Epigenetic Mechanisms in AML – A Target for Therapy

  • Yasuhiro Oki
  • Jean - Pierre J. Issa
Part of the Cancer Treatment and Research book series (CTAR, volume 145)


Epigenetics refers to a stable, mitotically perpetuated regulatory mechanism of gene expression without an alteration of the coding sequence. Epigenetic mechanisms include DNA methylation and histone tail modifications. Epigenetic regulation is part of physiologic development and becomes abnormal in neoplasia, where silencing of critical genes by DNA methylation or histone deacetylation can contribute to leukemogenesis as an alternative to deletion or loss-of-function mutation. In acute myelogenous leukemia (AML), aberrant DNA methylation can be observed in multiple functionally relevant genes such as p15, p73, E-cadherin, ID4, RARβ2. Abnormal activities of histone tail-modifying enzymes have also been seen in AML, frequently as a direct result of chromosomal translocations. It is now clear that these epigenetic changes play a significant role in development and progression of AML, and thus constitute important targets of therapy. The aim of targeting epigenetic effector protein or “epigenetic therapy” is to reverse epigenetic silencing and reactivate various genes to induce a therapeutic effect such as differentiation, growth arrest, or apoptosis. Recent clinical studies have shown the relative safety and efficacy of such epigenetic therapies.


HDAC Inhibitor Acute Myelogenous Leukemia DNMT Inhibitor Epigenetic Therapy Acute Myelogenous Leukemia Patient 
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.


  1. 1.
    Adams RL, Burdon RH. DNA methylation in eukaryotes. CRC Crit Rev Biochem. 1982;13(4):349–354.Google Scholar
  2. 2.
    Alland L, Muhle R, Hou H, Jr, et al. Role for N-CoR and histone deacetylase in Sin3-mediated transcriptional repression. Nature. 1997;387(6628):49–55.PubMedCrossRefGoogle Scholar
  3. 3.
    Aoki E, Ohashi H, Uchida T, Murate T, Saito H, Kinoshita T. Expression levels of DNA methyltransferase genes do not correlate with p15INK4B gene methylation in myelodysplastic syndromes. Leukemia. 2003;17(9):1903–1904.PubMedCrossRefGoogle Scholar
  4. 4.
    Aparicio A, Weber JS. Review of the clinical experience with 5-azacytidine and 5-aza-2′-deoxycytidine in solid tumors. Curr Opin Investig Drugs. 2002;3(4):627–633.PubMedGoogle Scholar
  5. 5.
    Arnould C, Philippe C, Bourdon V, Gr goire MJ, Berger R, Jonveaux P. The signal transducer and activator of transcription STAT5b gene is a new partner of retinoic acid receptor alpha in acute promyelocytic-like leukaemia. Hum Mol Genet. 1999;8(9):1741–1749.PubMedCrossRefGoogle Scholar
  6. 6.
    Austin GE, Zhao WG, Regmi A, Lu JP, Braun J. Identification of an upstream enhancer containing an AML1 site in the human myeloperoxidase (MPO) gene. Leuk Res. 1998;22(11):1037–1048.PubMedCrossRefGoogle Scholar
  7. 7.
    Bachman KE, Park BH, Rhee I, et al. Histone modifications and silencing prior to DNA methylation of a tumor suppressor gene. Cancer Cell. 2003;3(1):89–95.PubMedCrossRefGoogle Scholar
  8. 8.
    Bannister AJ, Miska EA, Gorlich D, Kouzarides T. Acetylation of importin-alpha nuclear import factors by CBP/p300. Curr Biol. 2000;10(8):467–470.PubMedCrossRefGoogle Scholar
  9. 9.
    Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–297.PubMedCrossRefGoogle Scholar
  10. 10.
    Bellet RE, Mastrangelo MJ, Engstrom PF, Strawitz JG, Weiss AJ, Yarbro JW. Clinical trial with subcutaneously administered 5-azacytidine (NSC-102816). Cancer Chemother Rep. 1974;58(2):217–222.PubMedGoogle Scholar
  11. 11.
    Bender CM, Zingg JM, Jones PA. DNA methylation as a target for drug design. Pharm Res. 1998;15(2):175–187.PubMedCrossRefGoogle Scholar
  12. 12.
    Bird A. DNA methylation patterns and epigenetic memory. Genes Dev. 2002;16(1):6–21.PubMedCrossRefGoogle Scholar
  13. 13.
    Bird AP. CpG-rich islands and the function of DNA methylation. Nature. 1986;321(6067):209–213.PubMedCrossRefGoogle Scholar
  14. 14.
    Blander G, Zalle N, Daniely Y, Taplick J, Gray MD, Oren M. DNA damage-induced translocation of the Werner helicase is regulated by acetylation. J Biol Chem. 2002;277(52):50934–50940.PubMedCrossRefGoogle Scholar
  15. 15.
    Borrow J, Stanton VP, Jr., Andresen JM, et al. The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein. Nat Genet. 1996;14(1):33–41.PubMedCrossRefGoogle Scholar
  16. 16.
    Bruniquel D, Schwartz RH. Selective, stable demethylation of the interleukin-2 gene enhances transcription by an active process. Nat Immunol. 2003;4(3):235–240.PubMedCrossRefGoogle Scholar
  17. 17.
    Bullinger L, Dohner K, Bair E, et al. Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia. N Engl J Med. 2004;350(16):1605–1616.PubMedCrossRefGoogle Scholar
  18. 18.
    Caligiuri MA, Strout MP, Lawrence D, et al. Rearrangement of ALL1 (MLL) in acute myeloid leukemia with normal cytogenetics. Cancer Res. 1998;58(1):55–59.PubMedGoogle Scholar
  19. 19.
    Caligiuri MA, Strout MP, Oberkircher AR, Yu F, de la Chapelle A, Bloomfield CD. The partial tandem duplication of ALL1 in acute myeloid leukemia with normal cytogenetics or trisomy 11 is restricted to one chromosome. Proc Natl Acad Sci USA. 1997;94(8):3899–3902.PubMedCrossRefGoogle Scholar
  20. 20.
    Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet. 1999;21(1):103–107.PubMedCrossRefGoogle Scholar
  21. 21.
    Chedin F, Lieber MR, Hsieh CL. The DNA methyltransferase-like protein DNMT3L stimulates de novo methylation by Dnmt3a. Proc Natl Acad Sci USA. 2002;99(26):16916–16921.PubMedCrossRefGoogle Scholar
  22. 22.
    Chen JD, Evans RM. A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature. 1995;377(6548):454–457.PubMedCrossRefGoogle Scholar
  23. 23.
    Chen JD, Umesono K, Evans RM. SMRT isoforms mediate repression and anti-repression of nuclear receptor heterodimers. Proc Natl Acad Sci USA. 1996;93(15):7567–7571.PubMedCrossRefGoogle Scholar
  24. 24.
    Chen RZ, Pettersson U, Beard C, Jackson-Grusby L, Jaenisch R. DNA hypomethylation leads to elevated mutation rates. Nature. 1998;395(6697):89–93.PubMedCrossRefGoogle Scholar
  25. 25.
    Chen Z, Brand NJ, Chen A, et al. Fusion between a novel Kruppel-like zinc finger gene and the retinoic acid receptor-alpha locus due to a variant t(11;17) translocation associated with acute promyelocytic leukaemia. EMBO J. 1993;12(3):1161–1167.PubMedGoogle Scholar
  26. 26.
    Chim CS, Wong AS, Kwong YL. Epigenetic dysregulation of the Jak/STAT pathway by frequent aberrant methylation of SHP1 but not SOCS1 in acute leukaemias. Ann Hematol. 2004;83(8):527–532.PubMedCrossRefGoogle Scholar
  27. 27.
    Chim CS, Wong AS, Kwong YL. Epigenetic inactivation of INK4/CDK/RB cell cycle pathway in acute leukemias. Ann Hematol. 2003;82(12):738–742.PubMedCrossRefGoogle Scholar
  28. 28.
    Christiansen DH, Andersen MK, Pedersen-Bjergaard J. Methylation of p15INK4B is common, is associated with deletion of genes on chromosome arm 7q and predicts a poor prognosis in therapy-related myelodysplasia and acute myeloid leukemia. Leukemia. 2003;17(9):1813–1819.PubMedCrossRefGoogle Scholar
  29. 29.
    Christman JK. 5-Azacytidine and 5-aza-2′-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. Oncogene. 2002;21(35):5483–5495.PubMedCrossRefGoogle Scholar
  30. 30.
    Cihak A, Vesely J. Prolongation of the lag period preceding the enhancement of thymidine and thymidylate kinase activity in regenerating rat liver by 5-azacytidine. Biochem Pharmacol. 1972;21(24):3257–3265.PubMedCrossRefGoogle Scholar
  31. 31.
    Cihak A, Vesely J, Skoda J. Azapyrimidine nucleosides: metabolism and inhibitory mechanisms. Adv Enzyme Regul. 1985;24:335–354.PubMedCrossRefGoogle Scholar
  32. 32.
    Cimino G, Moir DT, Canaani O, et al. Cloning of ALL-1, the locus involved in leukemias with the t(4;11)(q21;q23), t(9;11)(p22;q23), and t(11;19)(q23;p13) chromosome translocations. Cancer Res. 1991;51(24):6712–6714.PubMedGoogle Scholar
  33. 33.
    Cinatl J, Jr, Cinatl J, Driever PH, et al. Sodium valproate inhibits in vivo growth of human neuroblastoma cells. Anticancer Drugs. 1997;8(10):958–963.PubMedCrossRefGoogle Scholar
  34. 34.
    Cohen HY, Lavu S, Bitterman KJ, et al. Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis. Mol Cell. 2004;13(5):627–638.PubMedCrossRefGoogle Scholar
  35. 35.
    Creusot F, Acs G, Christman JK. Inhibition of DNA methyltransferase and induction of Friend erythroleukemia cell differentiation by 5-azacytidine and 5-aza-2′-deoxycytidine. J Biol Chem. 1982;257(4):2041–2048.PubMedGoogle Scholar
  36. 36.
    Cross SH, Meehan RR, Nan X, Bird A. A component of the transcriptional repressor MeCP1 shares a motif with DNA methyltransferase and HRX proteins. Nat Genet. 1997;16(3):256–259.PubMedCrossRefGoogle Scholar
  37. 37.
    Daskalakis M, Nguyen TT, Nguyen C, et al. Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2′-deoxycytidine (decitabine) treatment. Blood. 2002;100(8):2957–2964.PubMedCrossRefGoogle Scholar
  38. 38.
    De Marzo AM, Marchi VL, Yang ES, Veeraswamy R, Lin X, Nelson WG. Abnormal regulation of DNA methyltransferase expression during colorectal carcinogenesis. Cancer Res. 1999;59(16):3855–3860.PubMedGoogle Scholar
  39. 39.
    DiMartino JF, Ayton PM, Chen EH, Naftzger CC, Young BD, Cleary ML. The AF10 leucine zipper is required for leukemic transformation of myeloid progenitors by MLL-AF10. Blood. 2002;99(10):3780–3785.PubMedCrossRefGoogle Scholar
  40. 40.
    DiMartino JF, Miller T, Ayton PM, et al. A carboxy-terminal domain of ELL is required and sufficient for immortalization of myeloid progenitors by MLL-ELL. Blood. 2000;96(12):3887–3893.PubMedGoogle Scholar
  41. 41.
    Djabali M, Selleri L, Parry P, Bower M, Young BD, Evans GA. A trithorax-like gene is interrupted by chromosome 11q23 translocations in acute leukaemias. Nat Genet. 1992;2(2):113–118.PubMedCrossRefGoogle Scholar
  42. 42.
    Durst KL, Hiebert SW. Role of RUNX family members in transcriptional repression and gene silencing. Oncogene 2004;23(24):4220–4224.PubMedCrossRefGoogle Scholar
  43. 43.
    Eads CA, Danenberg KD, Kawakami K, Saltz LB, Danenberg PV, Laird PW. CpG island hypermethylation in human colorectal tumors is not associated with DNA methyltransferase overexpression. Cancer Res. 1999;59(10):2302–2306.PubMedGoogle Scholar
  44. 44.
    Eguchi M, Eguchi-Ishimae M, Greaves M. The small oligomerization domain of gephyrin converts MLL to an oncogene. Blood. 2004;103(10):3876–3882.PubMedCrossRefGoogle Scholar
  45. 45.
    Ekmekci CG, Gutierrez MI, Siraj AK, Ozbek U, Bhatia K. Aberrant methylation of multiple tumor suppressor genes in acute myeloid leukemia. Am J Hematol. 2004;77(3):233–240.PubMedCrossRefGoogle Scholar
  46. 46.
    el-Deiry WS, Nelkin BD, Celano P, et al. High expression of the DNA methyltransferase gene characterizes human neoplastic cells and progression stages of colon cancer. Proc Natl Acad Sci USA. 1991;88(8):3470–3474.PubMedCrossRefGoogle Scholar
  47. 47.
    Ernst P, Wang J, Huang M, Goodman RH, Korsmeyer SJ. MLL and CREB bind cooperatively to the nuclear coactivator CREB-binding protein. Mol Cell Biol. 2001;21(7):2249–2258.PubMedCrossRefGoogle Scholar
  48. 48.
    Esteller M, Guo M, Moreno V, et al. Hypermethylation-associated inactivation of the cellular retinol-binding-protein 1 gene in human cancer. Cancer Res. 2002;62(20):5902–5905.PubMedGoogle Scholar
  49. 49.
    Fair K, Anderson M, Bulanova E, Mi H, Tropschug M, Diaz MO. Protein interactions of the MLL PHD fingers modulate MLL target gene regulation in human cells. Mol Cell Biol. 2001;21(10):3589–3597.PubMedCrossRefGoogle Scholar
  50. 50.
    Feinberg AP, Vogelstein B. Hypomethylation of ras oncogenes in primary human cancers. Biochem Biophys Res Commun. 1983;111(1):47–54.PubMedCrossRefGoogle Scholar
  51. 51.
    Felsenfeld G, Groudine M. Controlling the double helix. Nature. 2003;421(6921):448–453.PubMedCrossRefGoogle Scholar
  52. 52.
    Fuino L, Bali P, Wittmann S, et al. Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B. Mol Cancer Ther. 2003;2(10):971–984.PubMedGoogle Scholar
  53. 53.
    Fuks F, Burgers WA, Brehm A, Hughes-Davies L, Kouzarides T. DNA methyltransferase Dnmt1 associates with histone deacetylase activity. Nat Genet. 2000;24(1):88–91.PubMedCrossRefGoogle Scholar
  54. 54.
    Galm O, Wilop S, Luders C, et al. Clinical implications of aberrant DNA methylation patterns in acute myelogenous leukemia. Ann Hematol. 2005;84 Suppl 13:39–46.PubMedCrossRefGoogle Scholar
  55. 55.
    Garcia-Manero G, Kantarjian H, Sanchez-Gonzalez B, et al. Final results of a phase I/II study of the combination of the hypomethylating agent 5-aza-2′-deoxycytidine (DAC) and the histone deacetylase inhibitor valproic acid (VPA) in patients with leukemia. Blood. 2005;106(11):(abstr 408).Google Scholar
  56. 56.
    Garcia-Manero G, Yang H, Sanchez-Gonzalez B, et al. Final results of a phase I study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA), in patients with leukemia and myelodysplastic syndrome. Blood. 2005;106(11):(abstr 2801).Google Scholar
  57. 57.
    Girault I, Tozlu S, Lidereau R, Bieche I. Expression analysis of DNA methyltransferases 1, 3A, and 3B in sporadic breast carcinomas. Clin Cancer Res. 2003;9(12):4415–4422.PubMedGoogle Scholar
  58. 58.
    Glover AB, Leyland-Jones BR, Chun HG, Davies B, Hoth DF. Azacitidine: 10 years later. Cancer Treat Rep. 1987;71(7–8):737–746.PubMedGoogle Scholar
  59. 59.
    Gore S, Baylin SB, Dauses T, et al. Changes in promoter methylation and gene expression in patients with MDS and MDS-AML treated with 5-azacitidine and sodium phenylbutyrate. Blood. 2004;104(11):(abstr 469).Google Scholar
  60. 60.
    Gottlicher M, Minucci S, Zhu P, et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 2001;20(24):6969–6978.PubMedCrossRefGoogle Scholar
  61. 61.
    Grignani F, De Matteis S, Nervi C, et al. Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukaemia. Nature. 1998;391(6669):815–818.PubMedCrossRefGoogle Scholar
  62. 62.
    Guo SX, Taki T, Ohnishi H, et al. Hypermethylation of p16 and p15 genes and RB protein expression in acute leukemia. Leuk Res. 2000;24(1):39–46.PubMedCrossRefGoogle Scholar
  63. 63.
    Haggarty SJ, Koeller KM, Wong JC, Grozinger CM, Schreiber SL. Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. Proc Natl Acad Sci USA. 2003;100(8):4389–4394.PubMedCrossRefGoogle Scholar
  64. 64.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70.PubMedCrossRefGoogle Scholar
  65. 65.
    He LZ, Guidez F, Tribioli C, et al. Distinct interactions of PML-RARalpha and PLZF-RARalpha with co-repressors determine differential responses to RA in APL. Nat Genet. 1998;18(2):126–135.PubMedCrossRefGoogle Scholar
  66. 66.
    Heinzel T, Lavinsky RM, Mullen TM, et al. A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression. Nature. 1997;387(6628):43–48.PubMedCrossRefGoogle Scholar
  67. 67.
    Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003;349(21):2042–2054.PubMedCrossRefGoogle Scholar
  68. 68.
    Herman JG, Civin CI, Issa JP, Collector MI, Sharkis SJ, Baylin SB. Distinct patterns of inactivation of p15INK4B and p16INK4A characterize the major types of hematological malignancies. Cancer Res. 1997;57(5):837–841.PubMedGoogle Scholar
  69. 69.
    Herman JG, Latif F, Weng Y, et al. Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc Natl Acad Sci USA. 1994;91(21):9700–9704.PubMedCrossRefGoogle Scholar
  70. 70.
    Hiebert SW, Sun W, Davis JN, et al. The t(12;21) translocation converts AML-1B from an activator to a repressor of transcription. Mol Cell Biol. 1996;16(4):1349–1355.PubMedGoogle Scholar
  71. 71.
    Horlein AJ, Naar AM, Heinzel T, et al. Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature. 1995;377(6548):397–404.PubMedCrossRefGoogle Scholar
  72. 72.
    Hubbert C, Guardiola A, Shao R, et al. HDAC6 is a microtubule-associated deacetylase. Nature. 2002;417(6887):455–458.PubMedCrossRefGoogle Scholar
  73. 73.
    Ibanez V, Sharma A, Buonamici S, et al. AML1-ETO decreases ETO-2 (MTG16) interactions with nuclear receptor corepressor, an effect that impairs granulocyte differentiation. Cancer Res. 2004;64(13):4547–4554.PubMedCrossRefGoogle Scholar
  74. 74.
    Ida K, Kitabayashi I, Taki T, et al. Adenoviral E1A-associated protein p300 is involved in acute myeloid leukemia with t(11;22)(q23;q13). Blood. 1997;90(12):4699–4704.PubMedGoogle Scholar
  75. 75.
    Issa JP. Aging, DNA methylation and cancer. Crit Rev Oncol Hematol. 1999;32(1):31–43.PubMedCrossRefGoogle Scholar
  76. 76.
    Issa JP. CpG island methylator phenotype in cancer. Nat Rev Cancer. 2004;4(12):988–993.PubMedCrossRefGoogle Scholar
  77. 77.
    Issa JP, Garcia-Manero G, Giles FJ, et al. Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2′-deoxycytidine (decitabine) in hematopoietic malignancies. Blood. 2004;103(5):1635–1640.PubMedCrossRefGoogle Scholar
  78. 78.
    Issa JP, Gharibyan V, Cortes J, et al. Phase II study of low-dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate. J Clin Oncol. 2005;23(17):3948–3956.PubMedCrossRefGoogle Scholar
  79. 79.
    Issa JP, Vertino PM, Wu J, et al. Increased cytosine DNA-methyltransferase activity during colon cancer progression. J Natl Cancer Inst. 1993;85(15):1235–1240.PubMedCrossRefGoogle Scholar
  80. 80.
    Iwai M, Kiyoi H, Ozeki K, et al. Expression and methylation status of the FHIT gene in acute myeloid leukemia and myelodysplastic syndrome. Leukemia. 2005;19(8):1367–1375.PubMedCrossRefGoogle Scholar
  81. 81.
    Jenuwein T, Allis CD. Translating the histone code. Science. 2001;293(5532):1074–1080.PubMedCrossRefGoogle Scholar
  82. 82.
    Jin F, Dowdy SC, Xiong Y, Eberhardt NL, Podratz KC, Jiang SW. Up-regulation of DNA methyltransferase 3B expression in endometrial cancers. Gynecol Oncol. 2005;96(2):531–538.PubMedCrossRefGoogle Scholar
  83. 83.
    Johnstone RW, Licht JD. Histone deacetylase inhibitors in cancer therapy: is transcription the primary target? Cancer Cell. 2003;4(1):13–8.PubMedCrossRefGoogle Scholar
  84. 84.
    Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002;3(6):415–428.PubMedGoogle Scholar
  85. 85.
    Jones PA, Taylor SM. Cellular differentiation, cytidine analogs and DNA methylation. Cell. 1980;20(1):85–93.PubMedCrossRefGoogle Scholar
  86. 86.
    Kaminskas E, Farrell A, Abraham S, et al. Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes. Clin Cancer Res. 2005;11(10):3604–3608.PubMedCrossRefGoogle Scholar
  87. 87.
    Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006;106(8):1794–1803.Google Scholar
  88. 88.
    Kantarjian H, Oki Y, Garcia-Manero G, et al. Results of a randomized study of three schedules of low-dose decitabine in higher risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood. 2007;109(1):52–57.Google Scholar
  89. 89.
    Kantarjian HM, O'Brien SM, Estey E, et al. Decitabine studies in chronic and acute myelogenous leukemia. Leukemia. 1997;11(suppl. 1):S35–36.PubMedGoogle Scholar
  90. 90.
    Khorasanizadeh S. The nucleosome: from genomic organization to genomic regulation. Cell. 2004;116(2):259–272.PubMedCrossRefGoogle Scholar
  91. 91.
    Kondo Y, Issa JP. Epigenetic changes in colorectal cancer. Cancer Metastasis Rev. 2004;23(1–2):29–39.PubMedCrossRefGoogle Scholar
  92. 92.
    Kuendgen A, Strupp C, Aivado M, et al. Treatment of myelodysplastic syndromes with valproic acid alone or in combination with all-trans retinoic acid. Blood. 2004;104(5):1266–1269.PubMedCrossRefGoogle Scholar
  93. 93.
    Kurokawa R, Soderstrom M, Horlein A, et al. Polarity-specific activities of retinoic acid receptors determined by a co-repressor. Nature. 1995;377(6548):451–454.PubMedCrossRefGoogle Scholar
  94. 94.
    Laherty CD, Yang WM, Sun JM, Davie JR, Seto E, Eisenman RN. Histone deacetylases associated with the mSin3 corepressor mediate mad transcriptional repression. Cell. 1997;89(3):349–356.PubMedCrossRefGoogle Scholar
  95. 95.
    Lasa A, Carnicer MJ, Aventin A, et al. MEIS 1 expression is downregulated through promoter hypermethylation in AML1-ETO acute myeloid leukemias. Leukemia. 2004;18(7):1231–1237.PubMedCrossRefGoogle Scholar
  96. 96.
    Lavau C, Du C, Thirman M, Zeleznik-Le N. Chromatin-related properties of CBP fused to MLL generate a myelodysplastic-like syndrome that evolves into myeloid leukemia. EMBO J. 2000;19(17):4655–4664.PubMedCrossRefGoogle Scholar
  97. 97.
    Lavau C, Luo RT, Du C, Thirman MJ. Retrovirus-mediated gene transfer of MLL-ELL transforms primary myeloid progenitors and causes acute myeloid leukemias in mice. Proc Natl Acad Sci USA. 2000;97(20):10984–10989.PubMedCrossRefGoogle Scholar
  98. 98.
    Lavau C, Szilvassy SJ, Slany R, Cleary ML. Immortalization and leukemic transformation of a myelomonocytic precursor by retrovirally transduced HRX-ENL. EMBO J. 1997;16(14):4226–4237.PubMedCrossRefGoogle Scholar
  99. 99.
    Lee PJ, Washer LL, Law DJ, Boland CR, Horon IL, Feinberg AP. Limited up-regulation of DNA methyltransferase in human colon cancer reflecting increased cell proliferation. Proc Natl Acad Sci USA. 1996;93(19):10366–10370.PubMedCrossRefGoogle Scholar
  100. 100.
    Lee TI, Jenner RG, Boyer LA, et al. Control of developmental regulators by Polycomb in human embryonic stem cells. Cell. 2006;125(2):301–313.PubMedCrossRefGoogle Scholar
  101. 101.
    Levi JA, Wiernik PH. A comparative clinical trial of 5-azacytidine and guanazole in previously treated adults with acute nonlymphocytic leukemia. Cancer. 1976;38(1):36–41.PubMedCrossRefGoogle Scholar
  102. 102.
    Li E. Chromatin modification and epigenetic reprogramming in mammalian development. Nat Rev Genet. 2002;3(9):662–673.PubMedCrossRefGoogle Scholar
  103. 103.
    Li LH, Olin EJ, Buskirk HH, Reineke LM. Cytotoxicity and mode of action of 5-azacytidine on L1210 leukemia. Cancer Res. 1970;30(11):2760–2769.PubMedGoogle Scholar
  104. 104.
    Li LH, Olin EJ, Fraser TJ, Bhuyan BK. Phase specificity of 5-azacytidine against mammalian cells in tissue culture. Cancer Res. 1970;30(11):2770–2775.PubMedGoogle Scholar
  105. 105.
    Lin RJ, Nagy L, Inoue S, Shao W, Miller WH, Jr, Evans RM. Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature. 1998;391(6669):811–814.PubMedCrossRefGoogle Scholar
  106. 106.
    Lindemann RK, Gabrielli B, Johnstone RW. Histone-deacetylase inhibitors for the treatment of cancer. Cell Cycle. 2004;3(6):779–788.PubMedGoogle Scholar
  107. 107.
    Luo RT, Lavau C, Du C, et al. The elongation domain of ELL is dispensable but its ELL-associated factor 1 interaction domain is essential for MLL-ELL-induced leukemogenesis. Mol Cell Biol. 2001;21(16):5678–5687.PubMedCrossRefGoogle Scholar
  108. 108.
    Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK. Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer. 2001;1(3):194–202.PubMedCrossRefGoogle Scholar
  109. 109.
    Marks PA, Rifkind RA, Richon VM, Breslow R. Inhibitors of histone deacetylase are potentially effective anticancer agents. Clin Cancer Res. 2001;7(4):759–60.PubMedGoogle Scholar
  110. 110.
    Melki JR, Vincent PC, Clark SJ. Cancer-specific region of hypermethylation identified within the HIC1 putative tumour suppressor gene in acute myeloid leukaemia. Leukemia. 1999;13(6):877–883.PubMedCrossRefGoogle Scholar
  111. 111.
    Melki JR, Vincent PC, Clark SJ. Concurrent DNA hypermethylation of multiple genes in acute myeloid leukemia. Cancer Res. 1999;59(15):3730–3740.PubMedGoogle Scholar
  112. 112.
    Meyers S, Downing JR, Hiebert SW. Identification of AML-1 and the (8;21) translocation protein (AML-1/ETO) as sequence-specific DNA-binding proteins: the runt homology domain is required for DNA binding and protein-protein interactions. Mol Cell Biol. 1993;13(10):6336–6345.PubMedGoogle Scholar
  113. 113.
    Milne TA, Briggs SD, Brock HW, et al. MLL targets SET domain methyltransferase activity to Hox gene promoters. Mol Cell. 2002;10(5):1107–1117.PubMedCrossRefGoogle Scholar
  114. 114.
    Mizuno S, Chijiwa T, Okamura T, et al. Expression of DNA methyltransferases DNMT1, 3A, and 3B in normal hematopoiesis and in acute and chronic myelogenous leukemia. Blood. 2001;97(5):1172–1179.PubMedCrossRefGoogle Scholar
  115. 115.
    Momparler RL, Rivard GE, Gyger M. Clinical trial on 5-aza-2′-deoxycytidine in patients with acute leukemia. Pharmacol Ther. 1985;30(3):277–286.PubMedCrossRefGoogle Scholar
  116. 116.
    Morgan HD, Santos F, Green K, Dean W, Reik W. Epigenetic reprogramming in mammals. Hum Mol Genet. 2005;14 Spec No 1:R47–58.CrossRefGoogle Scholar
  117. 117.
    Nakajima H, Kim YB, Terano H, Yoshida M, Horinouchi S. FR901228, a potent antitumor antibiotic, is a novel histone deacetylase inhibitor. Exp Cell Res. 1998;241(1):126–133.PubMedCrossRefGoogle Scholar
  118. 118.
    Nakamura T, Mori T, Tada S, et al. ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation. Mol Cell. 2002;10(5):1119–1128.PubMedCrossRefGoogle Scholar
  119. 119.
    Nan X, Ng HH, Johnson CA, et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature. 1998;393(6683):386–389.PubMedCrossRefGoogle Scholar
  120. 120.
    Nass SJ, Ferguson AT, El-Ashry D, Nelson WG, Davidson NE. Expression of DNA methyl-transferase (DMT) and the cell cycle in human breast cancer cells. Oncogene. 1999;18(52):7453–7461.PubMedCrossRefGoogle Scholar
  121. 121.
    Odenike OM, Alkan S, Sher D, et al. The histone deacetylase inhibitor depsipeptide has differential activity in specific cytogenetic subsets of acute myeloid leukemia (AML). Blood. 2004;104(11):(abstr 264).Google Scholar
  122. 122.
    Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999;99(3):247–257.PubMedCrossRefGoogle Scholar
  123. 123.
    Okano M, Xie S, Li E. Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nat Genet. 1998;19(3):219–220.PubMedCrossRefGoogle Scholar
  124. 124.
    Oki Y, Kantarjian H, Davis J, et al. Hypomethylation induction in MDS after treatment with decitabine at three different doses. J Clin Oncol. 2005;23(16S):(abstr 6546).Google Scholar
  125. 125.
    Olesen LH, Aggerholm A, Andersen BL, et al. Molecular typing of adult acute myeloid leukaemia: significance of translocations, tandem duplications, methylation, and selective gene expression profiling. Br J Haematol. 2005;131(4):457–467.PubMedCrossRefGoogle Scholar
  126. 126.
    Petti MC, Mandelli F, Zagonel V, et al. Pilot study of 5-aza-2′-deoxycytidine (Decitabine) in the treatment of poor prognosis acute myelogenous leukemia patients: preliminary results. Leukemia. 1993;(7 suppl. 1):36–41.Google Scholar
  127. 127.
    Piekarz RL, Robey R, Sandor V, et al. Inhibitor of histone deacetylation, depsipeptide (FR901228), in the treatment of peripheral and cutaneous T-cell lymphoma: a case report. Blood. 2001;98(9):2865–2868.PubMedCrossRefGoogle Scholar
  128. 128.
    Plass C, Yu F, Yu L, et al. Restriction landmark genome scanning for aberrant methylation in primary refractory and relapsed acute myeloid leukemia; involvement of the WIT-1 gene. Oncogene. 1999;18(20):3159–3165.PubMedCrossRefGoogle Scholar
  129. 129.
    Raffoux E, Chaibi P, Dombret H, Degos L. Valproic acid and all-trans retinoic acid for the treatment of elderly patients with acute myeloid leukemia. Haematologica. 2005;90(7):986–988.PubMedGoogle Scholar
  130. 130.
    Redner RL, Rush EA, Faas S, Rudert WA, Corey SJ. The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion. Blood. 1996;87(3):882–886.PubMedGoogle Scholar
  131. 131.
    Richards EJ, Elgin SC. Epigenetic codes for heterochromatin formation and silencing: rounding up the usual suspects. Cell 2002;108(4):489–500.PubMedCrossRefGoogle Scholar
  132. 132.
    Robertson KD. DNA methylation, methyltransferases, and cancer. Oncogene. 2001;20(24):3139–3155.PubMedCrossRefGoogle Scholar
  133. 133.
    Roman-Gomez J, Jimenez-Velasco A, et al. Promoter hypermethylation of cancer-related genes: a strong independent prognostic factor in acute lymphoblastic leukemia. Blood. 2004;104(8):2492–2498.PubMedCrossRefGoogle Scholar
  134. 134.
    Rountree MR, Bachman KE, Baylin SB. DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nat Genet. 2000;25(3): 269–277.PubMedCrossRefGoogle Scholar
  135. 135.
    Sakai T, Toguchida J, Ohtani N, Yandell DW, Rapaport JM, Dryja TP. Allele-specific hypermethylation of the retinoblastoma tumor-suppressor gene. Am J Hum Genet. 1991;48(5):880–888.PubMedGoogle Scholar
  136. 136.
    Scandura JM, Boccuni P, Cammenga J, Nimer SD. Transcription factor fusions in acute leukemia: variations on a theme. Oncogene. 2002;21(21):3422–3444.PubMedCrossRefGoogle Scholar
  137. 137.
    Schreiber SL, Bernstein BE. Signaling network model of chromatin. Cell. 2002;111(6):771–778.PubMedCrossRefGoogle Scholar
  138. 138.
    Schubeler D, MacAlpine DM, Scalzo D, et al. The histone modification pattern of active genes revealed through genome-wide chromatin analysis of a higher eukaryote. Genes Dev. 2004;18(11):1263–1271.PubMedCrossRefGoogle Scholar
  139. 139.
    Shnider BI, Baig M, Colsky J. A phase I study of 5-azacytidine (NSC-102816). J Clin Pharmacol. 1976;16(4):205–212.PubMedGoogle Scholar
  140. 140.
    Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002;20(10):2429–2440.PubMedCrossRefGoogle Scholar
  141. 141.
    Slany RK, Lavau C, Cleary ML. The oncogenic capacity of HRX-ENL requires the transcriptional transactivation activity of ENL and the DNA binding motifs of HRX. Mol Cell Biol. 1998;18(1):122–129.PubMedGoogle Scholar
  142. 142.
    So CW, Cleary ML. Common mechanism for oncogenic activation of MLL by forkhead family proteins. Blood. 2003;101(2):633–6739.PubMedCrossRefGoogle Scholar
  143. 143.
    So CW, Cleary ML. MLL-AFX requires the transcriptional effector domains of AFX to transform myeloid progenitors and transdominantly interfere with forkhead protein function. Mol Cell Biol. 2002;22(18):6542–6552.PubMedCrossRefGoogle Scholar
  144. 144.
    Speck NA. Core binding factor and its role in normal hematopoietic development. Curr Opin Hematol. 2001;8(4):192–196.PubMedCrossRefGoogle Scholar
  145. 145.
    Steuber CP, Holbrook T, Camitta B, Land VJ, Sexauer C, Krischer J. Toxicity trials of amsacrine (AMSA) and etoposide +/- azacitidine (AZ) in childhood acute non-lymphocytic leukemia (ANLL): a pilot study. Invest New Drugs. 1991;9(2):181–184.PubMedCrossRefGoogle Scholar
  146. 146.
    Strahl BD, Allis CD. The language of covalent histone modifications. Nature. 2000;403(6765):41–45.PubMedCrossRefGoogle Scholar
  147. 147.
    Suetake I, Shinozaki F, Miyagawa J, Takeshima H, Tajima S. DNMT3L stimulates the DNA methylation activity of Dnmt3a and Dnmt3b through a direct interaction. J Biol Chem. 2004;279(26):27816–27823.PubMedCrossRefGoogle Scholar
  148. 148.
    Szyf M, Bozovic V, Tanigawa G. Growth regulation of mouse DNA methyltransferase gene expression. J Biol Chem. 1991;266(16):10027–10030.PubMedGoogle Scholar
  149. 149.
    Tamaru H, Selker EU. A histone H3 methyltransferase controls DNA methylation in Neurospora crassa. Nature. 2001;414(6861):277–283.PubMedCrossRefGoogle Scholar
  150. 150.
    Tkachuk DC, Kohler S, Cleary ML. Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias. Cell. 1992;71(4):691–700.PubMedCrossRefGoogle Scholar
  151. 151.
    Toyota M, Kopecky KJ, Toyota MO, Jair KW, Willman CL, Issa JP. Methylation profiling in acute myeloid leukemia. Blood. 2001;97(9):2823–2829.PubMedCrossRefGoogle Scholar
  152. 152.
    Turner BM. Memorable transcription. Nat Cell Biol. 2003;5(5):390–393.PubMedCrossRefGoogle Scholar
  153. 153.
    Uchida H, Zhang J, Nimer SD. AML1A and AML1B can transactivate the human IL-3 promoter. J Immunol. 1997;158(5):2251–2558.PubMedGoogle Scholar
  154. 154.
    Uchida T, Kinoshita T, Nagai H, et al. Hypermethylation of the p15INK4B gene in myelodysplastic syndromes. Blood. 1997;90(4):1403–1409.PubMedGoogle Scholar
  155. 155.
    Vogler WR, Winton EF, Gordon DS, Raney MR, Go B, Meyer L. A randomized comparison of postremission therapy in acute myelogenous leukemia: a Southeastern Cancer Study Group trial. Blood. 1984;63(5):1039–1045.PubMedGoogle Scholar
  156. 156.
    Von Hoff DD, Slavik M, Muggia FM. 5-Azacytidine. A new anticancer drug with effectiveness in acute myelogenous leukemia. Ann Intern Med. 1976;85(2):237–245.Google Scholar
  157. 157.
    Wang SW, Speck NA. Purification of core-binding factor, a protein that binds the conserved core site in murine leukemia virus enhancers. Mol Cell Biol. 1992;12(1): 89–102.PubMedGoogle Scholar
  158. 158.
    Weiss AJ, Metter GE, Nealon TF, et al. Phase II study of 5-azacytidine in solid tumors. Cancer Treat Rep. 1977;61(1):55–58.PubMedGoogle Scholar
  159. 159.
    Wells RA, Catzavelos C, Kamel-Reid S. Fusion of retinoic acid receptor alpha to NuMA, the nuclear mitotic apparatus protein, by a variant translocation in acute promyelocytic leukaemia. Nat Genet. 1997;17(1):109–113.PubMedCrossRefGoogle Scholar
  160. 160.
    Werling U, Siehler S, Litfin M, Nau H, Gottlicher M. Induction of differentiation in F9 cells and activation of peroxisome proliferator-activated receptor delta by valproic acid and its teratogenic derivatives. Mol Pharmacol. 2001;59(5):1269–1276.PubMedGoogle Scholar
  161. 161.
    Wijermans P, Lubbert M, Verhoef G, et al. 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. 2000;18(5):956–962.PubMedGoogle Scholar
  162. 162.
    Wijermans PW, Krulder JW, Huijgens PC, Neve P. Continuous infusion of low-dose 5-Aza-2′-deoxycytidine in elderly patients with high-risk myelodysplastic syndrome. Leukemia. 1997;11(1):1–5.PubMedCrossRefGoogle Scholar
  163. 163.
    Willemze R, Suciu S, Archimbaud E, et al. 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. 1997;11(Suppl 1):S24–27.PubMedGoogle Scholar
  164. 164.
    Wolf D, Rodova M, Miska EA, Calvet JP, Kouzarides T. Acetylation of beta-catenin by CREB-binding protein (CBP). J Biol Chem. 2002;277(28):25562–25567.PubMedCrossRefGoogle Scholar
  165. 165.
    Xia ZB, Anderson M, Diaz MO, Zeleznik-Le NJ. MLL repression domain interacts with histone deacetylases, the polycomb group proteins HPC2 and BMI-1, and the corepressor C-terminal-binding protein. Proc Natl Acad Sci USA. 2003;100(14):8342–8347.PubMedCrossRefGoogle Scholar
  166. 166.
    Yang AS, Doshi KD, Choi SW, et al. DNA methylation changes after 5-aza-2 deoxycytidine therapy in patients with leukemia. Cancer Res. 2006. In press.Google Scholar
  167. 167.
    Yang AS, Estecio MR, Doshi K, Kondo Y, Tajara EH, Issa JP. A simple method for estimating global DNA methylation using bisulfite PCR of repetitive DNA elements. Nucleic Acids Res. 2004;32(3):e38.PubMedCrossRefGoogle Scholar
  168. 168.
    Yokoyama A, Kitabayashi I, Ayton PM, Cleary ML, Ohki M. Leukemia proto-oncoprotein MLL is proteolytically processed into 2 fragments with opposite transcriptional properties. Blood. 2002;100(10):3710–3718.PubMedCrossRefGoogle Scholar
  169. 169.
    Yu L, Liu C, Vandeusen J, et al. Global assessment of promoter methylation in a mouse model of cancer identifies ID4 as a putative tumor-suppressor gene in human leukemia. Nat Genet. 2005;37(3):265–274.PubMedCrossRefGoogle Scholar
  170. 170.
    Yu VC, Delsert C, Andersen B, et al. RXR beta: a coregulator that enhances binding of retinoic acid, thyroid hormone, and vitamin D receptors to their cognate response elements. Cell. 1991;67(6):1251–1266.PubMedCrossRefGoogle Scholar
  171. 171.
    Zagonel V, Lo Re G, Marotta G, et al. 5-Aza-2′-deoxycytidine (Decitabine) induces trilineage response in unfavourable myelodysplastic syndromes. Leukemia. 1993;7(suppl. 1):30–35.PubMedGoogle Scholar
  172. 172.
    Zeleznik-Le NJ, Harden AM, Rowley JD. 11q23 translocations split the “AT-hook” cruciform DNA-binding region and the transcriptional repression domain from the activation domain of the mixed-lineage leukemia (MLL) gene. Proc Natl Acad Sci USA. 1994;91(22):10610–10614.PubMedCrossRefGoogle Scholar
  173. 173.
    Zhang Y, Reinberg D. Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. Genes Dev. 2001;15(18):2343–2360.PubMedCrossRefGoogle Scholar
  174. 174.
    Ziemin-van der Poel S, McCabe NR, et al. Identification of a gene, MLL, that spans the breakpoint in 11q23 translocations associated with human leukemias. Proc Natl Acad Sci USA. 1991;88(23):10735–10739.CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of LeukemiaUniversity of Texas MD Anderson Cancer CenterHoustonUSA

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