Role of DNA Methyltransferases and DNA Methylation in Cell Fate Decisions During Blood Cell Development and Leukemia

  • Grant A. Challen
  • Jennifer J. Trowbridge
Part of the Epigenetics and Human Health book series (EHH)


Increasing evidence indicates that DNA methylation and the proteins responsible for catalyzing DNA methylation (the DNA methyltransferases or DNMTs) play critical roles in embryonic specification of the blood cell lineage and during differentiation of adult hematopoietic stem cells (HSCs). Furthermore, the identification of somatic mutations in DNMTs in a high frequency of human blood cancers suggests that altered DNA methylation is a critical component of leukemogenesis. This review will highlight our current understanding of the function of DNA methylation and the major DNMTs in hematopoiesis, describe the extent of characterization of mutant DNMTs in human blood cancer and other diseases, and discuss strategies to target altered DNA methylation or the activity of mutant DNMTs for more precise and effective leukemia therapy. Future studies aimed at understanding how DNA methylation regulates gene expression in concert with other epigenetic modifications, how DNMTs are directed to their cell type-specific target loci, and the exact biological functions of mutant DNMTs will be pivotal in the development of novel, targeted therapies for blood cancers.


DNA methylation DNMT Epigenetics Hematopoiesis Leukemia 


  1. Akalin A, Garrett-Bakelman FE, Kormaksson M et al (2012) Base-pair resolution DNA methylation sequencing reveals profoundly divergent epigenetic landscapes in acute myeloid leukemia. PLoS Genet 8:e1002781. doi: 10.1371/journal.pgen.1002781 PubMedCentralPubMedCrossRefGoogle Scholar
  2. Attwood JT, Yung RL, Richardson BC (2002) DNA methylation and the regulation of gene transcription. Cell Mol Life Sci 59:241–257PubMedCrossRefGoogle Scholar
  3. Ballestar E, Wolffe AP (2001) Methyl-CpG-binding proteins. Targeting specific gene repression. Eur J Biochem 268:1–6PubMedCrossRefGoogle Scholar
  4. Bock C, Beerman I, Lien WH et al (2012) DNA methylation dynamics during in vivo differentiation of blood and skin stem cells. Mol Cell 47:633–647. doi: 10.1016/j.molcel.2012.06.019 PubMedCentralPubMedCrossRefGoogle Scholar
  5. Borgel J, Guibert S, Li Y et al (2010) Targets and dynamics of promoter DNA methylation during early mouse development. Nat Genet 42:1093–1100. doi: 10.1038/ng.708 PubMedCrossRefGoogle Scholar
  6. Broske AM, Vockentanz L, Kharazi S et al (2009) DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction. Nat Genet 41:1207–1215. doi: 10.1038/ng.463 PubMedCrossRefGoogle Scholar
  7. Cancer Genome Atlas Research N (2013) Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 368:2059–2074. doi: 10.1056/NEJMoa1301689 CrossRefGoogle Scholar
  8. Cedar H, Bergman Y (2009) Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet 10:295–304PubMedCrossRefGoogle Scholar
  9. Challen GA, Sun D, Jeong M et al (2012) Dnmt3a is essential for hematopoietic stem cell differentiation. Nat Genet 44:23–31. doi: 10.1038/ng.1009 CrossRefGoogle Scholar
  10. Chen T, Ueda Y, Dodge JE, Wang Z, Li E (2003) Establishment and maintenance of genomic methylation patterns in mouse embryonic stem cells by Dnmt3a and Dnmt3b. Mol Cell Biol 23:5594–5605PubMedCentralPubMedCrossRefGoogle Scholar
  11. Clements EG, Mohammad HP, Leadem BR, Easwaran H, Cai Y, Van Neste L, Baylin SB (2012) DNMT1 modulates gene expression without its catalytic activity partially through its interactions with histone-modifying enzymes. Nucleic Acids Res 40:4334–4346. doi: 10.1093/nar/gks031 PubMedCentralPubMedCrossRefGoogle Scholar
  12. Couronne L, Bastard C, Bernard OA (2012) TET2 and DNMT3A mutations in human T-cell lymphoma. N Engl J Med 366:95–96. doi: 10.1056/NEJMc1111708 PubMedCrossRefGoogle Scholar
  13. Dang L, White DW, Gross S et al (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462:739–744. doi: 10.1038/nature08617 PubMedCentralPubMedCrossRefGoogle Scholar
  14. Dean W, Santos F, Reik W (2003) Epigenetic reprogramming in early mammalian development and following somatic nuclear transfer. Semin Cell Dev Biol 14:93–100PubMedCrossRefGoogle Scholar
  15. Dolnik A, Engelmann JC, Scharfenberger-Schmeer M et al (2012) Commonly altered genomic regions in acute myeloid leukemia are enriched for somatic mutations involved in chromatin remodeling and splicing. Blood 120:e83–e92. doi: 10.1182/blood-2011-12-401471 PubMedCrossRefGoogle Scholar
  16. Ehrlich M, Sanchez C, Shao C et al (2008) ICF, an immunodeficiency syndrome: DNA methyltransferase 3B involvement, chromosome anomalies, and gene dysregulation. Autoimmunity 41:253–271. doi: 10.1080/08916930802024202 PubMedCentralPubMedCrossRefGoogle Scholar
  17. Ewalt M, Galili NG, Mumtaz M et al (2011) DNMT3a mutations in high-risk myelodysplastic syndrome parallel those found in acute myeloid leukemia. Blood Cancer J 1:e9. doi: 10.1038/bcj.2011.7 PubMedCentralPubMedCrossRefGoogle Scholar
  18. Fernandez AF, Huidobro C, Fraga MF (2012) De novo DNA methyltransferases: oncogenes, tumor suppressors, or both? Trends Genet 28:474–479. doi: 10.1016/j.tig.2012.05.006 PubMedCrossRefGoogle Scholar
  19. Fuks F, Burgers WA, Brehm A, Hughes-Davies L, Kouzarides T (2000) DNA methyltransferase Dnmt1 associates with histone deacetylase activity. Nat Genet 24:88–91. doi: 10.1038/71750 PubMedCrossRefGoogle Scholar
  20. Gaudet F, Hodgson JG, Eden A et al (2003) Induction of tumors in mice by genomic hypomethylation. Science 300:489–492. doi: 10.1126/science.1083558 PubMedCrossRefGoogle Scholar
  21. Ghoshal K, Datta J, Majumder S, Bai S, Kutay H, Motiwala T, Jacob ST (2005) 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 25:4727–4741. doi: 10.1128/MCB.25.11.4727-4741.2005 PubMedCentralPubMedCrossRefGoogle Scholar
  22. Gross S, Cairns RA, Minden MD et al (2010) Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med 207:339–344. doi: 10.1084/jem.20092506 PubMedCentralPubMedCrossRefGoogle Scholar
  23. Grossmann V, Haferlach C, Weissmann S et al (2013) The molecular profile of adult T-cell acute lymphoblastic leukemia: mutations in RUNX1 and DNMT3A are associated with poor prognosis in T-ALL. Genes Chromosomes Cancer 52:410–422. doi: 10.1002/gcc.22039 PubMedCrossRefGoogle Scholar
  24. Hodges E, Molaro A, Dos Santos CO et al (2011) Directional DNA methylation changes and complex intermediate states accompany lineage specificity in the adult hematopoietic compartment. Mol Cell 44:17–28. doi: 10.1016/j.molcel.2011.08.026 PubMedCentralPubMedCrossRefGoogle Scholar
  25. Jackson-Grusby L, Beard C, Possemato R et al (2001) Loss of genomic methylation causes p53-dependent apoptosis and epigenetic deregulation. Nat Genet 27:31–39. doi: 10.1038/83730 PubMedCrossRefGoogle Scholar
  26. Jia D, Jurkowska RZ, Zhang X, Jeltsch A, Cheng X (2007) Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylation. Nature 449:248–251. doi: 10.1038/nature06146 PubMedCentralPubMedCrossRefGoogle Scholar
  27. Jiang YL, Rigolet M, Bourc’his D et al (2005) DNMT3B mutations and DNA methylation defect define two types of ICF syndrome. Hum Mutat 25:56–63. doi: 10.1002/humu.20113 PubMedCrossRefGoogle Scholar
  28. Jin B, Tao Q, Peng J et al (2008) DNA methyltransferase 3B (DNMT3B) mutations in ICF syndrome lead to altered epigenetic modifications and aberrant expression of genes regulating development, neurogenesis and immune function. Hum Mol Genet 17:690–709. doi: 10.1093/hmg/ddm341 PubMedCrossRefGoogle Scholar
  29. Juergens RA, Wrangle J, Vendetti FP et al (2011) Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov 1:598–607. doi: 10.1158/2159-8290.CD-11-0214 PubMedCentralPubMedCrossRefGoogle Scholar
  30. Kantarjian H, Issa JP, Rosenfeld CS et al (2006) Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 106:1794–1803. doi: 10.1002/cncr.21792 PubMedCrossRefGoogle Scholar
  31. Ko M, Huang Y, Jankowska AM et al (2010) Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 468:839–843. doi: 10.1038/nature09586 PubMedCentralPubMedCrossRefGoogle Scholar
  32. Lei H, Oh SP, Okano M, Juttermann R, Goss KA, Jaenisch R, Li E (1996) De novo DNA cytosine methyltransferase activities in mouse embryonic stem cells. Development 122:3195–3205PubMedGoogle Scholar
  33. Ley TJ, Ding L, Walter MJ et al (2010) DNMT3A mutations in acute myeloid leukemia. N Engl J Med 363:2424–2433. doi: 10.1056/NEJMoa1005143 PubMedCentralPubMedCrossRefGoogle Scholar
  34. Meehan R, Lewis J, Cross S, Nan X, Jeppesen P, Bird A (1992) Transcriptional repression by methylation of CpG. J Cell Sci Suppl 16:9–14PubMedCrossRefGoogle Scholar
  35. Okano M, Xie S, Li E (1998) Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nat Genet 19:219–220. doi: 10.1038/890 PubMedCrossRefGoogle Scholar
  36. Okano M, Bell DW, Haber DA, Li E (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99:247–257. doi: 10.1016/S0092-8674(00)81656-6 [pii]PubMedCrossRefGoogle Scholar
  37. Paganin M, Pigazzi M, Bresolin S et al (2011) DNA methyltransferase 3a hot-spot locus is not mutated in pediatric patients affected by acute myeloid or T-cell acute lymphoblastic leukemia: an Italian study. Haematologica 96:1886–1887. doi: 10.3324/haematol.2011.049825 PubMedCentralPubMedCrossRefGoogle Scholar
  38. Reik W, Dean W, Walter J (2001) Epigenetic reprogramming in mammalian development. Science 293:1089–1093PubMedCrossRefGoogle Scholar
  39. Robertson KD (2005) DNA methylation and human disease. Nat Rev Genet 6:597–610. doi: 10.1038/nrg1655 PubMedCrossRefGoogle Scholar
  40. Robertson KD, Ait-Si-Ali S, Yokochi T, Wade PA, Jones PL, Wolffe AP (2000) DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nat Genet 25:338–342. doi: 10.1038/77124 PubMedCrossRefGoogle Scholar
  41. Rountree MR, Bachman KE, Baylin SB (2000) DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nat Genet 25:269–277. doi: 10.1038/77023 PubMedCrossRefGoogle Scholar
  42. Stegelmann F, Bullinger L, Schlenk RF et al (2011) DNMT3A mutations in myeloproliferative neoplasms. Leukemia 25:1217–1219. doi: 10.1038/leu.2011.77 PubMedCrossRefGoogle Scholar
  43. Tadokoro Y, Ema H, Okano M, Li E, Nakauchi H (2007) De novo DNA methyltransferase is essential for self-renewal, but not for differentiation, in hematopoietic stem cells. J Exp Med 204:715–722. doi: 10.1084/jem.20060750, jem.20060750 [pii]PubMedCentralPubMedCrossRefGoogle Scholar
  44. Thol F, Heuser M, Damm F, Klusmann JH, Reinhardt K, Reinhardt D (2011a) DNMT3A mutations are rare in childhood acute myeloid leukemia. Haematologica 96:1238–1240. doi: 10.3324/haematol.2011.046839 PubMedCentralPubMedCrossRefGoogle Scholar
  45. Thol F, Winschel C, Ludeking A et al (2011b) Rare occurrence of DNMT3A mutations in myelodysplastic syndromes. Haematologica 96:1870–1873. doi: 10.3324/haematol.2011.045559 PubMedCentralPubMedCrossRefGoogle Scholar
  46. Trowbridge JJ, Snow JW, Kim J, Orkin SH (2009) DNA methyltransferase 1 is essential for and uniquely regulates hematopoietic stem and progenitor cells. Cell Stem Cell 5:442–449. doi: 10.1016/j.stem.2009.08.016 PubMedCentralPubMedCrossRefGoogle Scholar
  47. Trowbridge JJ, Sinha AU, Zhu N, Li M, Armstrong SA, Orkin SH (2012) Haploinsufficiency of Dnmt1 impairs leukemia stem cell function through derepression of bivalent chromatin domains. Genes Dev 26:344–349. doi: 10.1101/gad.184341.111 PubMedCentralPubMedCrossRefGoogle Scholar
  48. Tsai HC, Li H, Van Neste L et al (2012) Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer Cell 21:430–446. doi: 10.1016/j.ccr.2011.12.029 PubMedCentralPubMedCrossRefGoogle Scholar
  49. Tsumura A, Hayakawa T, Kumaki Y et al (2006) Maintenance of self-renewal ability of mouse embryonic stem cells in the absence of DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b. Genes Cells 11:805–814. doi: 10.1111/j.1365-2443.2006.00984.x PubMedCrossRefGoogle Scholar
  50. Walter MJ, Ding L, Shen D et al (2011) Recurrent DNMT3A mutations in patients with myelodysplastic syndromes. Leukemia 25:1153–1158. doi: 10.1038/leu.2011.44 PubMedCentralPubMedCrossRefGoogle Scholar
  51. Welch JS, Ley TJ, Link DC et al (2012) The origin and evolution of mutations in acute myeloid leukemia. Cell 150:264–278. doi: 10.1016/j.cell.2012.06.023 PubMedCentralPubMedCrossRefGoogle Scholar
  52. Wijermans PW, Lubbert M, Verhoef G, Klimek V, Bosly A (2005) An epigenetic approach to the treatment of advanced MDS; the experience with the DNA demethylating agent 5-aza-2′-deoxycytidine (decitabine) in 177 patients. Ann Hematol 84(Suppl 1):9–17. doi: 10.1007/s00277-005-0012-1 PubMedCrossRefGoogle Scholar
  53. Winkelmann J, Lin L, Schormair B et al (2012) Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy. Hum Mol Genet 21:2205–2210. doi: 10.1093/hmg/dds035 PubMedCentralPubMedCrossRefGoogle Scholar
  54. Wu J, Issa JP, Herman J, Bassett DE Jr, Nelkin BD, Baylin SB (1993) Expression of an exogenous eukaryotic DNA methyltransferase gene induces transformation of NIH 3T3 cells. Proc Natl Acad Sci U S A 90:8891–8895PubMedCentralPubMedCrossRefGoogle Scholar
  55. Xiang Y, Ma N, Wang D, et al (2013) MiR-152 and miR-185 co-contribute to ovarian cancer cells cisplatin sensitivity by targeting DNMT1 directly: a novel epigenetic therapy independent of decitabine. Oncogene. doi:10.1038/onc.2012.575Google Scholar
  56. Xu GL, Bestor TH, Bourc’his D et al (1999) Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 402:187–191. doi: 10.1038/46052 PubMedCrossRefGoogle Scholar
  57. Yan XJ, Xu J, Gu ZH et al (2011) Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat Genet 43:309–315. doi: 10.1038/ng.788 PubMedCrossRefGoogle Scholar
  58. Yu DH, Ware C, Waterland RA et al (2013) Developmentally programmed 3′ CpG island methylation confers tissue- and cell-type-specific transcriptional activation. Mol Cell Biol 33:1845–1858. doi: 10.1128/MCB.01124-12 PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Division of Oncology, Department of Internal MedicineWashington University in St. LouisSt. LouisUSA
  2. 2.The Jackson LaboratoryBar HarborUSA

Personalised recommendations