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Advances in Hematology
Volume 2014 (2014), Article ID 103175, 15 pages
http://dx.doi.org/10.1155/2014/103175
Review Article

The Epigenetic Landscape of Acute Myeloid Leukemia

Brighton and Sussex Medical School, University of Sussex, Falmer, Brighton BN1 9PS, UK

Received 25 October 2013; Revised 27 January 2014; Accepted 3 February 2014; Published 23 March 2014

Academic Editor: Myriam Labopin

Copyright © 2014 Emma Conway O’Brien et al. 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. Ferrara and C. A. Schiffer, “Acute myeloid Leukemia in adults,” The Lancet, vol. 381, no. 9865, pp. 484–495, 2013. View at Publisher · View at Google Scholar
  2. M. R. O'Donnell, C. N. Abboud, J. Altman et al., “Acute myeloid Leukemia,” Journal of the National Comprehensive Cancer Network, vol. 10, no. 8, pp. 984–1021, 2012. View at Google Scholar
  3. Y. Koh, I. Kim, J.-Y. Bae et al., “Prognosis of secondary acute myeloid Leukemia is affected by the type of the preceding hematologic disorders and the presence of trisomy 8,” Japanese Journal of Clinical Oncology, vol. 40, no. 11, pp. 1037–1045, 2010. View at Publisher · View at Google Scholar · View at Scopus
  4. E. H. Estey, “Acute myeloid Leukemia: 2013 update on risk-stratification and management,” American Journal of Hematology, vol. 88, no. 4, pp. 318–327, 2013. View at Google Scholar
  5. T. L. Lin and B. D. Smith, “Prognostically important molecular markers in cytogenetically normal acute myeloid Leukemia,” American Journal of the Medical Sciences, vol. 341, no. 5, pp. 404–408, 2011. View at Publisher · View at Google Scholar · View at Scopus
  6. O. Abdel-Wahab and A. T. Fathi, “Mutations in epigenetic modifiers in myeloid malignancies and the prospect of novel epigenetic-targeted therapy,” Advances in Hematology, vol. 2012, Article ID 469592, 12 pages, 2012. View at Publisher · View at Google Scholar · View at Scopus
  7. Y. Oki and J. P. Issa, “Epigenetic mechanisms in AML—a target for therapy,” Cancer Treatment and Research, vol. 145, pp. 19–40, 2010. View at Publisher · View at Google Scholar · View at Scopus
  8. A. H. Shih, O. Abdel-Wahab, J. P. Patel, and R. L. Levine, “The role of mutations in epigenetic regulators in myeloid malignancies,” Nature Reviews Cancer, vol. 12, no. 9, pp. 599–612, 2012. View at Publisher · View at Google Scholar
  9. D. Grimwade, H. Walker, G. Harrison et al., “The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid Leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial,” Blood, vol. 98, no. 5, pp. 1312–1320, 2001. View at Publisher · View at Google Scholar · View at Scopus
  10. D. Grimwade, H. Walker, F. Oliver et al., “The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial,” Blood, vol. 92, no. 7, pp. 2322–2333, 1998. View at Google Scholar · View at Scopus
  11. W.-J. Hong and B. C. Medeiros, “Unfavorable-risk cytogenetics in acute myeloid Leukemia,” Expert Review of Hematology, vol. 4, no. 2, pp. 173–184, 2011. View at Publisher · View at Google Scholar · View at Scopus
  12. H. Döhner, E. H. Estey, S. Amadori et al., “Diagnosis and management of acute myeloid Leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet,” Blood, vol. 115, no. 3, pp. 453–474, 2010. View at Publisher · View at Google Scholar · View at Scopus
  13. J. W. Vardiman, J. Thiele, D. A. Arber et al., “The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute Leukemia: rationale and important changes,” Blood, vol. 114, no. 5, pp. 937–951, 2009. View at Publisher · View at Google Scholar · View at Scopus
  14. L. M. Kelly and D. G. Gilliland, “Genetics of myeloid Leukemias,” Annual Review of Genomics and Human Genetics, vol. 3, pp. 179–198, 2002. View at Publisher · View at Google Scholar · View at Scopus
  15. J. Basecke, L. Cepek, C. Mannhalter et al., “Transcription of AML1/ETO in bone marrow and cord blood of individuals without acute myelogenous Leukemia,” Blood, vol. 100, no. 6, pp. 2267–2268, 2002. View at Publisher · View at Google Scholar · View at Scopus
  16. J. Song, D. Mercer, X. Hu, H. Liu, and M. M. Li, “Common Leukemia- and lymphoma-associated genetic aberrations in healthy individuals,” Journal of Molecular Diagnostics, vol. 13, no. 2, pp. 213–219, 2011. View at Publisher · View at Google Scholar · View at Scopus
  17. J. R. Downing, “The core-binding factor Leukemias: lessons learned from murine models,” Current Opinion in Genetics and Development, vol. 13, no. 1, pp. 48–54, 2003. View at Publisher · View at Google Scholar · View at Scopus
  18. M. Higuchi, D. O'Brien, P. Kumaravelu, N. Lenny, E.-J. Yeoh, and J. R. Downing, “Expression of a conditional AML1-ETO oncogene bypasses embryonic lethality and establishes a murine model of human t(8;21) acute myeloid Leukemia,” Cancer Cell, vol. 1, no. 1, pp. 63–74, 2002. View at Publisher · View at Google Scholar · View at Scopus
  19. T. Pabst, M. Eyholzer, S. Haefliger, J. Schardt, and B. U. Mueller, “Somatic CEBPA mutations are a frequent second event in families with germline CEBPA mutations and familial acute myeloid Leukemia,” Journal of Clinical Oncology, vol. 26, no. 31, pp. 5088–5093, 2008. View at Publisher · View at Google Scholar · View at Scopus
  20. J. S. Welch, T. J. Ley, D. C. Link et al., “The origin and evolution of mutations in acute myeloid Leukemia,” Cell, vol. 150, no. 2, pp. 264–278, 2012. View at Google Scholar
  21. A. Murati, M. Brecqueville, R. Devillier, M. J. Mozziconacci, V. Gelsi-Boyer, and D. Birnbaum, “Myeloid malignancies: mutations, models and management,” BMC Cancer, vol. 12, article 304, 2012. View at Google Scholar
  22. M. M. Suzuki and A. Bird, “DNA methylation landscapes: provocative insights from epigenomics,” Nature Reviews Genetics, vol. 9, no. 6, pp. 465–476, 2008. View at Publisher · View at Google Scholar · View at Scopus
  23. M. H. Saied, J. Marzec, S. Khalid et al., “Genome wide analysis of acute myeloid Leukemia reveal Leukemia specific methylome and subtype specific hypomethylation of repeats,” PLoS ONE, vol. 7, no. 3, Article ID e33213, 2012. View at Publisher · View at Google Scholar · View at Scopus
  24. 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 Scopus
  25. J. T. Reilly, “Pathogenesis of acute myeloid leukaemia and inv(16)(p13;q22): a paradigm for understanding leukaemogenesis?” British Journal of Haematology, vol. 128, no. 1, pp. 18–34, 2005. View at Publisher · View at Google Scholar · View at Scopus
  26. J. Borgel, S. Guibert, Y. Li et al., “Targets and dynamics of promoter DNA methylation during early mouse development,” Nature Genetics, vol. 42, no. 12, pp. 1093–1100, 2010. View at Publisher · View at Google Scholar · View at Scopus
  27. E. Bartova, J. Krejci, A. Harnicarova, G. Galiova, and S. Kozubek, “Histone modifications and nuclear architecture: a review,” Journal of Histochemistry & Cytochemistry, vol. 56, no. 8, pp. 711–721, 2008. View at Publisher · View at Google Scholar
  28. S. Takahashi, “Current findings for recurring mutations in acute myeloid Leukemia,” Journal of Hematology and Oncology, vol. 4, article 36, 2011. View at Publisher · View at Google Scholar · View at Scopus
  29. 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 Scopus
  30. A. Akalin, F. E. Garrett-Bakelman, M. Kormaksson et al., “Base-pair resolution DNA methylation sequencing reveals profoundly divergent epigenetic landscapes in acute myeloid Leukemia,” PLOS Genetics, vol. 8, no. 6, Article ID e1002781, 2012. View at Google Scholar
  31. L. Bullinger, M. Ehrich, K. Döhner et al., “Quantitative DNA methylation predicts survival in adult acute myeloid Leukemia,” Blood, vol. 115, no. 3, pp. 636–642, 2010. View at Publisher · View at Google Scholar · View at Scopus
  32. 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
  33. J. P. Patel, M. Gonen, M. E. Figueroa et al., “Prognostic relevance of integrated genetic profiling in acute myeloid Leukemia,” The New England Journal of Medicine, vol. 366, no. 12, pp. 1079–1089, 2012. View at Google Scholar
  34. I. Fried, C. Bodner, M. M. Pichler et al., “Frequency, onset and clinical impact of somatic DNMT3A mutations in therapy-related and secondary acute myeloid Leukemia,” Haematologica, vol. 97, no. 2, pp. 246–250, 2012. View at Publisher · View at Google Scholar · View at Scopus
  35. A. F. Ribeiro, M. Pratcorona, C. Erpelinck-Verschueren et al., “Mutant DNMT3A: a marker of poor prognosis in acute myeloid Leukemia,” Blood, vol. 119, no. 24, pp. 5824–5831, 2012. View at Google Scholar
  36. F. Thol, F. Damm, A. Lüdeking et al., “Incidence and prognostic influence of DNMT3A mutations in acute myeloid Leukemia,” Journal of Clinical Oncology, vol. 29, no. 21, pp. 2889–2896, 2011. View at Publisher · View at Google Scholar · View at Scopus
  37. 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. 309–317, 2011. View at Publisher · View at Google Scholar · View at Scopus
  38. G. A. Challen, D. Sun, M. Jeong et al., “Dnmt3a is essential for hematopoietic stem cell differentiation,” Nature Genetics, vol. 44, no. 1, pp. 23–31, 2012. View at Publisher · View at Google Scholar · View at Scopus
  39. 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 Scopus
  40. E. A. Eklund, “The role of hox proteins in leukemogenesis: insights into key regulatory events in hematopoiesis,” Critical Reviews in Oncogenesis, vol. 16, no. 1-2, pp. 65–76, 2011. View at Google Scholar · View at Scopus
  41. H. Wu, V. Coskun, J. Tao et al., “Dnmt3a-dependent nonpromoter DNA methylation facilitates transcription of neurogenic genes,” Science, vol. 329, no. 5990, pp. 444–447, 2010. View at Publisher · View at Google Scholar · View at Scopus
  42. J. Krönke, L. Bullinger, V. Teleanu et al., “Clonal evolution in relapsed NPM1-mutated acute myeloid Leukemia,” Blood, vol. 122, no. 1, pp. 100–108, 2013. View at Google Scholar
  43. S. Wakita, H. Yamaguchi, I. Omori et al., “Mutations of the epigenetics-modifying gene (DNMT3a, TET2, IDH1/2) at diagnosis may induce FLT3-ITD at relapse in de novo acute myeloid Leukemia,” Leukemia, vol. 27, no. 5, pp. 1044–1052, 2012. View at Publisher · View at Google Scholar
  44. G. Marcucci, K. H. Metzeler, S. Schwind et al., “Age-related prognostic impact of different types of DNMT3A mutations in adults with primary cytogenetically normal acute myeloid Leukemia,” Journal of Clinical Oncology, vol. 30, no. 7, pp. 742–750, 2012. View at Publisher · View at Google Scholar · View at Scopus
  45. V. I. Gaidzik, R. F. Schlenk, P. Paschka et al., “Clinical impact of DNMT3A mutations in younger adult patients with acute myeloid Leukemia: results of the AML Study Group (AMLSG),” Blood, vol. 121, no. 23, pp. 4769–4777, 2013. View at Publisher · View at Google Scholar
  46. 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 Scopus
  47. 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 Scopus
  48. S. Weissmann, T. Alpermann, V. Grossmann et al., “Landscape of TET2 mutations in acute myeloid Leukemia,” Leukemia, vol. 26, pp. 934–942, 2011. View at Publisher · View at Google Scholar · View at Scopus
  49. V. I. Gaidzik, P. Paschka, D. Spath et al., “TET2 mutations in acute myeloid leukemia (AML): results from a comprehensive genetic and clinical analysis of the AML study group,” Journal of Clinical Oncology, vol. 30, no. 12, pp. 1350–1357, 2012. View at Publisher · View at Google Scholar
  50. F. Delhommeau, S. Dupont, V. Della 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 Scopus
  51. 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 Scopus
  52. 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 Scopus
  53. 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 Scopus
  54. A. Tefferi, “Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1,” Leukemia, vol. 24, no. 6, pp. 1128–1138, 2010. View at Google Scholar · View at Scopus
  55. K. Moran-Crusio, L. Reavie, A. Shih et al., “Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation,” Cancer Cell, vol. 20, no. 1, pp. 11–24, 2011. View at Publisher · View at Google Scholar · View at Scopus
  56. 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 Scopus
  57. O. Nibourel, O. Kosmider, M. Cheok et al., “Incidence and prognostic value of TET2 alterations in de novo acute myeloid Leukemia achieving complete remission,” Blood, vol. 116, no. 7, pp. 1132–1135, 2010. View at Publisher · View at Google Scholar · View at Scopus
  58. W.-C. Chou, S.-C. Chou, C.-Y. Liu et al., “TET2 mutation is an unfavorable prognostic factor in acute myeloid Leukemia patients with intermediate-risk cytogenetics,” Blood, vol. 118, no. 14, pp. 3803–3810, 2011. View at Publisher · View at Google Scholar · View at Scopus
  59. D. Rakheja, S. Konoplev, L. J. Medeiros, and W. Chen, “IDH mutations in acute myeloid Leukemia,” Human Pathology, vol. 43, no. 10, pp. 1541–1551, 2012. View at Publisher · View at Google Scholar
  60. 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 Scopus
  61. 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 Scopus
  62. 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 Scopus
  63. 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 Scopus
  64. K. Wagner, F. Damm, G. Göhring et al., “Impact of IDH1 R132 mutations and an IDH1 single nucleotide polymorphism in cytogenetically normal acute myeloid Leukemia: SNP rs11554137 is an adverse prognostic factor,” Journal of Clinical Oncology, vol. 28, no. 14, pp. 2356–2364, 2010. View at Publisher · View at Google Scholar · View at Scopus
  65. W.-C. Chou, W.-C. Lei, B.-S. Ko et al., “The prognostic impact and stability of Isocitrate dehydrogenase 2 mutation in adult patients with acute myeloid Leukemia,” Leukemia, vol. 25, no. 2, pp. 246–253, 2011. View at Publisher · View at Google Scholar · View at Scopus
  66. 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 Scopus
  67. 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 Scopus
  68. F. Thol, F. Damm, K. Wagner et al., “Prognostic impact of IDH2 mutations in cytogenetically normal acute myeloid Leukemia,” Blood, vol. 116, no. 4, pp. 614–616, 2010. View at Publisher · View at Google Scholar · View at Scopus
  69. J. H. Feng, X. P. Guo, Y. Y. Chen, Z. J. Wang, Y. P. Cheng, and Y. M. Tang, “Prognostic significance of IDH1 mutations in acute myeloid Leukemia: a meta-analysis,” American Journal of Blood Research, vol. 2, no. 4, pp. 254–264, 2012. View at Google Scholar
  70. C. L. Green, C. M. Evans, L. Zhao et al., “The prognostic significance of IDH2 mutations in AML depends on the location of the mutation,” Blood, vol. 118, no. 2, pp. 409–412, 2011. View at Publisher · View at Google Scholar · View at Scopus
  71. M. Brecqueville, J. Rey, F. Bertucci et al., “Mutation analysis of ASXL1, CBL, DNMT3A, IDH1, IDH2, JAK2, MPL, NF1, SF3B1, SUZ12, and TET2 in myeloproliferative neoplasms,” Genes Chromosomes and Cancer, vol. 51, no. 8, pp. 743–755, 2012. View at Publisher · View at Google Scholar · View at Scopus
  72. H. Boukarabila, A. J. Saurin, E. Batsché et al., “The PRC1 polycomb group complex interacts with PLZF/RARA to mediate leukemic transformation,” Genes and Development, vol. 23, no. 10, pp. 1195–1206, 2009. View at Publisher · View at Google Scholar · View at Scopus
  73. O. Abdel-Wahab, M. Adli, L. M. LaFave et al., “ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression,” Cancer Cell, vol. 22, no. 2, pp. 180–193, 2012. View at Publisher · View at Google Scholar
  74. L. M. Kamminga, L. V. Bystrykh, A. de Boer et al., “The Polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion,” Blood, vol. 107, no. 5, pp. 2170–2179, 2006. View at Publisher · View at Google Scholar · View at Scopus
  75. F. Xu and X. Li, “The role of histone methyltransferase EZH2 in myelodysplastic syndromes,” Expert Review of Hematology, vol. 5, no. 2, pp. 177–185, 2012. View at Publisher · View at Google Scholar
  76. 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 Scopus
  77. 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 Scopus
  78. O. Abdel-Wahab and A. T. Fathi, “Mutations in epigenetic modifiers in myeloid malignancies and the prospect of novel epigenetic-targeted therapy,” Advances in Hematology, vol. 2012, Article ID 469592, 12 pages, 2012. View at Publisher · View at Google Scholar · View at Scopus
  79. X. Wang, H. Dai, Q. Wang et al., “EZH2 mutations are related to low blast percentage in bone marrow and -7/del(7q) in de novo acute myeloid Leukemia,” PLoS ONE, vol. 8, no. 4, Article ID e61341, 2013. View at Google Scholar
  80. V. Gelsi-Boyer, M. Brecqueville, R. Devillier, A. Murati, M.-J. Mozziconacci, and D. Birnbaum, “Mutations in ASXL1 are associated with poor prognosis across the spectrum of malignant myeloid diseases,” Journal of Hematology & Oncology, vol. 5, p. 12, 2012. View at Publisher · View at Google Scholar · View at Scopus
  81. F. Thol, I. Friesen, F. Damm et al., “Prognostic significance of ASXL1 mutations in patients with myelodysplastic syndromes,” Journal of Clinical Oncology, vol. 29, no. 18, pp. 2499–2506, 2011. View at Publisher · View at Google Scholar · View at Scopus
  82. M. Pratcorona, S. Abbas, M. A. Sanders et al., “Acquired mutations in ASXL1 in acute myeloid Leukemia: prevalence and prognostic value,” Haematologica, vol. 97, no. 3, pp. 388–392, 2012. View at Publisher · View at Google Scholar · View at Scopus
  83. S. Schnittger, C. Eder, S. Jeromin et al., “ASXL1 exon 12 mutations are frequent in AML with intermediate risk karyotype and are independently associated with an adverse outcome,” Leukemia, vol. 27, no. 1, pp. 82–91, 2013. View at Publisher · View at Google Scholar
  84. C. L. Fisher, I. Lee, S. Bloyer et al., “Additional sex combs-like 1 belongs to the enhancer of trithorax and polycomb group and genetically interacts with Cbx2 in mice,” Developmental Biology, vol. 337, no. 1, pp. 9–15, 2010. View at Publisher · View at Google Scholar · View at Scopus
  85. C. L. Fisher, N. Pineault, C. Brookes et al., “Loss-of-function additional sex combs like 1 mutations disrupt hematopoiesis but do not cause severe myelodysplasia or Leukemia,” Blood, vol. 115, no. 1, pp. 38–46, 2010. View at Publisher · View at Google Scholar · View at Scopus
  86. B. Falini, M. P. Martelli, N. Bolli et al., “Acute myeloid Leukemia with mutated nucleophosmin (NPM1): is it a distinct entity?” Blood, vol. 117, no. 4, pp. 1109–1120, 2011. View at Publisher · View at Google Scholar · View at Scopus
  87. H. Liu, E. H.-Y. Cheng, and J. J.-D. Hsieh, “MLL fusions: pathways to Leukemia,” Cancer Biology and Therapy, vol. 8, no. 13, pp. 1204–1211, 2009. View at Google Scholar · View at Scopus
  88. 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 Scopus
  89. R. Rau and P. Brown, “Nucleophosmin (NPM1) mutations in adult and childhood acute myeloid leukaemia: towards definition of a new leukaemia entity,” Hematological Oncology, vol. 27, no. 4, pp. 171–181, 2009. View at Publisher · View at Google Scholar · View at Scopus
  90. Y. Zhang, A. Chen, X. M. Yan, and G. Huang, “Disordered epigenetic regulation in MLL-related Leukemia,” International Journal of Hematology, vol. 96, no. 4, pp. 428–437, 2012. View at Publisher · View at Google Scholar
  91. A. Dufour, F. Schneider, K. H. Metzeler et al., “Acute myeloid Leukemia with biallelic CEBPA gene mutations and normal karyotype represents a distinct genetic entity associated with a favorable clinical outcome,” Journal of Clinical Oncology, vol. 28, no. 4, pp. 570–577, 2010. View at Publisher · View at Google Scholar · View at Scopus
  92. P. D. Kottaridis, R. E. Gale, M. E. Frew et al., “The presence of a FLT3 internal tandem duplication in patients with acute myeloid Leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials,” Blood, vol. 98, no. 6, pp. 1752–1759, 2001. View at Publisher · View at Google Scholar · View at Scopus
  93. 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 Scopus
  94. S. Schnittger, C. Schoch, M. Dugas et al., “Analysis of FLT3 length mutations in 1003 patients with acute myeloid Leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease,” Blood, vol. 100, no. 1, pp. 59–66, 2002. View at Publisher · View at Google Scholar · View at Scopus
  95. C. Thiede, S. Koch, E. Creutzig et al., “Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid Leukemia (AML),” Blood, vol. 107, no. 10, pp. 4011–4020, 2006. View at Publisher · View at Google Scholar · View at Scopus
  96. D. Small, “FLT3 mutations: biology and treatment,” Hematology, pp. 178–184, 2006. View at Google Scholar · View at Scopus
  97. K. H. Metzeler, H. Becker, K. Maharry et al., “ASXL1 mutations identify a high-risk subgroup of older patients with primary cytogenetically normal AML within the ELN Favorable genetic category,” Blood, vol. 118, no. 26, pp. 6920–6929, 2011. View at Publisher · View at Google Scholar · View at Scopus
  98. Y. Shen, Y.-M. Zhu, X. Fan et al., “Gene mutation patterns and their prognostic impact in a cohort of 1185 patients with acute myeloid Leukemia,” Blood, vol. 118, no. 20, pp. 5593–5603, 2011. View at Publisher · View at Google Scholar · View at Scopus
  99. W.-C. Chou, H.-H. Huang, H.-A. Hou et al., “Distinct clinical and biological features of de novo acute myeloid Leukemia with additional sex comb-like 1 (ASXL1) mutations,” Blood, vol. 116, no. 20, pp. 4086–4094, 2010. View at Publisher · View at Google Scholar · View at Scopus
  100. C. P. Leith, K. J. Kopecky, J. Godwin et al., “Acute myeloid Leukemia in the elderly: assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy. A Southwest Oncology Group Study,” Blood, vol. 89, no. 9, pp. 3323–3329, 1997. View at Google Scholar · View at Scopus
  101. D. Small, “Targeting FLT3 for the treatment of Leukemia,” Seminars in Hematology, vol. 45, supplement 2, pp. S17–S21, 2008. View at Publisher · View at Google Scholar · View at Scopus
  102. M. Bornhäuser, T. Illmer, M. Schaich, S. Soucek, G. Ehninger, and C. Thiede, “Improved outcome after stem-cell transplantation in FLT3/ITD-positive AML,” Blood, vol. 109, no. 5, pp. 2264–2265, 2007. View at Publisher · View at Google Scholar · View at Scopus
  103. R. E. Gale, R. Hills, P. D. Kottaridis et al., “No evidence that FLT3 status should be considered as an indicator for transplantation in acute myeloid Leukemia (AML): an analysis of 1135 patients, excluding acute promyelocytic Leukemia, from the UK MRCAML10 and 12 trials,” Blood, vol. 106, no. 10, pp. 3658–3665, 2005. View at Publisher · View at Google Scholar · View at Scopus
  104. G. Marcucci, K. Maharry, M. D. Radmacher et al., “Prognostic significance of, and gene and MicroRNA expression signatures associated with, CEBPA mutations in cytogenetically normal acute myeloid Leukemia with high-risk molecular features: a cancer and Leukemia group B study,” Journal of Clinical Oncology, vol. 26, no. 31, pp. 5078–5087, 2008. View at Publisher · View at Google Scholar · View at Scopus
  105. U. Bacher, C. Haferlach, W. Kern, T. Haferlach, and S. Schnittger, “Prognostic relevance of FLT3-TKD mutations in AML: the combination matters an analysis of 3082 patients,” Blood, vol. 111, no. 5, pp. 2527–2537, 2008. View at Publisher · View at Google Scholar · View at Scopus
  106. U. Bacher, T. Haferlach, C. Schoch, W. Kern, and S. Schnittger, “Implications of NRAS mutations in AML: a study of 2502 patients,” Blood, vol. 107, no. 10, pp. 3847–3853, 2006. View at Publisher · View at Google Scholar · View at Scopus