene expression. Microbiol Rev 55:451–458

    CAS  PubMed  Google Scholar 

  4. Bird AP, Wolffe AP (1999) Methylation-induced repression—belts, braces, and chromatin. Cell 99:451–454

    Article  CAS  PubMed  Google Scholar 

  5. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C (1976) Proposals for the classification of the acute leukaemias. French–American–British (FAB) co-operative group. Br J Haematol 33:451–458

    CAS  PubMed  Google Scholar 

  6. Jaffe ES, Harris NL, Stein H, Vardiman JW (2001) World Health Organisation classification of tumours: pathology and genetics of tumours of haematopoietic and lymphoid tissues. IARC, Lyon

    Google Scholar 

  7. 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 

  8. 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 

  9. 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 

  10. 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 

  11. 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 

  12. 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 

  13. 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

    CAS  PubMed  Google Scholar 

  14. Kawano S, Miller CW, Gombart AF, Bartram CR, Matsuo Y, Asou H, Sakashita A, Said J, Tatsumi E, Koeffler HP (1999) Loss of p73 gene expression in leukemias/lymphomas due to hypermethylation. Blood 94:1113–1120

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  16. Costello JF, Fruhwald MC, Smiraglia DJ, Rush LJ, Robertson GP, Gao X, Wright FA, Feramisco JD, Peltomaki P, Lang JC, Schuller DE, Yu L, Bloomfield CD, Caligiuri MA, Yates A, Nishikawa R, Su Huang H, Petrelli NJ, Zhang X, O’Dorisio MS, Held WA, Cavenee WK, Plass C (2000) Aberrant CpG-island methylation has non-random and tumour-type-specific patterns. Nat Genet 24:132–138

    Article  CAS  PubMed  Google Scholar 

  17. Esteller M, Corn PG, Baylin SB, Herman JG (2001) A gene hypermethylation profile of human cancer. Cancer Res 61:3225–3229

    CAS  PubMed  Google Scholar 

  18. Huang TH, Perry MR, Laux DE (1999) Methylation profiling of CpG islands in human breast cancer cells. Hum Mol Genet 8:459–470

    Article  CAS  PubMed  Google Scholar 

  19. Suzuki H, Gabrielson E, Chen W, Anbazhagan R, van Engeland M, Weijenberg MP, Herman JG, Baylin SB (2002) A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nat Genet 31:141–149

    Article  CAS  PubMed  Google Scholar 

  20. 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 

  21. Olek A, Oswald J, Walter J (1996) A modified and improved method for bisulphite based cytosine methylation analysis. Nucleic Acids Res 24:5064–5066

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  23. Mardia KV, Kent JT, Bibby JM (1979) Multivariate analysis. Academic, London

    Google Scholar 

  24. Shaffer JP (1995) Multiple hypothesis testing. Annu Rev Psychol 46:561–576

    Article  Google Scholar 

  25. Ihaka R, Gentleman R (1996) A language for data analysis and graphics. J Comput Graph Stat 5:299–314

    Google Scholar 

  26. Warnecke PM, Stirzaker C, Melki JR, Millar DS, Paul CL, Clark SJ (1997) Detection and measurement of PCR bias in quantitative methylation analysis of bisulphite-treated DNA. Nucleic Acids Res 25:4422–4426

    Article  CAS  PubMed  Google Scholar 

  27. Yang H, Chen CM, Yan P, Huang TH, Shi H, Burger M, Nimmrich I, Maier S, Berlin K, Caldwell CW (2003) The androgen receptor gene is preferentially hypermethylated in follicular non-Hodgkin’s lymphomas. Clin Cancer Res 9:4034–4042

    CAS  PubMed  Google Scholar 

  28. Felgner J, Heidorn K, Korbacher D, Frahm SO, Parwaresch R (1999) Cell lineage specificity in G-CSF receptor gene methylation. Leukemia 13:530–534

    Article  CAS  PubMed  Google Scholar 

  29. Wilson CB, Makar KW, Perez-Melgosa M (2002) Epigenetic regulation of T cell fate and function. J Infect Dis 185 [Suppl 1]:S37–S45

    Article  CAS  PubMed  Google Scholar 

  30. Chan MF, Liang G, Jones PA (2000) Relationship between transcription and DNA methylation. Curr Top Microbiol Immunol 249:75–86

    CAS  PubMed  Google Scholar 

  31. Herman JG, Jen J, Merlo A, Baylin SB (1996) Hypermethylation-associated inactivation indicates a tumor suppressor role for p15INK4B. Cancer Res 56:722–727

    CAS  PubMed  Google Scholar 

  32. 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 

  33. Nyce J (1989) Drug-induced DNA hypermethylation and drug resistance in human tumors. Cancer Res 49:5829–5836

    CAS  PubMed  Google Scholar 

  34. Ishii H, Vecchione A, Murakumo Y, Baldassarre G, Numata S, Trapasso F, Alder H, Baffa R, Croce CM (2001) FEZ1/LZTS1 gene at 8p22 suppresses cancer cell growth and regulates mitosis. Proc Natl Acad Sci U S A 98:10374–10379

    Article  CAS  PubMed  Google Scholar 

  35. Li Q, Jedlicka A, Ahuja N, Gibbons MC, Baylin SB, Burger PC, Issa JP (1998) Concordant methylation of the ER and N33 genes in glioblastoma multiforme. Oncogene 16:3197–3202

    Article  CAS  PubMed  Google Scholar 

  36. Vecchione A, Ishii H, Shiao YH, Trapasso F, Rugge M, Tamburrino JF, Murakumo Y, Alder H, Croce CM, Baffa R (2001) Fez1/lzts1 alterations in gastric carcinoma. Clin Cancer Res 7:1546–1552

    CAS  PubMed  Google Scholar 

  37. MacGrogan D, Levy A, Bova GS, Isaacs WB, Bookstein R (1996) Structure and methylation-associated silencing of a gene within a homozygously deleted region of human chromosome band 8p22. Genomics 35:55–65

    Article  CAS  PubMed  Google Scholar 

  38. O’Donovan KJ, Tourtellotte WG, Millbrandt J, Baraban JM (1999) The EGR family of transcription-regulatory factors: progress at the interface of molecular and systems neuroscience. Trends Neurosci 22:167–173

    Article  CAS  PubMed  Google Scholar 

  39. Coleman TR, Dunphy WG (1994) Cdc2 regulatory factors. Curr Opin Cell Biol 6:877–882

    Article  CAS  PubMed  Google Scholar 

  40. Evron E, Umbricht CB, Korz D, Raman V, Loeb DM, Niranjan B, Buluwela L, Weitzman SA, Marks J, Sukumar S (2001) Loss of cyclin D2 expression in the majority of breast cancers is associated with promoter hypermethylation. Cancer Res 61:2782–2787

    CAS  PubMed  Google Scholar 

  41. Yu J, Leung WK, Ebert MP, Leong RW, Tse PC, Chan MW, Bai AH, To KF, Malfertheiner P, Sung JJ (2003) Absence of cyclin D2 expression is associated with promoter hypermethylation in gastric cancer. Br J Cancer 88:1560–1565

    Article  CAS  PubMed  Google Scholar 

  42. Sinclair AJ, Palmero I, Holder A, Peters G, Farrell PJ (1995) Expression of cyclin D2 in Epstein-Barr virus-positive Burkitt’s lymphoma cell lines is related to methylation status of the gene. J Virol 69:1292–1295

    CAS  PubMed  Google Scholar 

  43. Matsubayashi H, Sato N, Fukushima N, Yeo CJ, Walter KM, Brune K, Sahin F, Hruban RH, Goggins M (2003) Methylation of cyclin D2 is observed frequently in pancreatic cancer but is also an age-related phenomenon in gastrointestinal tissues. Clin Cancer Res 9:1446–1452

    CAS  PubMed  Google Scholar 

  44. Fukasawa K, Vande Woude GF (1997) Synergy between the Mos/mitogen-activated protein kinase pathway and loss of p53 function in transformation and chromosome instability. Mol Cell Biol 17:506–518

    CAS  PubMed  Google Scholar 

  45. Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP (1999) CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci U S A 96:8681–8686

    Article  CAS  PubMed  Google Scholar 

  46. Toyota M, Ahuja N, Suzuki H, Itoh F, Ohe-Toyota M, Imai K, Baylin SB, Issa JP (1999) Aberrant methylation in gastric cancer associated with the CpG island methylator phenotype. Cancer Res 59:5438–5442

    CAS  PubMed  Google Scholar 

  47. Liang G, Salem CE, Yu MC, Nguyen HD, Gonzales FA, Nguyen TT, Nichols PW, Jones PA (1998) DNA methylation differences associated with tumor tissues identified by genome scanning analysis. Genomics 53:260–268

    Article  CAS  PubMed  Google Scholar 

  48. Itano O, Ueda M, Kikuchi K, Hashimoto O, Hayatsu S, Kawaguchi M, Seki H, Aiura K, Kitajima M (2002) Correlation of postoperative recurrence in hepatocellular carcinoma with demethylation of repetitive sequences. Oncogene 21:789–797

    Article  CAS  PubMed  Google Scholar 

  49. 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 

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Authors and Affiliations

  1. Department of Hematology and Oncology, Universitätsmedizin Berlin, Charité Campus Virchow-Klinikum, Berlin, Germany

    Christian Scholz & Bernd Dörken

  2. Epigenomics AG, Berlin, Germany

    Inko Nimmrich, Matthias Burger, Evelyne Becker & Sabine Maier

  3. Department of Hematology, Oncology and Tumor Immunology, Universitätsmedizin Berlin, Charité Campus Buch, Robert-Rössle Klinik, HELIOS Clinic, Berlin, Germany

    Bernd Dörken & Wolf-Dieter Ludwig

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  1. Christian Scholz
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  2. Inko Nimmrich
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  5. Bernd Dörken
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  7. Sabine Maier
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Correspondence to Christian Scholz.

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Scholz, C., Nimmrich, I., Burger, M. et al. Distinction of acute lymphoblastic leukemia from acute myeloid leukemia through microarray-based DNA methylation analysis. Ann Hematol 84, 236–244 (2005). https://doi.org/10.1007/s00277-004-0969-1

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  • DOI: https://doi.org/10.1007/s00277-004-0969-1

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