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On the potential role of DNMT1 in acute myeloid leukemia and myelodysplastic syndromes: not another mutated epigenetic driver

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Abstract

DNA methylation is the most common epigenetic modification in the mammalian genome. DNA methylation is governed by the DNA methyltransferases mainly DNMT1, DNMT3A, and DNMT3B. DNMT1 methylates hemimethylated DNA ensuring accurate DNA methylation maintenance. DNMT1 is involved in the proper differentiation of hematopoietic stem cells (HSCs) through the interaction with effector molecules. DNMT1 is deregulated in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) as early as the leukemic stem cell stage. Through the interaction with fundamental transcription factors, non-coding RNAs, fusion oncogenes and by modulating core members of signaling pathways, it can affect leukemic cells biology. DNMT1 action might be also catalytic-independent highlighting a methylation-independent mode of action. In this review, we have gathered some current facts of DNMT1 role in AML and MDS and we also propose some perspectives for future studies.

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References

  1. Hackett JA, Surani MA (2013) DNA methylation dynamics during the mammalian life cycle. Philos Trans R Soc Lond B Biol Sci 368:20110328

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  2. Timp W, Feinberg AP (2013) Cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host. Nat Rev Cancer 13:497–510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Koh KP, Rao A (2013) DNA methylation and methylcytosine oxidation in cell fate decisions. Curr Opin Cell Biol 25:152–161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Jones PA (2010) Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet 13:484–492

    Article  CAS  Google Scholar 

  5. Portela A, Esteller M (2010) Epigenetic modifications and human disease. Nat Biotechnol 28:1057–1068

    Article  CAS  PubMed  Google Scholar 

  6. Chen CC, Wang KY, Shen CK (2013) DNA 5-methylcytosine demethylation activities of the mammalian DNA methyltransferases. J Biol Chem 288:9084–9091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Li Z, Dai H, Martos SN, Xu B, Gao Y, Li T, Zhu G, Schones DE, Wang Z (2015) Distinct roles of DNMT1-dependent and DNMT1-independent methylation patterns in the genome of mouse embryonic stem cells. Genome Biol 16:115

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Tiedemann RL, Putiri EL, Lee JH, Hlady RA, Kashiwagi K, Ordog T, Zhang Z, Liu C, Choi JH, Robertson KD (2014) Acute depletion redefines the division of labor among DNA methyltransferases in methylating the human genome. Cell Rep 9:1554–1566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Aran D, Sabato S, Hellman A (2013) DNA methylation of distal regulatory sites characterizes dysregulation of cancer genes. Genome Biol 14:R21

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Benetatos L, Hatzimichael E, Dasoula A, Dranitsaris G, Tsiara S, Syrrou M, Georgiou I, Bourantas KL (2010) CpG methylation analysis of the MEG3 and SNRPN imprinted genes in acute myeloid leukemia and myelodysplastic syndromes. Leuk Res 34:148–153

    Article  CAS  PubMed  Google Scholar 

  11. Zhang L, Padron E, Lancet J (2015) The molecular basis and clinical significance of genetic mutations identified in myelodysplastic syndromes. Leuk Res 39:6–17

    Article  PubMed  CAS  Google Scholar 

  12. Zhang ZM, Liu S, Lin K, Luo Y, Perry JJ, Wang Y, Song J (2015) Crystal structure of human DNA methyltransferase 1. J Mol Biol 427:2520–2531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. McGraw S, Oakes CC, Martel J, Cirio MC, de Zeeuw P, Mak W, Plass C, Bartolomei MS, Chaillet JR, Trasler JM (2013) Loss of DNMT1o disrupts imprinted X chromosome inactivation and accentuates placental defects in females. PLoS Genet 9:e1003873

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Das R, Lee YK, Strogantsev R, Jin S, Lim YC, Ng PY, Lin XM, Chng K, Yeo GS, Ferguson-Smith AC, Ding C (2013) DNMT1 and AIM1 imprinting in human placenta revealed through a genome-wide screen for allele-specific DNA methylation. BMC Genomics 14:685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Novakovic B, Wong NC, Sibson M, Ng HK, Morley R, Manuelpillai U, Down T, Rakyan VK, Beck S, Hiendleder S, Roberts CT, Craig JM, Saffery R (2010) DNA methylation-mediated down-regulation of DNA methyltransferase-1 (DNMT1) is coincident with, but not essential for, global hypomethylation in human placenta. J Biol Chem 285:9583–9593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Du Z, Song J, Wang Y, Zhao Y, Guda K, Yang S, Kao HY, Xu Y, Willis J, Markowitz SD, Sedwick D, Ewing RM, Wang Z (2010) DNMT1 stability is regulated by proteins coordinating deubiquitination and acetylation-driven ubiquitination. Sci Signal 3:ra80

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Svedružić ŽM (2011) Dnmt1 structure and function. Prog Mol Biol Transl Sci 101:221–254

    Article  PubMed  CAS  Google Scholar 

  18. Kar S, Deb M, Sengupta D, Shilpi A, Parbin S, Torrisani J, Pradhan S, Patra S (2012) An insight into the various regulatory mechanisms modulating human DNA methyltransferase 1 stability and function. Epigenetics 7:994–1007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Frauer C, Rottach A, Meilinger D, Bultmann S, Fellinger K, Hasenöder S, Wang M, Qin W, Söding J, Spada F, Leonhardt H (2011) Different binding properties and function of CXXC zinc finger domains in Dnmt1 and Tet1. PLoS One 6:e16627

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Garvilles RG, Hasegawa T, Kimura H, Sharif J, Muto M, Koseki H, Takahashi S, Suetake I, Tajima S (2015) Dual functions of the RFTS domain of Dnmt1 in replication-coupled DNA methylation and in protection of the genome from aberrant methylation. PLoS One 10:e0137509

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Song J, Rechkoblit O, Bestor TH, Patel DJ (2011) Structure of DNMT1-DNA complex reveals a role for autoinhibition in maintenance DNA methylation. Science 331:1036–1040

    Article  CAS  PubMed  Google Scholar 

  22. Bashtrykov P, Jankevicius G, Smarandache A, Jurkowska RZ, Ragozin S, Jeltsch A (2012) Specificity of Dnmt1 for methylation of hemimethylated CpG sites resides in its catalytic domain. Chem Biol 19:572–578

    Article  CAS  PubMed  Google Scholar 

  23. Syeda F, Fagan RL, Wean M, Avvakumov GV, Walker JR, Xue S, Dhe-Paganon S, Brenner C (2011) The replication focus targeting sequence (RFTS) domain is a DNA-competitive inhibitor of Dnmt1. J Biol Chem 286:15344–15351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Takebayashi S, Tamura T, Matsuoka C, Okano M (2007) Major and essential role for the DNA methylation mark in mouse embryogenesis and stable association of DNMT1 with newly replicated regions. Mol Cell Biol 27:8243–8258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Jacob V, Chernyavskaya Y, Chen X, Tan PS, Kent B, Hoshida Y, Sadler KC (2015) DNA hypomethylation induces a DNA replication-associated cell cycle arrest to block hepatic outgrowth in uhrf1 mutant zebrafish embryos. Development 142:510–521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Berkyurek AC, Suetake I, Arita K, Takeshita K, Nakagawa A, Shirakawa M, Tajima S (2014) The DNA methyltransferase Dnmt1 directly interacts with the SET and RING finger-associated (SRA) domain of the multifunctional protein Uhrf1 to facilitate accession of the catalytic center to hemi-methylated DNA. J Biol Chem 289:379–386

    Article  CAS  PubMed  Google Scholar 

  28. Estève PO, Chin HG, Benner J, Feehery GR, Samaranayake M, Horwitz GA, Jacobsen SE, Pradhan S (2009) Regulation of DNMT1 stability through SET7-mediate d lysine methylation in mammalian cells. Proc Natl Acad Sci U S A 106:5076–5081

    Article  PubMed  PubMed Central  Google Scholar 

  29. Peng L, Yuan Z, Ling H, Fukasawa K, Robertson K, Olashaw N, Koomen J, Chen J, Lane WS, Seto E (2011) SIRT1 deacetylates the DNA methyltransferase 1 (DNMT1) protein and alters its activities. Mol Cell Biol 31:4720–4734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cheng J, Yang H, Fang J, Ma L, Gong R, Wang P, Li Z, Xu Y (2015) Molecular mechanism for USP7-mediated DNMT1 stabilization by acetylation. Nat Commun 6:7023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Qin W, Leonhardt H, Pichler G (2011) Regulation of DNA methyltransferase 1 by interactions and modifications. Nucleus 2:392–402

    Article  PubMed  Google Scholar 

  32. Fuks F, Hurd PJ, Deplus R, Kouzarides T (2003) The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase. Nucleic Acids Res 31:2305–2312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kinney SR, Pradhan S (2011) Regulation of expression and activity of DNA (cytosine-5) methyltransferases in mammalian cells. Prog Mol Biol Transl Sci 101:311–333

    Article  CAS  PubMed  Google Scholar 

  34. Denis H, Ndlovu MN, Fuks F (2011) Regulation of mammalian DNA methyltransferases: a route to new mechanisms. EMBO Rep 12:647–656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Braconi C, Huang N, Patel T (2010) MicroRNA-dependent regulation of DNA methyltransferase-1 and tumor suppressor gene expression by interleukin-6 in human malignant cholangiocytes. Hepatology 51:881–890

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Di Ruscio A, Ebralidze AK, Benoukraf T, Amabile G, Goff LA, Terragni J, Figueroa ME, De Figueiredo Pontes LL, Alberich-Jorda M, Zhang P, Wu M, D’Alò F, Melnick A, Leone G, Ebralidze KK, Pradhan S, Rinn JL, Tenen DG (2013) DNMT1-interacting RNAs block gene-specific DNA methylation. Nature 503:371–376

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Tsai CC, Su PF, Huang YF, Yew TL, Hung SC (2012) Oct4 and Nanog directly regulate Dnmt1 to maintain self-renewal and undifferentiated state in mesenchymal stem cells. Mol Cell 47:169–182

    Article  CAS  PubMed  Google Scholar 

  38. Schmidt CS, Bultmann S, Meilinger D, Zacher B, Tresch A, Maier KC, Peter C, Martin DE, Leonhardt H, Spada F (2012) Global DNA hypomethylation prevents consolidation of differentiation programs and allows reversion to the embryonic stem cell state. PLoS One 7:e52629

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Biniszkiewicz D, Gribnau J, Ramsahoye B, Gaudet F, Eggan K, Humpherys D, Mastrangelo MA, Jun Z, Walter J, Jaenisch R (2002) Dnmt1 overexpression causes genomic hypermethylation, loss of imprinting, and embryonic lethality. Mol Cell Biol 22:2124–2135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Rhee KD, Yu J, Zhao CY, Fan G, Yang XJ (2012) Dnmt1-dependent DNA methylation is essential for photoreceptor terminal differentiation and retinal neuron survival. Cell Death Dis 3:e427

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Sun Z, Wu Y, Ordog T, Baheti S, Nie J, Duan X, Hojo K, Kocher JP, Dyck PJ, Klein CJ (2014) Aberrant signature methylome by DNMT1 hot spot mutation in hereditary sensory and autonomic neuropathy 1E. Epigenetics 9:1184–1193

    Article  PubMed  PubMed Central  Google Scholar 

  42. Baets J, Duan X, Wu Y, Smith G, Seeley WW, Mademan I, McGrath NM, Beadell NC, Khoury J, Botuyan MV, Mer G, Worrell GA, Hojo K, DeLeon J, Laura M, Liu YT, Senderek J, Weis J, Van den Bergh P, Merrill SL, Reilly MM, Houlden H, Grossman M, Scherer SS, De Jonghe P, Dyck PJ, Klein CJ (2015) Defects of mutant DNMT1 are linked to a spectrum of neurological disorders. Brain 138(Pt 4):845–861

    Article  PubMed  Google Scholar 

  43. Hutnick LK, Golshani P, Namihira M, Xue Z, Matynia A, Yang XW, Silva AJ, Schweizer FE, Fan G (2009) DNA hypomethylation restricted to the murine forebrain induces cortical degeneration and impairs postnatal neuronal maturation. Hum Mol Genet 18:2875–2888

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Georgia S, Kanji M, Bhushan A (2013) DNMT1 represses p53 to maintain progenitor cell survival during pancreatic organogenesis. Genes Dev 27:372–377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Elliott EN, Sheaffer KL, Schug J, Stappenbeck TS, Kaestner KH (2015) Dnmt1 is essential to maintain progenitors in the perinatal intestinal epithelium. Development 142:2163–2172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sheaffer KL, Kim R, Aoki R, Elliott EN, Schug J, Burger L, Schübeler D, Kaestner KH (2014) DNA methylation is required for the control of stem cell differentiation in the small intestine. Genes Dev 28:652–664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sen GL, Reuter JA, Webster DE, Zhu L, Khavari PA (2010) DNMT1 maintains progenitor function in self-renewing somatic tissue. Nature 463:563–567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Yin LJ, Zhang Y, Lv PP, He WH, Wu YT, Liu AX, Ding GL, Dong MY, Qu F, Xu CM, Zhu XM, Huang HF (2012) Insufficient maintenance DNA methylation is associated with abnormal embryonic development. BMC Med 10:26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. De Carvalho DD, Sharma S, You JS, Su SF, Taberlay PC, Kelly TK, Yang X, Liang G, Jones PA (2012) DNA methylation screening identifies driver epigenetic events of cancer cell survival. Cancer Cell 21:655–667

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Merry CR, Forrest ME, Sabers JN, Beard L, Gao XH, Hatzoglou M, Jackson MW, Wang Z, Markowitz SD, Khalil AM (2015) DNMT1-associated long non-coding RNAs regulate global gene expression and DNA methylation in colon cancer. Hum Mol Genet 24:6240–6253

    Article  CAS  PubMed  Google Scholar 

  51. Shukla V, Coumoul X, Lahusen T, Wang RH, Xu X, Vassilopoulos A, Xiao C, Lee MH, Man YG, Ouchi M, Ouchi T, Deng CX (2010) BRCA1 affects global DNA methylation through regulation of DNMT1. Cell Res 20:1201–1215

    Article  CAS  PubMed  Google Scholar 

  52. You H, Ding W, Rountree CB (2010) Epigenetic regulation of cancer stem cell marker CD133 by transforming growth factor-beta. Hepatology 51:1635–1644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Mudbhary R, Hoshida Y, Chernyavskaya Y, Jacob V, Villanueva A, Fiel MI, Chen X, Kojima K, Thung S, Bronson RT, Lachenmayer A, Revill K, Alsinet C, Sachidanandam R, Desai A, SenBanerjee S, Ukomadu C, Llovet JM, Sadler KC (2014) UHRF1 overexpression drives DNA hypomethylation and hepatocellular carcinoma. Cancer Cell 25:196–209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Shamma A, Suzuki M, Hayashi N, Kobayashi M, Sasaki N, Nishiuchi T, Doki Y, Okamoto T, Kohno S, Muranaka H, Kitajima S, Yamamoto K, Takahashi C (2013) ATM mediates pRB function to control DNMT1 protein stability and DNA methylation. Mol Cell Biol 33:3113–3124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Peng DF, Kanai Y, Sawada M, Ushijima S, Hiraoka N, Kitazawa S, Hirohashi S (2006) DNA methylation of multiple tumor-related genes in association with overexpression of DNA methyltransferase 1 (DNMT1) during multistage carcinogenesis of the pancreas. Carcinogenesis 27:1160–1168

    Article  CAS  PubMed  Google Scholar 

  56. Morita R, Hirohashi Y, Suzuki H, Takahashi A, Tamura Y, Kanaseki T, Asanuma H, Inoda S, Kondo T, Hashino S, Hasegawa T, Tokino T, Toyota M, Asaka M, Torigoe T, Sato N (2013) DNA methyltransferase 1 is essential for initiation of the colon cancers. Exp Mol Pathol 94:322–329

    Article  CAS  PubMed  Google Scholar 

  57. Pathania R, Ramachandran S, Elangovan S, Padia R, Yang P, Cinghu S, Veeranan-Karmegam R, Arjunan P, Gnana-Prakasam JP, Sadanand F, Pei L, Chang CS, Choi JH, Shi H, Manicassamy S, Prasad PD, Sharma S, Ganapathy V, Jothi R, Thangaraju M (2015) DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis. Nat Commun 6:6910

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Liu CC, Lin JH, Hsu TW, Su K, Li AF, Hsu HS, Hung SC (2015) IL-6 enriched lung cancer stem-like cell population by inhibition of cell cycle regulators via DNMT1 upregulation. Int J Cancer 136:547–559

    CAS  PubMed  Google Scholar 

  59. Espada J, Peinado H, Lopez-Serra L, Setién F, Lopez-Serra P, Portela A, Renart J, Carrasco E, Calvo M, Juarranz A, Cano A, Esteller M (2011) Regulation of SNAIL1 and E-cadherin function by DNMT1 in a DNA methylation-independent context. Nucleic Acids Res 39:9194–9205

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Ha K, Lee GE, Palii SS, Brown KD, Takeda Y, Liu K, Bhalla KN, Robertson KD (2011) Rapid and transient recruitment of DNMT1 to DNA double-strand breaks is mediated by its interaction with multiple components of the DNA damage response machinery. Hum Mol Genet 20:126–140

    Article  CAS  PubMed  Google Scholar 

  61. Loughery JE, Dunne PD, O’Neill KM, Meehan RR, McDaid JR, Walsh CP (2011) DNMT1 deficiency triggers mismatch repair defects in human cells through depletion of repair protein levels in a process involving the DNA damage response. Hum Mol Genet 20:3241–3255

    Article  CAS  PubMed  Google Scholar 

  62. Kim M, Trinh BN, Long TI, Oghamian S, Laird PW (2004) Dnmt1 deficiency leads to enhanced microsatellite instability in mouse embryonic stem cells. Nucleic Acids Res 32:5742–5749

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Unterberger A, Andrews SD, Weaver IC, Szyf M (2006) DNA methyltransferase 1 knockdown activates a replication stress checkpoint. Mol Cell Biol 26:7575–7586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Notta F, Zandi S, Takayama N, Dobson S, Gan OI, Wilson G, Kaufmann KB, McLeod J, Laurenti E, Dunant CF, McPherson JD, Stein LD, Dror Y, Dick JE (2015) Distinct routes of lineage development reshape the human blood hierarchy across ontogeny. Science. doi:10.1126/science.aab2116

    PubMed  PubMed Central  Google Scholar 

  65. Ratajczak MZ (2015) A novel view of the adult bone marrow stem cell hierarchy and stem cell trafficking. Leukemia 29:776–782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Anjos-Afonso F, Currie E, Palmer HG, Foster KE, Taussig DC, Bonnet D (2013) CD34(-) cells at the apex of the human hematopoietic stem cell hierarchy have distinctive cellular and molecular signatures. Cell Stem Cell 13:161–174

    Article  CAS  PubMed  Google Scholar 

  67. Cedar H, Bergman Y (2011) Epigenetics of haematopoietic cell development. Nat Rev Immunol 11:478–488

    Article  CAS  PubMed  Google Scholar 

  68. Cullen SM, Goodell MA (2015) Dynamic DNA methylation discovered during HSC differentiation. Cell Cycle 14:693–694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Bock C, Beerman I, Lien WH, Smith ZD, Gu H, Boyle P, Gnirke A, Fuchs E, Rossi DJ, Meissner A (2012) DNA methylation dynamics during in vivo differentiation of blood and skin stem cells. Mol Cell 47:633–647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Hodges E, Molaro A, Dos Santos CO, Thekkat P, Song Q, Uren PJ, Park J, Butler J, Rafii S, McCombie WR, Smith AD, Hannon GJ (2011) Directional DNA methylation changes and complex intermediate states accompany lineage specificity in the adult hematopoietic compartment. Mol Cell 44:17–28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Bocker MT, Hellwig I, Breiling A, Eckstein V, Ho AD, Lyko F (2011) Blood 117:e182–e189

    Article  CAS  PubMed  Google Scholar 

  72. Cabezas-Wallscheid N, Klimmeck D, Hansson J, Lipka DB, Reyes A, Wang Q, Weichenhan D, Lier A, von Paleske L, Renders S, Wünsche P, Zeisberger P, Brocks D, Gu L, Herrmann C, Haas S, Essers MA, Brors B, Eils R, Huber W, Milsom MD, Plass C, Krijgsveld J, Trumpp A (2014) Identification of regulatory networks in HSCs and their immediate progeny via integrated proteome, transcriptome, and DNA methylome analysis. Cell Stem Cell 15:507–522

    Article  CAS  PubMed  Google Scholar 

  73. Schoofs T, Berdel WE, Müller-Tidow C (2014) Origins of aberrant DNA methylation in acute myeloid leukemia. Leukemia 28:1–14

    Article  CAS  PubMed  Google Scholar 

  74. Maurano MT, Wang H, John S, Shafer A, Canfield T, Lee K, Stamatoyannopoulos JA (2015) Role of DNA methylation in modulating transcription factor occupancy. Cell Rep 12:1184–1195

    Article  CAS  PubMed  Google Scholar 

  75. Benayoun BA, Pollina EA, Brunet A (2015) Epigenetic regulation of ageing: linking environmental inputs to genomic stability. Nat Rev Mol Cell Biol 16:593–610

    Article  CAS  PubMed  Google Scholar 

  76. Ji H, Ehrlich LI, Seita J, Murakami P, Doi A, Lindau P, Lee H, Aryee MJ, Irizarry RA, Kim K, Rossi DJ, Inlay MA, Serwold T, Karsunky H, Ho L, Daley GQ, Weissman IL, Feinberg AP (2010) Comprehensive methylome map of lineage commitment from haematopoietic progenitors. Nature 467:338–342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Liu X, Jia X, Yuan H, Ma K, Chen Y, Jin Y, Deng M, Pan W, Chen S, Chen Z, de The H, Zon LI, Zhou Y, Zhou J, Zhu J (2015) DNA methyltransferase 1 functions through C/ebpa to maintain hematopoietic stem and progenitor cells in zebrafish. J Hematol Oncol 8:15

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Bröske AM, Vockentanz L, Kharazi S, Huska MR, Mancini E, Scheller M, Kuhl C, Enns A, Prinz M, Jaenisch R, Nerlov C, Leutz A, Andrade-Navarro MA, Jacobsen SE, Rosenbauer F (2009) DNA methylation protects hematopoietic stem cell multipotency from myeloerythroid restriction. Nat Genet 41:1207–1215

    Article  PubMed  CAS  Google Scholar 

  79. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Figueroa ME, Lugthart S, Li Y, Erpelinck-Verschueren C, Deng X, Christos PJ, Schifano E, Booth J, van Putten W, Skrabanek L, Campagne F, Mazumdar M, Greally JM, Valk PJ, Löwenberg B, Delwel R, Melnick A (2010) DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell 17:13–27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Itzykson R, Fenaux P (2014) Epigenetics of myelodysplastic syndromes. Leukemia 28:497–506

    Article  CAS  PubMed  Google Scholar 

  82. 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 

  83. Länger F, Dingemann J, Kreipe H, Lehmann U (2005) Up-regulation of DNA methyltransferases DNMT1, 3A, and 3B in myelodysplastic syndrome. Leuk Res 29:325–329

    Article  PubMed  CAS  Google Scholar 

  84. Hopfer O, Komor M, Koehler IS, Freitag C, Schulze M, Hoelzer D, Thiel E, Hofmann WK (2009) Aberrant promotor methylation in MDS hematopoietic cells during in vitro lineage specific differentiation is differently associated with DNMT isoforms. Leuk Res 33:434–442

    Article  CAS  PubMed  Google Scholar 

  85. Cancer Genome Atlas Research Network (2013) Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 368:2059–2074

    Article  CAS  Google Scholar 

  86. Dolnik A, Engelmann JC, Scharfenberger-Schmeer M, Mauch J, Kelkenberg-Schade S, Haldemann B, Fries T, Krönke J, Kühn MW, Paschka P, Kayser S, Wolf S, Gaidzik VI, Schlenk RF, Rücker FG, Döhner H, Lottaz C, Döhner K, Bullinger L (2012) Commonly altered genomic regions in acute myeloid leukemia are enriched for somatic mutations involved in chromatin remodeling and splicing. Blood 120:e83–e92

    Article  CAS  PubMed  Google Scholar 

  87. Shlush LI, Zandi S, Mitchell A, Chen WC, Brandwein JM, Gupta V, Kennedy JA, Schimmer AD, Schuh AC, Yee KW, McLeod JL, Doedens M, Medeiros JJ, Marke R, Kim HJ, Lee K, McPherson JD, Hudson TJ, Pan-Leukemia Gene Panel Consortium HALT, Brown AM, Yousif F, Trinh QM, Stein LD, Minden MD, Wang JC, Dick JE (2014) Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 506:328–333

    Article  CAS  PubMed  Google Scholar 

  88. Corces-Zimmerman MR, Hong WJ, Weissman IL, Medeiros BC, Majeti R (2014) Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission. Proc Natl Acad Sci U S A 111:2548–2553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Challen GA, Sun D, Jeong M, Luo M, Jelinek J, Berg JS, Bock C, Vasanthakumar A, Gu H, Xi Y, Liang S, Lu Y, Darlington GJ, Meissner A, Issa JP, Godley LA, Li W, Goodell MA (2011) Dnmt3a is essential for hematopoietic stem cell differentiation. Nat Genet 44:23–31

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Chao MP, Seita J, Weissman IL (2008) Establishment of a normal hematopoietic and leukemia stem cell hierarchy. Cold Spring Harb Symp Quant Biol 73:439–449

    Article  CAS  PubMed  Google Scholar 

  92. Liu S, Liu Z, Xie Z, Pang J, Yu J, Lehmann E, Huynh L, Vukosavljevic T, Takeki M, Klisovic RB, Baiocchi RA, Blum W, Porcu P, Garzon R, Byrd JC, Perrotti D, Caligiuri MA, Chan KK, Wu LC, Marcucci G (2008) Bortezomib induces DNA hypomethylation and silenced gene transcription by interfering with Sp1/NF-kappaB-dependent DNA methyltransferase activity in acute myeloid leukemia. Blood 111:2364–2373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Shen N, Yan F, Pang J, Wu LC, Al-Kali A, Litzow MR, Liu S (2014) A nucleolin-DNMT1 regulatory axis in acute myeloid leukemogenesis. Oncotarget 5:5494–5509

    Article  PubMed  PubMed Central  Google Scholar 

  94. Gu X, Hu Z, Ebrahem Q, Crabb JS, Mahfouz RZ, Radivoyevitch T, Crabb JW, Saunthararajah Y (2014) Runx1 regulation of Pu.1 corepressor/coactivator exchange identifies specific molecular targets for leukemia differentiation therapy. J Biol Chem 289:14881–14895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Hu Z, Negrotto S, Gu X, Mahfouz R, Ng KP, Ebrahem Q, Copelan E, Singh H, Maciejewski JP, Saunthararajah Y (2010) Decitabine maintains hematopoietic precursor self-renewal by preventing repression of stem cell genes by a differentiation-inducing stimulus. Mol Cancer Ther 9:1536–1543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Sun D, Luo M, Jeong M, Rodriguez B, Xia Z, Hannah R, Wang H, Le T, Faull KF, Chen R, Gu H, Bock C, Meissner A, Göttgens B, Darlington GJ, Li W, Goodell MA (2014) Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal. Cell Stem Cell 14:673–688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Will B, Vogler TO, Narayanagari S, Bartholdy B, Todorova TI, da Silva FM, Chen J, Yu Y, Mayer J, Barreyro L, Carvajal L, Neriah DB, Roth M, van Oers J, Schaetzlein S, McMahon C, Edelmann W, Verma A, Steidl U (2015) Minimal PU.1 reduction induces a preleukemic state and promotes development of acute myeloid leukemia. Nat Med 21:1172–1181

    Article  CAS  PubMed  Google Scholar 

  98. Yang L, Rau R, Goodell MA (2015) DNMT3A in haematological malignancies. Nat Rev Cancer 15:152–165

    Article  CAS  PubMed  Google Scholar 

  99. Schoofs T, Rohde C, Hebestreit K, Klein HU, Göllner S, Schulze I, Lerdrup M, Dietrich N, Agrawal-Singh S, Witten A, Stoll M, Lengfelder E, Hofmann WK, Schlenke P, Büchner T, Hansen K, Berdel WE, Rosenbauer F, Dugas M, Müller-Tidow C (2013) DNA methylation changes are a late event in acute promyelocytic leukemia and coincide with loss of transcription factor binding. Blood 121:178–187

    Article  CAS  PubMed  Google Scholar 

  100. Di Croce L, Raker VA, Corsaro M, Fazi F, Fanelli M, Faretta M, Fuks F, Lo Coco F, Kouzarides T, Nervi C, Minucci S, Pelicci PG (2002) Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 295:1079–1082

    Article  PubMed  Google Scholar 

  101. Liu S, Shen T, Huynh L, Klisovic MI, Rush LJ, Ford JL, Yu J, Becknell B, Li Y, Liu C, Vukosavljevic T, Whitman SP, Chang KS, Byrd JC, Perrotti D, Plass C, Marcucci G (2005) Interplay of RUNX1/MTG8 and DNA methyltransferase 1 in acute myeloid leukemia. Cancer Res 65:1277–1284

    Article  CAS  PubMed  Google Scholar 

  102. Benetatos L, Vartholomatos G (2013) MicroRNAs mark in the MLL-rearranged leukemia. Ann Hematol 92:1439–1450

    Article  CAS  PubMed  Google Scholar 

  103. Risner LE, Kuntimaddi A, Lokken AA, Achille NJ, Birch NW, Schoenfelt K, Bushweller JH, Zeleznik-Le NJ (2013) Functional specificity of CpG DNA-binding CXXC domains in mixed lineage leukemia. J Biol Chem 288:29901–29910

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Deveau AP, Forrester AM, Coombs AJ, Wagner GS, Grabher C, Chute IC, Léger D, Mingay M, Alexe G, Rajan V, Liwski R, Hirst M, Steigmaier K, Lewis SM, Look AT, Berman JN (2015) Epigenetic therapy restores normal hematopoiesis in a zebrafish model of NUP98-HOXA9-induced myeloid disease. Leukemia 29:2086–2097

    Article  CAS  PubMed  Google Scholar 

  105. Beerman I, Bhattacharya D, Zandi S, Sigvardsson M, Weissman IL, Bryder D, Rossi DJ (2010) Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion. Proc Natl Acad Sci U S A 107:5465–5470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Beerman I, Bock C, Garrison BS, Smith ZD, Gu H, Meissner A, Rossi DJ (2013) Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging. Cell Stem Cell 12:413–425

    Article  CAS  PubMed  Google Scholar 

  107. Beerman I, Rossi DJ (2015) Epigenetic control of stem cell potential during homeostasis, aging, and disease. Cell Stem Cell 16:613–625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Zhou T, Hasty P, Walter CA, Bishop AJ, Scott LM, Rebel VI (2013) Myelodysplastic syndrome: an inability to appropriately respond to damaged DNA? Exp Hematol 41:665–674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Benetatos L, Hatzimichael E, Londin E, Vartholomatos G, Loher P, Rigoutsos I, Briasoulis E (2013) The microRNAs within the DLK1-DIO3 genomic region: involvement in disease pathogenesis. Cell Mol Life Sci 70:795–814

    Article  CAS  PubMed  Google Scholar 

  110. Marcucci G, Mrózek K, Radmacher MD, Garzon R, Bloomfield CD (2011) The prognostic and functional role of microRNAs in acute myeloid leukemia. Blood 117:1121–1129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Song SJ, Pandolfi PP (2014) MicroRNAs in the pathogenesis of myelodysplastic syndromes and myeloid leukaemia. Curr Opin Hematol 21:276–282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Garzon R, Liu S, Fabbri M, Liu Z, Heaphy CE, Callegari E, Schwind S, Pang J, Yu J, Muthusamy N, Havelange V, Volinia S, Blum W, Rush LJ, Perrotti D, Andreeff M, Bloomfield CD, Byrd JC, Chan K, Wu LC, Croce CM, Marcucci G (2009) MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1. Blood 113:6411–6418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Bernot KM, Nemer JS, Santhanam R, Liu S, Zorko NA, Whitman SP, Dickerson KE, Zhang M, Yang X, McConnell KK, Ahmed EH, Muñoz MR, Siebenaler RF, Marcucci GG, Mundy-Bosse BL, Brook DL, Garman S, Dorrance AM, Zhang X, Zhang J, Lee RJ, Blum W, Caligiuri MA, Marcucci G (2013) Eradicating acute myeloid leukemia in a Mll(PTD/wt):Flt3(ITD/wt) murine model: a path to novel therapeutic approaches for human disease. Blood 122:3778–3783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Benetatos L, Hatzimichael E (2014) Delta-like homologue 1 and its role in the bone marrow niche and hematologic malignancies. Clin Lymphoma Myeloma Leuk 14:451–455

    Article  PubMed  Google Scholar 

  115. Cogle CR, Saki N, Khodadi E, Li J, Shahjahani M, Azizidoost S (2015) Bone marrow niche in the myelodysplastic syndromes. Leuk Res 39:1020–1027

    Article  PubMed  Google Scholar 

  116. Lin SP, Chiu FY, Wang Y, Yen ML, Kao SY, Hung SC (2014) RB maintains quiescence and prevents premature senescence through upregulation of DNMT1 in mesenchymal stromal cells. Stem Cell Rep 3:975–986

    Article  CAS  Google Scholar 

  117. Zou J, Hong Y, Tong Y, Wei J, Qin Y, Shao S, Wang C, Zhou K (2015) Sonic hedgehog produced by bone marrow-derived mesenchymal stromal cells supports cell survival in myelodysplastic syndrome. Stem Cells Int 2015:957502

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  118. Zou J, Zhou Z, Wan L, Tong Y, Qin Y, Wang C, Zhou K (2015) Targeting the sonic hedgehog-Gli1 pathway as a potential new therapeutic strategy for myelodysplastic syndromes. PLoS One 10:e0136843

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Miraki-Moud F, Anjos-Afonso F, Hodby KA, Griessinger E, Rosignoli G, Lillington D, Jia L, Davies JK, Cavenagh J, Smith M, Oakervee H, Agrawal S, Gribben JG, Bonnet D, Taussig DC (2013) Acute myeloid leukemia does not deplete normal hematopoietic stem cells but induces cytopenias by impeding their differentiation. Proc Natl Acad Sci U S A 110:13576–13581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Ye M, Zhang H, Yang H, Koche R, Staber PB, Cusan M, Levantini E, Welner RS, Bach CS, Zhang J, Krivtsov AV, Armstrong SA, Tenen DG (2015) Hematopoietic differentiation is required for initiation of acute myeloid leukemia. Cell Stem Cell 17:611–623

    Article  CAS  PubMed  Google Scholar 

  121. Gonzalo S, Jaco I, Fraga MF, Chen T, Li E, Esteller M, Blasco MA (2006) DNA methyltransferases control telomere length and telomere recombination in mammalian cells. Nat Cell Biol 8:416–424

    Article  CAS  PubMed  Google Scholar 

  122. Colla S, Ong DS, Ogoti Y, Marchesini M, Mistry NA, Clise-Dwyer K, Ang SA, Storti P, Viale A, Giuliani N, Ruisaard K, Ganan Gomez I, Bristow CA, Estecio M, Weksberg DC, Ho YW, Hu B, Genovese G, Pettazzoni P, Multani AS, Jiang S, Hua S, Ryan MC, Carugo A, Nezi L, Wei Y, Yang H, D’Anca M, Zhang L, Gaddis S, Gong T, Horner JW, Heffernan TP, Jones P, Cooper LJ, Liang H, Kantarjian H, Wang YA, Chin L, Bueso-Ramos C, Garcia-Manero G, DePinho RA (2015) Telomere dysfunction drives aberrant hematopoietic differentiation and myelodysplastic syndrome. Cancer Cell 27:644–657

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Jung N, Dai B, Gentles AJ, Majeti R, Feinberg AP (2015) An LSC epigenetic signature is largely mutation independent and implicates the HOXA cluster in AML pathogenesis. Nat Commun 6:8489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Yu J, Peng Y, Wu LC, Xie Z, Deng Y, Hughes T, He S, Mo X, Chiu M, Wang QE, He X, Liu S, Grever MR, Chan KK, Liu Z (2013) Curcumin down-regulates DNA methyltransferase 1 and plays an anti-leukemic role in acute myeloid leukemia. PLoS One 8:e55934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Vispé S, Deroide A, Davoine E, Desjobert C, Lestienne F, Fournier L, Novosad N, Bréand S, Besse J, Busato F, Tost J, De Vries L, Cussac D, Riond J, Arimondo PB (2015) Consequences of combining siRNA-mediated DNA methyltransferase 1 depletion with 5-aza-2′-deoxycytidine in human leukemic KG1 cells. Oncotarget 6:15265–15282

    Article  PubMed  PubMed Central  Google Scholar 

  126. Kode A, Manavalan JS, Mosialou I, Bhagat G, Rathinam CV, Luo N, Khiabanian H, Lee A, Murty VV, Friedman R, Brum A, Park D, Galili N, Mukherjee S, Teruya-Feldstein J, Raza A, Rabadan R, Berman E, Kousteni S (2014) Leukaemogenesis induced by an activating β-catenin mutation in osteoblasts. Nature 506:240–244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Craddock C, Quek L, Goardon N, Freeman S, Siddique S, Raghavan M, Aztberger A, Schuh A, Grimwade D, Ivey A, Virgo P, Hills R, McSkeane T, Arrazi J, Knapper S, Brookes C, Davies B, Price A, Wall K, Griffiths M, Cavenagh J, Majeti R, Weissman I, Burnett A, Vyas P (2013) Azacitidine fails to eradicate leukemic stem/progenitor cell populations in patients with acute myeloid leukemia and myelodysplasia. Leukemia 27:1028–1036

    Article  CAS  PubMed  Google Scholar 

  128. Pollyea DA, Gutman JA, Gore L, Smith CA, Jordan CT (2014) Targeting acute myeloid leukemia stem cells: a review and principles for the development of clinical trials. Haematologica 99:1277–1284

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Schepers K, Campbell TB, Passegué E (2015) Normal and leukemic stem cell niches: insights and therapeutic opportunities. Cell Stem Cell 16:254–267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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LB and GV collected data and wrote the manuscript.

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  1. Blood Bank, Preveza General Hospital, Preveza, Greece

    Leonidas Benetatos

  2. Molecular Biology Laboratory, Ioannina University Hospital, Ioannina, Greece

    Georgios Vartholomatos

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  1. Leonidas Benetatos
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Correspondence to Leonidas Benetatos.

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Benetatos, L., Vartholomatos, G. On the potential role of DNMT1 in acute myeloid leukemia and myelodysplastic syndromes: not another mutated epigenetic driver. Ann Hematol 95, 1571–1582 (2016). https://doi.org/10.1007/s00277-016-2636-8

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