Molecular Biology Reports

, Volume 37, Issue 5, pp 2471–2476 | Cite as

DNA methyltransferase expression differs with proliferation in childhood acute lymphoblastic leukemia

  • Derya Beyza Sayin
  • Emin Kürekçi
  • Halil Gürhan Karabulut
  • Üstün Ezer
  • Isik Bökesoy


DNA methylation is involved in genomic imprinting, tissue and stage specific gene regulation, X chromosome inactivation and especially necessary in normal mammalian development [1]. Methylation of DNA at cytosine base occurs at most CpG islands in the mammalian genome, with exception of CpG islands of gene promoters which are usually unmethylated. Methylation of promoter CpG islands inhibits the activity of the gene by inhibiting the association of some DNA-binding factors with methylated DNA sequences or by silencing transcription via methyl-CpG binding proteins with co-repressors and chromatin modifiers [2].

Cancer is known as a genetic disease, in which epigenetic alterations play important roles. Cancer cells show global genomic hypomethylation, but the CpG islands of the promoters, especially the promoters of the tumour suppressor genes are hypermethylated [3]. Aberrant methylation of CpG islands is a major epigenetic mechanism of gene expression in human cancers....


Acute Lymphoblastic Leukemia Proliferate Cell Nuclear Antigen Endometrial Carcinoma AdoMet Blast Count 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We acknowledge to Timur Tuncalı, Ongun Onaran and Uygar Tazebay for their technical support and to Kenan Köse for performing statistical analysis. This study was granted by The Scientific and Technological Research Council of Turkey (TUBİTAK).


  1. 1.
    Bestor TH (2000) The DNA methyltransferases of mammals. Hum Mol Genet 9:2395–2402CrossRefPubMedGoogle Scholar
  2. 2.
    Klose RJ, Bird AP (2006) Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci 1:89–97CrossRefGoogle Scholar
  3. 3.
    Ehrlich M, Woods CB, Yu MC et al (2006) Quantitive analysis of associations between DNA hypermethylation, hypomethylation and DNMT RNA levels in ovarian tumors. Oncogene 25:2636–2645CrossRefPubMedGoogle Scholar
  4. 4.
    Chen RZ, Pettersson U, Beard C et al (1998) DNA hypomethylation leads to elevated mutation rates. Nature 395:89–93CrossRefPubMedGoogle Scholar
  5. 5.
    Robertson KD, Jones PA (2000) DNA methylation: past, present and future directions. Carcinogenesis 21:461–467CrossRefPubMedGoogle Scholar
  6. 6.
    Melki JR, Vincent PC, Brown RD et al (2006) Hypermethylation of E-cadherin in leukemia. Blood 95:3208–3213Google Scholar
  7. 7.
    Gutierrez MI, Siraj AK, Bhargava M et al (2003) Concurrent methylation of multiple genes in childhood ALL: correlation with phenotype and molecular subgroup. Leukemia 17:1845–1850CrossRefPubMedGoogle Scholar
  8. 8.
    Garcia-Manero G, Jeha S, Daniel J et al (2003) Aberrant DNA methylation in pediatric patients with acute lymphocytic leukemia. Cancer 97:695–702CrossRefPubMedGoogle Scholar
  9. 9.
    Jeltsch A (2002) Beyond Watson and Crick: DNA methylation and molecular enzymology of DNA methyltransferases. ChemBioChem 3:274–293Google Scholar
  10. 10.
    Aapola U, Kawasaki K, Scott HS et al (2002) Isolation and initial characterization of a novel zinc finger gene, DNMT3L, on 21q22.3, relatend to the cytosine-5-methyltransferase 3 gene family. Genomics 65:293–298CrossRefGoogle Scholar
  11. 11.
    Dong A, Yoder JA, Zhang X et al (2001) Structure of human DNMT2, an enigmatic DNA methyltransferase homolog that displays denaturant resistant binding to DNA. Nucleic Acids Res 29:439–448CrossRefPubMedGoogle Scholar
  12. 12.
    Robertson KD, Ait-Si-Ali S, Yokochi T et al (2000) DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nat Genet 25:338–342CrossRefPubMedGoogle Scholar
  13. 13.
    Rountree MR, Bachman KE, Baylin SB (2000) DNMT1 binds HDAC2 and a new co-repressor, DMAP1 to form complex at replication foci. Nat Genet 25:269–277CrossRefPubMedGoogle Scholar
  14. 14.
    Hermann A, Schmitt S, Jeltsch A (2003) The human Dnmt2 has residual DNA-(Cytosine-C5) methyltransferase activity. J Biochem 278:31717–31721Google Scholar
  15. 15.
    Goll MG, Kirpekar F, Maggert KA et al (2006) Methylation of tRNAAsp by the DNA methyltransferase homolog Dnmt2. Science 311:395–398CrossRefPubMedGoogle Scholar
  16. 16.
    Jurkowski TP, Meusburger M, Phalke S et al (2008) Human DNMT2 methylates tRNAAsp molecules using DNA methyltransferase-like catalytic mechanism. RNA 14:1663–1670CrossRefPubMedGoogle Scholar
  17. 17.
    Jeltsch A, Nellen W, Lyko F (2006) Two substrates are better than one: dual specificities for Dnmt2 methyltransferases. Trends in Biochem Sci 31:306–308CrossRefGoogle Scholar
  18. 18.
    Okano M, Xie S, Li E (1998) Dnmt2 is not required for de novo and maintenance methylation of viral DNA in embryonic stem cells. Nucleic Acids Res 26:2536–2540CrossRefPubMedGoogle Scholar
  19. 19.
    Pradhan S, Esteve P (2003) Mammalian DNA (Cytosine-5) methyltransferases and their expression. Clinical Immunol 109:6–16CrossRefGoogle Scholar
  20. 20.
    Xie S, Wang Z, Okano M et al (1999) Cloning, expression and chromosome locations of the human DNMT3 gene family. Gene 236:87–95CrossRefPubMedGoogle Scholar
  21. 21.
    Li E, Bestor TH, Jaenisch R (1992) Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69:915–926CrossRefPubMedGoogle Scholar
  22. 22.
    Okano M, Bell DW, Haber DA et al (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99:247–257CrossRefPubMedGoogle Scholar
  23. 23.
    Saito Y, Kanai Y, Sakamoto M et al (2001) Expression of mRNA for DNA methyltransferases and methyl-CpG-binding proteins and DNA methylation status onCpG islands and pericentromeric satellite regions during human hepatocarcinogenesis. Hepatology 33:561–568CrossRefPubMedGoogle Scholar
  24. 24.
    Mizuno S, Chijiwa T, Okamura T et al (2001) Expression of DNA methyltransferases DNMT, 3A and 3B in normal hematopoiesis and in acute and chronic myelogenous leukemia. Blood 97:1172–1179CrossRefPubMedGoogle Scholar
  25. 25.
    Kanai Y, Ushijima S, Kondo Y et al (2001) DNA methyltransferase expression and DNA methylation of CpG islands and peri-centromeric satellite regions in human colorectal and stomach cancers. Int J Cancer 91:205–212CrossRefPubMedGoogle Scholar
  26. 26.
    Melki JR, Warnecke P, Vincent PC et al (1998) Increased DNA methyltransferase expression in leukaemia. Leukemia 12:311–316CrossRefPubMedGoogle Scholar
  27. 27.
    Choi MS, Shim YH, Hwa JY et al (2003) Expression of DNA methyltransferases in multistep hepatocarcinogenesis. Hum Pathol 34:11–17CrossRefPubMedGoogle Scholar
  28. 28.
    Kim H, Kwon YM, Kim JS et al (2006) Elevated mRNA levels of DNA methyltransferase-1 as an independent prognostic factor in primary nonsmall cell lung cancer. Cancer 107:1042–1049CrossRefPubMedGoogle Scholar
  29. 29.
    Eads CA, Danenberg KD, Kawakami K et al (1999) CpG island hypermethylation in human colorectal tumors is not associated with DNA methyltransferase overexpression. Cancer Res 59:2302–2306PubMedGoogle Scholar
  30. 30.
    Xiong Y, Dowdy SC, Xue A et al (2005) Opposite alterations of DNA methyltransferase gene expression in endometrioid and serous endometrial cancers. Gynecol Oncol 96:601–609CrossRefPubMedGoogle Scholar
  31. 31.
    Park HJ, Yu E, Shim YH (2006) DNA methyltransferase expression and DNA hypermethylation in human hepatocellular carcinoma. Cancer Lett 233:271–278CrossRefPubMedGoogle Scholar
  32. 32.
    Oh BK, Kim H, Park HJ et al (2007) DNA methyltransferase expression and DNA methylation in human hepatocellular carcinoma and their clinicopathological correlation. Int J Mol Med 20:65–73PubMedGoogle Scholar
  33. 33.
    Girault I, Tozlu S, Lidereau R et al (2003) Expression analysis of DNA methlytransferases 1, 3A and 3B in sporadic breast carcinomas. Clin Cancer Res 9:4415–4422PubMedGoogle Scholar
  34. 34.
    Länger F, Dingemann J, Kreipe H et al (2005) Up-regulation of DNA methyltransferases DNMT1, 3A, and 3B in myelodysplastic syndrome. Leuk Res 29:325–329CrossRefPubMedGoogle Scholar
  35. 35.
    Jin F, Dowdy SC, Xiong Y et al (2005) Up-regulation of DNA methyltransferase 3B expression in endometrial cancers. Gynecol Oncol 96:531–538CrossRefPubMedGoogle Scholar
  36. 36.
    Roll JD, Rivenbark AG, Jones WD et al (2008) DNMT3B overexpression contributes to a hypermethylator phenotype in human breast cancer cell lines. Molecular Cancer 7:15CrossRefPubMedGoogle Scholar
  37. 37.
    Beaulieu N, Morin S, Chute IC et al (2002) An essential role for DNA methyltransferase DNMT3B in cancer cell survival. J Biol Chem 277:28176–28181CrossRefPubMedGoogle Scholar
  38. 38.
    Rhee I, Bachman KE, Park BH et al (2002) DNMT1 and DNMT3B cooperate to silence genes in human cancer cells. Nature 416:552–556CrossRefPubMedGoogle Scholar
  39. 39.
    Egger G, Jeong S, Escobar SG et al (2006) Identification of DNMT1 (DNA methyltransferase 1) hypomorphs in somatic knockouts suggests an essential role for DNMT1 in cell survival. PNAS 103:14080–14085CrossRefPubMedGoogle Scholar
  40. 40.
    Aoki E, Ohashı H, Uchıda T et al (2003) Expression levels of DNA methyltransferase genes do not correlate with p15INK4B gene methylation in myelodysplastic syndromes. Leukemia 17:1903–1918CrossRefPubMedGoogle Scholar
  41. 41.
    Qiao SK, Xu SR, Guo XN et al (2005) Clinical significance of the expression of DNA methyltransferase genes (DNMT) in acute leukemia patients. Zhongguo Shi Yan Xui Za Zhi 13:260–265Google Scholar
  42. 42.
    Robertson KD, Uzvolgyi E, Liang G et al (1999) The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors. Nucleic Acids Res 27:2291–2298CrossRefPubMedGoogle Scholar
  43. 43.
    Lin RK, Hsu HS, Chang JW et al (2007) Alteration of DNA methyltransferases contributes to 5’CpG methylation and poor prognosis in lung cancer. Lung Cancer 55:205–213CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Derya Beyza Sayin
    • 1
    • 2
    • 3
  • Emin Kürekçi
    • 4
  • Halil Gürhan Karabulut
    • 1
  • Üstün Ezer
    • 5
  • Isik Bökesoy
    • 1
  1. 1.Department of Medical GeneticsAnkara University School of MedicineAnkaraTurkey
  2. 2.Kirikkale Universitesi Tip FakültesiKirikkaleTurkey
  3. 3.Department of Medical Biology, School of MedicineKirikkale UniversityKirikkaleTurkey
  4. 4.Department of Pediatric HematologyGulhane Military Medical AcademyAnkaraTurkey
  5. 5.Foundation For Children With Leukemia-LOSEVAnkaraTurkey

Personalised recommendations