Table of Contents Author Guidelines Submit a Manuscript
Advances in Hematology
Volume 2012 (2012), Article ID 469592, 12 pages
http://dx.doi.org/10.1155/2012/469592
Review Article

Mutations in Epigenetic Modifiers in Myeloid Malignancies and the Prospect of Novel Epigenetic-Targeted Therapy

1Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
2Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA

Received 6 May 2011; Accepted 2 June 2011

Academic Editor: Kevin D. Bunting

Copyright © 2012 Amir T. Fathi and Omar Abdel-Wahab. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. F. Ducray, Y. Marie, and M. Sanson, “IDH1 and IDH2 mutations in gliomas,” The The New England Journal of Medicine, vol. 360, p. 2248, 2009. View at Google Scholar
  2. C. Hartmann, J. Meyer, J. Balss et al., “Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas,” Acta Neuropathologica, vol. 118, no. 4, pp. 469–474, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  3. D. W. Parsons, S. Jones, X. Zhang et al., “An integrated genomic analysis of human glioblastoma multiforme,” Science, vol. 321, no. 5897, pp. 1807–1812, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  4. M. Sanson, Y. Marie, S. Paris et al., “Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas,” Journal of Clinical Oncology, vol. 27, no. 25, pp. 4150–4154, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  5. T. Watanabe, S. Nobusawa, P. Kleihues, and H. Ohgaki, “IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas,” American Journal of Pathology, vol. 174, no. 4, pp. 1149–1153, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  6. Y. Sonoda, T. Kumabe, T. Nakamura et al., “Analysis of IDH1 and IDH2 mutations in Japanese glioma patients,” Cancer Science, vol. 100, no. 10, pp. 1996–1998, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  7. E. R. Mardis, L. Ding, D. J. Dooling et al., “Recurring mutations found by sequencing an acute myeloid leukemia genome,” The New England Journal of Medicine, vol. 361, no. 11, pp. 1058–1066, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  8. A. Tefferi, T. L. Lasho, O. Abdel-Wahab et al., “IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis,” Leukemia, vol. 24, no. 7, pp. 1302–1309, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  9. S. Gross, R. A. Cairns, M. D. Minden et al., “Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations,” Journal of Experimental Medicine, vol. 207, no. 2, pp. 339–344, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  10. S. Abbas, S. Lugthart, F. G. Kavelaars et al., “Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: prevalence and prognostic value,” Blood, vol. 116, no. 12, pp. 2122–2126, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  11. N. Boissel, O. Nibourel, A. Renneville et al., “Prognostic impact of isocitrate dehydrogenase enzyme isoforms 1 and 2 mutations in acute myeloid leukemia: a study by the acute leukemia French association group,” Journal of Clinical Oncology, vol. 28, no. 23, pp. 3717–3723, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  12. G. Marcucci, K. Maharry, Y. Z. Wu et al., “IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study,” Journal of Clinical Oncology, vol. 28, no. 14, pp. 2348–2355, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  13. P. Paschka, R. F. Schlenk, V. I. Gaidzik et al., “IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication,” Journal of Clinical Oncology, vol. 28, no. 22, pp. 3636–3643, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  14. S. Schnittger, C. Haferlach, M. Ulke, T. Alpermann, W. Kern, and T. Haferlach, “IDH1 mutations are detected in 6.6% of 1414 AML patients and are associated with intermediate risk karyotype and unfavorable prognosis in adults younger than 60 years and unmutated NPM1 status,” Blood, vol. 116, no. 25, pp. 5486–5496, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  15. P. S. Ward, J. Patel, D. R. Wise et al., “The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting α-ketoglutarate to 2-hydroxyglutarate,” Cancer Cell, vol. 17, no. 3, pp. 225–234, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  16. H. Yan, D. W. Parsons, G. Jin et al., “IDH1 and IDH2 mutations in gliomas,” The New England Journal of Medicine, vol. 360, no. 8, pp. 765–773, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  17. L. Dang, D. W. White, S. Gross et al., “Cancer-associated IDH1 mutations produce 2-hydroxyglutarate,” Nature, vol. 462, no. 7274, pp. 739–744, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  18. Z. J. Reitman, D. W. Parsons, and H. Yan, “IDH1 and IDH2: not your typical oncogenes,” Cancer Cell, vol. 17, no. 3, pp. 215–216, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  19. Z. J. Reitman and H. Yan, “Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism,” Journal of the National Cancer Institute, vol. 102, no. 13, pp. 932–941, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  20. S. Kölker, V. Pawlak, B. Ahlemeyer et al., “NMDA receptor activation and respiratory chain complex V inhibition contribute to neurodegeneration in D-2-hydroxyglutaric aciduria,” European Journal of Neuroscience, vol. 16, no. 1, pp. 21–28, 2002. View at Publisher · View at Google Scholar · View at Scopus
  21. A. Latini, K. Scussiato, R. B. Rosa et al., “D-2-hydroxyglutaric acid induces oxidative stress in cerebral cortex of young rats,” European Journal of Neuroscience, vol. 17, no. 10, pp. 2017–2022, 2003. View at Publisher · View at Google Scholar · View at Scopus
  22. C. Frezza, D. A. Tennant, and E. Gottlieb, “IDH1 mutations in gliomas: when an enzyme loses its grip,” Cancer Cell, vol. 17, no. 1, pp. 7–9, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  23. M. E. Figueroa, O. Abdel-Wahab, C. Lu et al., “Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation,” Cancer Cell, vol. 18, no. 6, pp. 553–567, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  24. J. Boultwood and J. S. Wainscoat, “Gene silencing by DNA methylation in haematological malignancies,” British Journal of Haematology, vol. 138, no. 1, pp. 3–11, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  25. G. Leone, L. Teofili, M. T. Voso, and M. Lübbert, “DNA methylation and demethylating drugs in myelodysplastic syndromes and secondary leukemias,” Haematologica, vol. 87, no. 12, pp. 1324–1341, 2002. View at Google Scholar · View at Scopus
  26. M. E. Figueroa, S. Lugthart, Y. Li et al., “DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia,” Cancer Cell, vol. 17, no. 1, pp. 13–27, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  27. S. D. Gore, S. Baylin, E. Sugar et al., “Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms,” Cancer Research, vol. 66, no. 12, pp. 6361–6369, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  28. R. Khan, J. Schmidt-Mende, M. Karimi et al., “Hypomethylation and apoptosis in 5-azacytidine-treated myeloid cells,” Experimental Hematology, vol. 36, no. 2, pp. 149–157, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  29. S. Lugthart, M. E. Figueroa, E. Bindels et al., “Aberrant DNA hypermethylation signature in acute myeloid leukemia directed by EVI1,” Blood, vol. 117, no. 1, pp. 234–241, 2011. View at Publisher · View at Google Scholar · View at PubMed
  30. S. Ito, A. C. D'Alessio, O. V. Taranova, K. Hong, L. C. Sowers, and Y. Zhang, “Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification,” Nature, vol. 466, no. 7310, pp. 1129–1133, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  31. M. Tahiliani, K. P. Koh, Y. Shen et al., “Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1,” Science, vol. 324, no. 5929, pp. 930–935, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  32. W. Xu, H. Yang, Y. Liu et al., “Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases,” Cancer Cell, vol. 19, no. 1, pp. 17–30, 2011. View at Publisher · View at Google Scholar · View at PubMed
  33. Y. Wang, J. Wysocka, J. Sayegh et al., “Human PAD4 regulates histone arginine methylation levels via demethylimination,” Science, vol. 306, no. 5694, pp. 279–283, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  34. Y. Shi, F. Lan, C. Matson et al., “Histone demethylation mediated by the nuclear amine oxidase homolog LSD1,” Cell, vol. 119, no. 7, pp. 941–953, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  35. R. J. Klose, K. Yamane, Y. Bae et al., “The transcriptional repressor JHDM3A demethylates trimethyl histone H3 lysine 9 and lysine 36,” Nature, vol. 442, no. 7100, pp. 312–316, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  36. K. Yamane, C. Toumazou, Y. I. Tsukada et al., “JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by androgen receptor,” Cell, vol. 125, no. 3, pp. 483–495, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  37. D. J. Seward, G. Cubberley, S. Kim et al., “Demethylation of trimethylated histone H3 Lys4 in vivo by JARID1 JmjC proteins,” Nature Structural and Molecular Biology, vol. 14, no. 3, pp. 240–242, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  38. K. Agger, P. A. C. Cloos, J. Christensen et al., “UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development,” Nature, vol. 449, no. 7163, pp. 731–734, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  39. B. Chang, Y. Chen, Y. Zhao, and R. K. Bruick, “JMJD6 is a histone arginine demethylase,” Science, vol. 318, no. 5849, pp. 444–447, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  40. R. F. Schlenk, K. Döhner, J. Krauter et al., “Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia,” The New England Journal of Medicine, vol. 358, no. 18, pp. 1909–1918, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  41. S. Fröhling, R. F. Schlenk, J. Breitruck et al., “Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML study group Ulm,” Blood, vol. 100, no. 13, pp. 4372–4380, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  42. S. Schnittger, C. Schoch, W. Kern et al., “Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype,” Blood, vol. 106, no. 12, pp. 3733–3739, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  43. K. Döhner, R. F. Schlenk, M. Habdank et al., “Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations,” Blood, vol. 106, no. 12, pp. 3740–3746, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  44. S. Fröhling, R. F. Schlenk, I. Stolze et al., “CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: prognostic relevance and analysis of cooperating mutations,” Journal of Clinical Oncology, vol. 22, no. 4, pp. 624–633, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  45. C. Preudhomme, C. Sagot, N. Boissel et al., “Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA),” Blood, vol. 100, no. 8, pp. 2717–2723, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  46. C. L. Green, C. M. Evans, R. K. Hills, A. K. Burnett, D. C. Linch, and R. E. Gale, “The prognostic significance of IDH1 mutations in younger adult patients with acute myeloid leukemia is dependent on FLT3/ITD status,” Blood, vol. 116, no. 15, pp. 2779–2782, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  47. S. Schnittger, C. Haferlach, T. Alpermann, W. Kern, and T. Haferlach, “IDH mutations can be detected In 28.7% of all normal karyotype AML and have unfavourable impact on the NPM1+/FLT3-ITD- genotype,” Blood, vol. 116, 2010, ASH Annual Meeting Abstracts, Abstract 102. View at Google Scholar
  48. F. Ravandi, K. P. Patel, R. Luthra et al., “Prognostic significance of mutations in isocitrate dehydrogenase (IDH) enzyme isoforms 1 and 2 and single nucleotide polymorphisms (SNP) in IDH1, in patients with acute myeloid leukemia treated with high dose cytarabine and idarubicin induction,” Blood, vol. 116, 2010, ASH Annual Meeting Abstracts, Abstract 2706. View at Google Scholar
  49. D. Caramazza, T. Lasho, C. Finke et al., “IDH mutations and trisomy 8 in myelodysplastic syndromes and acute myeloid leukemia,” Blood, vol. 116, 2010, ASH Annual Meeting Abstracts, Abstract 4009. View at Google Scholar
  50. F. Delhommeau, S. Dupont, V. D. Valle et al., “Mutation in TET2 in myeloid cancers,” The New England Journal of Medicine, vol. 360, no. 22, pp. 2289–2301, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  51. O. Abdel-Wahab, A. Mullally, C. Hedvat et al., “Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies,” Blood, vol. 114, no. 1, pp. 144–147, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  52. A. M. Jankowska, H. Szpurka, R. V. Tiu et al., “Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms,” Blood, vol. 113, no. 25, pp. 6403–6410, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  53. A. Tefferi, A. Pardanani, K. H. Lim et al., “TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis,” Leukemia, vol. 23, no. 5, pp. 905–911, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  54. S. M. C. Langemeijer, R. P. Kuiper, M. Berends et al., “Acquired mutations in TET2 are common in myelodysplastic syndromes,” Nature Genetics, vol. 41, no. 7, pp. 838–842, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  55. O. Abdel-Wahab, T. Manshouri, J. Patel et al., “Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias,” Cancer Research, vol. 70, no. 2, pp. 447–452, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  56. J. U. Guo, Y. Su, C. Zhong, G. L. Ming, and H. Song, “Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain,” Cell, vol. 145, no. 3, pp. 423–434, 2011. View at Publisher · View at Google Scholar · View at PubMed
  57. M. Ko, Y. Huang, A. M. Jankowska et al., “Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2,” Nature, vol. 468, no. 7325, pp. 839–843, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  58. O. Kosmider, V. Gelsi-Boyer, M. Ciudad et al., “TET2 gene mutation is a frequent and adverse event in chronic myelomonocytic leukemia,” Haematologica, vol. 94, no. 12, pp. 1676–1681, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  59. O. Nibourel, O. Kosminder, M. Cheok et al., “Association of TET2 alterations with NPM1 mutations and prognostic value in de novo Acute Myeloid Leukemia (AML),” Blood, vol. 114, no. 22, 2009. View at Google Scholar
  60. V. Gaidzik, R. F. Schlenk, P. Paschka et al., “TET2 mutations in Acute Myeloid Leukemia (AML): results on 783 patients treated within the AML HD98A study of the AML Study Group (AMLSG),” Blood, vol. 116, 2010. View at Google Scholar
  61. O. Kosmider, V. Gelsi-Boyer, M. Cheok et al., “TET2 mutation is an independent favorable prognostic factor in myelodysplastic syndromes (MDSs),” Blood, vol. 114, no. 15, pp. 3285–3291, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  62. K. H. Metzeler, K. Maharry, M. D. Radmacher et al., “TET2 mutations improve the new European LeukemiaNet risk classification of acute myeloid leukemia: a cancer and leukemia group B study,” Journal of Clinical Oncology, vol. 29, no. 10, pp. 1373–1381, 2011. View at Publisher · View at Google Scholar · View at PubMed
  63. T. J. Ley, L. Ding, M. J. Walter et al., “DNMT3A mutations in acute myeloid leukemia,” The New England Journal of Medicine, vol. 363, no. 25, pp. 2424–2433, 2010. View at Publisher · View at Google Scholar · View at PubMed
  64. Y. Yamashita, J. Yuan, I. Suetake et al., “Array-based genomic resequencing of human leukemia,” Oncogene, vol. 29, no. 25, pp. 3723–3731, 2010. View at Publisher · View at Google Scholar · View at PubMed
  65. X. J. Yan, J. Xu, Z. H. Gu et al., “Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia,” Nature Genetics, vol. 43, no. 4, pp. 309–315, 2011. View at Publisher · View at Google Scholar · View at PubMed
  66. M. J. Walter, L. Ding, D. Shen et al., “Recurrent DNMT3A mutations in patients with myelodysplastic syndromes,” Leukemia. In press.
  67. O. Abdel-Wahab, A. Pardanani, R. Rampal, T. L. Lasho, R. L. Levine, and A. Tefferi, “DNMT3A mutational analysis in primary myelofibrosis, chronic myelomonocytic leukemia and advanced phases of myeloproliferative neoplasms,” Leukemia. In press.
  68. R. D. Morin, N. A. Johnson, T. M. Severson et al., “Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin,” Nature Genetics, vol. 42, no. 2, pp. 181–185, 2010. View at Publisher · View at Google Scholar · View at PubMed
  69. O. Abdel-Wahab, A. Pardanani, J. Patel et al., “Concomitant analysis of EZH2 and ASXL1 mutations in myelofibrosis, chronic myelomonocytic leukemia and blast-phase myeloproliferative neoplasms,” Leukemia. In press.
  70. T. Ernst, A. J. Chase, J. Score et al., “Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders,” Nature Genetics, vol. 42, no. 8, pp. 722–726, 2010. View at Publisher · View at Google Scholar · View at PubMed
  71. G. Nikoloski, S. M. C. Langemeijer, R. P. Kuiper et al., “Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes,” Nature Genetics, vol. 42, no. 8, pp. 665–667, 2010. View at Publisher · View at Google Scholar · View at PubMed
  72. E. Viré, C. Brenner, R. Deplus et al., “The Polycomb group protein EZH2 directly controls DNA methylation,” Nature, vol. 439, no. 7078, pp. 871–874, 2006. View at Publisher · View at Google Scholar · View at PubMed
  73. K. Döhner, J. Brown, U. Hehmann et al., “Molecular cytogenetic characterization of a critical region in bands 7q35-q36 commonly deleted in malignant myeloid disorders,” Blood, vol. 92, no. 11, pp. 4031–4035, 1998. View at Google Scholar
  74. M. M. Le Beau, R. Espinosa III, E. M. Davis, J. D. Eisenbart, R. A. Larson, and E. D. Green, “Cytogenetic and molecular delineation of a region of chromosome 7 commonly deleted in malignant myeloid diseases,” Blood, vol. 88, no. 6, pp. 1930–1935, 1996. View at Google Scholar
  75. G. Garcia-Manero, S. D. Gore, C. R. Cogle et al., “Evaluation of oral azacitidine using extended treatment schedules: a phase I study,” Blood, vol. 116, 2010. View at Google Scholar
  76. A. S. Yang, K. D. Doshi, S. W. Choi et al., “DNA methylation changes after 5-aza-2′-deoxycytidine therapy in patients with leukemia,” Cancer Research, vol. 66, no. 10, pp. 5495–5503, 2006. View at Publisher · View at Google Scholar · View at PubMed
  77. L. Zhou, X. Cheng, B. A. Connolly, M. J. Dickman, P. J. Hurd, and D. P. Hornby, “Zebularine: a novel DNA methylation inhibitor that forms a covalent complex with DNA methyltransferases,” Journal of Molecular Biology, vol. 321, no. 4, pp. 591–599, 2002. View at Publisher · View at Google Scholar
  78. J. C. Cheng, C. B. Matsen, F. A. Gonzales et al., “Inhibition of DNA methylation and reactivation of silenced genes by zebularine,” Journal of the National Cancer Institute, vol. 95, no. 5, pp. 399–409, 2003. View at Google Scholar
  79. J. C. Cheng, C. B. Yoo, D. J. Weisenberger et al., “Preferential response of cancer cells to zebularine,” Cancer Cell, vol. 6, no. 2, pp. 151–158, 2004. View at Publisher · View at Google Scholar · View at PubMed
  80. A. J. Davis, K. A. Gelmon, L. L. Siu et al., “Phase I and pharmacologic study of the human DNA methyltransferase antisense oligodeoxynucleotide MG98 given as a 21-day continuous infusion every 4 weeks,” Investigational New Drugs, vol. 21, no. 1, pp. 85–97, 2003. View at Publisher · View at Google Scholar
  81. D. J. Stewart, R. C. Donehower, E. A. Eisenhauer et al., “A phase I pharmacokinetic and pharmacodynamic study of the DNA methyltransferase 1 inhibitor MG98 administered twice weekly,” Annals of Oncology, vol. 14, no. 5, pp. 766–774, 2003. View at Publisher · View at Google Scholar
  82. R. B. Klisovic, W. Stock, S. Cataland et al., “A phase I biological study of MG98, an oligodeoxynucleotide antisense to DNA methyltransferase 1, in patients with high-risk myelodysplasia and acute myeloid leukemia,” Clinical Cancer Research, vol. 14, no. 8, pp. 2444–2449, 2008. View at Publisher · View at Google Scholar · View at PubMed
  83. E. Winquist, J. Knox, J. P. Ayoub et al., “Phase II trial of DNA methyltransferase 1 inhibition with the antisense oligonucleotide MG98 in patients with metastatic renal carcinoma: a National Cancer Institute of Canada Clinical Trials Group investigational new drug study,” Investigational New Drugs, vol. 24, no. 2, pp. 159–167, 2006. View at Publisher · View at Google Scholar · View at PubMed
  84. B. Brueckner, R. G. Boy, P. Siedlecki et al., “Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA methyltransferases,” Cancer Research, vol. 65, no. 14, pp. 6305–6311, 2005. View at Publisher · View at Google Scholar · View at PubMed
  85. D. Kuck, N. Singh, F. Lyko, and J. L. Medina-Franco, “Novel and selective DNA methyltransferase inhibitors: docking-based virtual screening and experimental evaluation,” Bioorganic and Medicinal Chemistry, vol. 18, no. 2, pp. 822–829, 2010. View at Publisher · View at Google Scholar · View at PubMed
  86. R. Itzykson, O. Kosmider, T. Cluzeau et al., “Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias,” Leukemia. In press.
  87. D. A. Pollyea, A. Raval, B. Kusler, J. R. Gotlib, A. A. Alizadeh, and B. S. Mitchell, “Impact of TET2 mutations on mRNA expression and clinical outcomes in MDS patients treated with DNA methyltransferase inhibitors,” Journal of Hematology & Oncology, 2010. View at Google Scholar
  88. A. V. Krivtsov and S. A. Armstrong, “MLL translocations, histone modifications and leukaemia stem-cell development,” Nature Reviews Cancer, vol. 7, no. 11, pp. 823–833, 2007. View at Publisher · View at Google Scholar · View at PubMed
  89. G. G. Wang, L. Cai, M. P. Pasillas, and M. P. Kamps, “NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis,” Nature Cell Biology, vol. 9, no. 7, pp. 804–812, 2007. View at Publisher · View at Google Scholar · View at PubMed
  90. C. Meyer, E. Kowarz, J. Hofmann et al., “New insights to the MLL recombinome of acute leukemias,” Leukemia, vol. 23, no. 8, pp. 1490–1499, 2009. View at Publisher · View at Google Scholar · View at PubMed
  91. S. Y. Jo, E. M. Granowicz, I. Maillard, D. Thomas, and J. L. Hess, “Requirement for Dot1l in murine postnatal hematopoiesis and leukemogenesis by MLL translocation,” Blood, vol. 117, no. 18, pp. 4759–4768, 2011. View at Publisher · View at Google Scholar · View at PubMed
  92. K. Bernt, N. Zhu, J. Faber et al., “Demonstration of a role for Dot1l in MLL-rearranged leukemia using a conditional loss of function model,” Blood, vol. 116, 2010. View at Google Scholar
  93. R. Pollock, S. R. Daigle, E. J. Olhava et al., “Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor,” Blood, vol. 116, 2010. View at Google Scholar
  94. A. V. Krivtsov, Z. Feng, M. E. Lemieux et al., “H3K79 methylation profiles define murine and human MLL-AF4 leukemias,” Cancer Cell, vol. 14, no. 5, pp. 355–368, 2008. View at Publisher · View at Google Scholar · View at PubMed
  95. A. Bursen, K. Schwabe, B. Rüster et al., “The AF4·MLL fusion protein is capable of inducing ALL in mice without requirement of MLL·AF4,” Blood, vol. 115, no. 17, pp. 3570–3579, 2010. View at Publisher · View at Google Scholar · View at PubMed
  96. A. Benedikt, S. Baltruschat, B. Scholz et al., “The leukemogenic AF4-MLL fusion protein causes P-TEFb kinase activation and altered epigenetic signatures,” Leukemia, vol. 25, pp. 135–144, 2010. View at Publisher · View at Google Scholar · View at PubMed
  97. A. T. Nguyen, B. Xiao, R. L. Neppl et al., “DOT1L regulates dystrophin expression and is critical for cardiac function,” Genes and Development, vol. 25, no. 3, pp. 263–274, 2011. View at Publisher · View at Google Scholar · View at PubMed
  98. A. Jankowska, H. Makishima, R. V. Tiu et al., “Mutational spectrum in chronic myelomonocytic leukemia includes genes associated with epigenetic regulation such as UTX and EZH2,” Blood, vol. 116, 2010. View at Google Scholar
  99. M. Allan, S. Manku, E. Therrien et al., “N-benzyl-1-heteroaryl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamides as inhibitors of co-activator associated arginine methyltransferase 1 (CARM1),” Bioorganic and Medicinal Chemistry Letters, vol. 19, no. 4, pp. 1218–1223, 2009. View at Publisher · View at Google Scholar · View at PubMed
  100. J. Eeckhoute, E. K. Keeton, M. Lupien, S. A. Krum, J. S. Carroll, and M. Brown, “Positive cross-regulatory loop ties GATA-3 to estrogen receptor α expression in breast cancer,” Cancer Research, vol. 67, no. 13, pp. 6477–6483, 2007. View at Publisher · View at Google Scholar · View at PubMed
  101. Y. R. Kim, B. K. Lee, R. Y. Park et al., “Differential CARM1 expression in prostate and colorectal cancers,” BioMed Central Cancer, vol. 10, p. 197, 2010. View at Publisher · View at Google Scholar · View at PubMed