Vol 9, No 2 (2018)
Review paper
Published online: 2018-08-17

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Alterations of epigenetic mechanisms in acute myeloid leukemia

Kamil Wiśniewski1, Emilia Białopiotrowicz, Joanna Góra-Tybor1
Hematologia 2018;9(2):100-109.

Abstract

Epigenetic regulation influences gene expression without changing the nucleotide sequence of the deoxyribonucleic acid (DNA). The most important epigenetic mechanisms include DNA methylation, modifications of histone proteins and non-coding RNAs. The dysregulation of the above mentioned processes plays a significant role in the pathogenesis of acute myeloid leukemia (AML). Mutations in the genes that are essential for epigenetic regulations are common in 70% of patients with AML. The most frequent mutations involve the DNMT3A, TET2, IDH1/2 and ASXL1 genes. Their presence or absence may constitute a vital prognostic factor in the future as well as become a potential basis for targeted therapies. The present paper manifests the importance of epigenetic alterations in the development of acute myeloid leukemia and their impact on the course of the disease. The article also discusses some possibilities for the use of epigenetic modifications in the AML therapy.

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References

  1. Estey E, Döhner H. Acute myeloid leukaemia. Lancet. 2006; 368(9550): 1894–1907.
  2. Zhou HS, Carter BZ, Andreeff M. Bone marrow niche-mediated survival of leukemia stem cells in acute myeloid leukemia: Yin and Yang. Cancer Biol Med. 2016; 13(2): 248–259.
  3. Oran B, Weisdorf DJ. Survival for older patients with acute myeloid leukemia: a population-based study. Haematologica. 2012; 97(12): 1916–1924.
  4. Burnett A, Wetzler M, Löwenberg B. Therapeutic advances in acute myeloid leukemia. J Clin Oncol. 2011; 29(5): 487–494.
  5. Shah A, Andersson TML, Rachet B, et al. Survival and cure of acute myeloid leukaemia in England, 1971-2006: a population-based study. Br J Haematol. 2013; 162(4): 509–516.
  6. Klepin HD. Elderly acute myeloid leukemia: assessing risk. Curr Hematol Malig Rep. 2015; 10(2): 118–125.
  7. Mrózek K, Carroll AJ, Maharry K, et al. Cytogenetics in acute leukemia. Blood Rev. 2004; 18(2): 115–136.
  8. Mardis ER, Ding Li, Dooling DJ, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009; 361(11): 1058–1066.
  9. Welch JS, Petti AA, Miller CA, et al. The origin and evolution of mutations in acute myeloid leukemia. Cell. 2012; 150(2): 264–278.
  10. Esteller M. Epigenetics in cancer. N Engl J Med. 2008; 358(11): 1148–1159.
  11. Figueroa ME, Lugthart S, Li Y, et al. DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell. 2010; 17(1): 13–27.
  12. Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007; 128(4): 683–692.
  13. Gutierrez SE, Romero-Oliva FA. Epigenetic changes: a common theme in acute myelogenous leukemogenesis. J Hematol Oncol. 2013; 6: 57.
  14. Egger G, Liang G, Aparicio A, et al. Epigenetics in human disease and prospects for epigenetic therapy. Nature. 2004; 429(6990): 457–463.
  15. Tollervey JR, Lunyak VV. Epigenetics: judge, jury and executioner of stem cell fate. Epigenetics. 2012; 7(8): 823–840.
  16. Fong CY, Morison J, Dawson MA. Epigenetics in the hematologic malignancies. Haematologica. 2014; 99(12): 1772–1783.
  17. Greenblatt SM, Nimer SD. Chromatin modifiers and the promise of epigenetic therapy in acute leukemia. Leukemia. 2014; 28(7): 1396–1406.
  18. Łukasik M, Karmalska J, Szutowski MM, et al. Wpływ metylacji DNA na funkcjonowanie genomu. Biuletyn Wydziału Farmaceutycznego Warszawskiego Uniwersytetu Medycznego. 2009; 2: 13–18.
  19. Lopez-Serra L, Esteller M. Proteins that bind methylated DNA and human cancer: reading the wrong words. Br J Cancer. 2008; 98(12): 1881–1885.
  20. Ley TJ, Miller C, Ding Li, et al. Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013; 368(22): 2059–2074.
  21. Baylin SB, Jones PA. A decade of exploring the cancer epigenome - biological and translational implications. Nat Rev Cancer. 2011; 11(10): 726–734.
  22. Kroeger H, Jelinek J, Estécio MRH, et al. Aberrant CpG island methylation in acute myeloid leukemia is accentuated at relapse. Blood. 2008; 112(4): 1366–1373.
  23. Qu Y, Lennartsson A, Gaidzik VI, et al. Differential methylation in CN-AML preferentially targets non-CGI regions and is dictated by DNMT3A mutational status and associated with predominant hypomethylation of HOX genes. Epigenetics. 2014; 9(8): 1108–1119.
  24. Toyota M, Ahuja N, Ohe-Toyota M, et al. CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci USA. 1999; 96(15): 8681–8686.
  25. Boyes J, Bird A. DNA methylation inhibits transcription indirectly via a methyl-CpG binding protein. Cell. 1991; 64(6): 1123–1134.
  26. Watt F, Molloy PL. Cytosine methylation prevents binding to DNA of a HeLa cell transcription factor required for optimal expression of the adenovirus major late promoter. Genes Dev. 1988; 2(9): 1136–1143.
  27. Gonzalgo ML, Jones PA. Mutagenic and epigenetic effects of DNA methylation. Mutat Res. 1997; 386(2): 107–118.
  28. Shen L, Kantarjian H, Guo Yi, et al. DNA methylation predicts survival and response to therapy in patients with myelodysplastic syndromes. J Clin Oncol. 2010; 28(4): 605–613.
  29. Ehrlich M. DNA hypomethylation in cancer cells. Epigenomics. 2009; 1(2): 239–259.
  30. Saied MH, Marzec J, Khalid S, et al. Genome wide analysis of acute myeloid leukemia reveal leukemia specific methylome and subtype specific hypomethylation of repeats. PLoS One. 2012; 7(3): e33213.
  31. Chan SM, Majeti R. Role of DNMT3A, TET2, and IDH1/2 mutations in pre-leukemic stem cells in acute myeloid leukemia. Int J Hematol. 2013; 98(6): 648–657.
  32. Yamashita Y, Yuan J, Suetake I, et al. Array-based genomic resequencing of human leukemia. Oncogene. 2010; 29(25): 3723–3731.
  33. Ley TJ, Ding Li, Walter MJ, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med. 2010; 363(25): 2424–2433.
  34. Rice KL, Licht JD. HOX deregulation in acute myeloid leukemia. J Clin Invest. 2007; 117(4): 865–868.
  35. Alharbi RA, Pettengell R, Pandha HS, et al. The role of HOX genes in normal hematopoiesis and acute leukemia. Leukemia. 2013; 27(5): 1000–1008.
  36. Shah N, Sukumar S. The Hox genes and their roles in oncogenesis. Nat Rev Cancer. 2010; 10(5): 361–371.
  37. Challen GA, Sun D, Jeong M, et al. Dnmt3a is essential for hematopoietic stem cell differentiation. Nat Genet. 2011; 44(1): 23–31.
  38. Marcucci G, Metzeler KH, Schwind S, et al. Age-related prognostic impact of different types of DNMT3A mutations in adults with primary cytogenetically normal acute myeloid leukemia. J Clin Oncol. 2012; 30(7): 742–750.
  39. Hájková H, Marková J, Haškovec C, et al. Decreased DNA methylation in acute myeloid leukemia patients with DNMT3A mutations and prognostic implications of DNA methylation. Leuk Res. 2012; 36(9): 1128–1133.
  40. Thol F, Damm F, Lüdeking A, et al. Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia. J Clin Oncol. 2011; 29(21): 2889–2896.
  41. Yuan XQ, Peng Li, Zeng WJ, et al. DNMT3A R882 mutations predict a poor prognosis in AML: a meta-analysis from 4474 patients. Medicine (Baltimore). 2016; 95(18): e3519.
  42. Hopfer O, Komor M, Koehler IS, et al. Aberrant promotor methylation in MDS hematopoietic cells during in vitro lineage specific differentiation is differently associated with DNMT isoforms. Leuk Res. 2009; 33(3): 434–442.
  43. Ribeiro AF, Pratcorona M, Erpelinck-Verschueren C, et al. Mutant DNMT3A: a marker of poor prognosis in acute myeloid leukemia. Blood. 2012; 119(24): 5824–5831.
  44. Walter MJ, Ding L, Shen D, et al. Recurrent DNMT3A mutations in patients with myelodysplastic syndromes. Leukemia. 2011; 25(7): 1153–1158.
  45. Traina F, Visconte V, Elson P, et al. Impact of molecular mutations on treatment response to DNMT inhibitors in myelodysplasia and related neoplasms. Leukemia. 2014; 28(1): 78–87.
  46. Metzeler KH, Walker A, Geyer S, et al. DNMT3A mutations and response to the hypomethylating agent decitabine in acute myeloid leukemia. Leukemia. 2012; 26(5): 1106–1107.
  47. Tahiliani M, Koh KP, Shen Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009; 324(5929): 930–935.
  48. Ito S, D'Alessio AC, Taranova OV, et al. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature. 2010; 466(7310): 1129–1133.
  49. Valinluck V, Sowers LC. Endogenous cytosine damage products alter the site selectivity of human DNA maintenance methyltransferase DNMT1. Cancer Res. 2007; 67(3): 946–950.
  50. Valinluck V, Tsai HH, Rogstad DK, et al. Oxidative damage to methyl-CpG sequences inhibits the binding of the methyl-CpG binding domain (MBD) of methyl-CpG binding protein 2 (MeCP2). Nucleic Acids Res. 2004; 32(14): 4100–4108.
  51. Pastor WA, Pape UJ, Huang Y, et al. Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells. Nature. 2011; 473(7347): 394–397.
  52. Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010; 18(6): 553–567.
  53. Metzeler KH, Maharry K, Radmacher MD, et al. TET2 mutations improve the new European LeukemiaNet risk classification of acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol. 2011; 29(10): 1373–1381.
  54. Patel KP, Ravandi F, Ma D. Acute myeloid leukemia with IDH1 or IDH2 mutation: frequency and clinicopathologic features. Am J Clin Pathol. 2011; 135(1): 35–45.
  55. Bejar R, Lord A, Stevenson K, et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood. 2014; 124(17): 2705–2712.
  56. Kouzarides T. Chromatin modifications and their function. Cell. 2007; 128(4): 693–705.
  57. Wang Y, Fischle W, Cheung W, et al. Beyond the double helix: writing and reading the histone code. Novartis Found Symp. 2004; 259: 3–17; discussion 17.
  58. de la Cruz X, Lois S, Sánchez-Molina S, et al. Do protein motifs read the histone code? Bioessays. 2005; 27(2): 164–175.
  59. Sterner DE, Berger SL. Acetylation of histones and transcription-related factors. Microbiol Mol Biol Rev. 2000; 64(2): 435–459.
  60. Vettese-Dadey M, Grant PA, Hebbes TR, et al. Acetylation of histone H4 plays a primary role in enhancing transcription factor binding to nucleosomal DNA in vitro. EMBO J. 1996; 15(10): 2508–2518.
  61. Lee JY, Lee TH. Effects of histone acetylation and CpG methylation on the structure of nucleosomes. Biochim Biophys Acta. 2012; 1824: 974–982.
  62. Delcuve GP, Khan DH, Davie JR. Roles of histone deacetylases in epigenetic regulation: emerging paradigms from studies with inhibitors. Clin Epigenetics. 2012; 4(1): 5.
  63. Verdin E, Ott M. 50 years of protein acetylation: from gene regulation to epigenetics, metabolism and beyond. Nat Rev Mol Cell Biol. 2015; 16(4): 258–264.
  64. Advani AS, Gibson SE, Douglas E, et al. Histone H4 acetylation by immunohistochemistry and prognosis in newly diagnosed adult acute lymphoblastic leukemia (ALL) patients. BMC Cancer. 2010; 10: 387.
  65. Rozman M, Camós M, Colomer D, et al. Type I MOZ/CBP (MYST3/CREBBP) is the most common chimeric transcript in acute myeloid leukemia with t(8;16)(p11;p13) translocation. Genes Chromosomes Cancer. 2004; 40(2): 140–145.
  66. Deguchi K, Ayton PM, Carapeti M, et al. MOZ-TIF2-induced acute myeloid leukemia requires the MOZ nucleosome binding motif and TIF2-mediated recruitment of CBP. Cancer Cell. 2003; 3(3): 259–271.
  67. Izutsu K, Kurokawa M, Imai Y, et al. The corepressor CtBP interacts with Evi-1 to repress transforming growth factor beta signaling. Blood. 2001; 97(9): 2815–2822.
  68. Martens JHA, Brinkman AB, Simmer F, et al. PML-RARalpha/RXR alters the epigenetic landscape in acute promyelocytic leukemia. Cancer Cell. 2010; 17(2): 173–185.
  69. Minucci S, Nervi C, Lo Coco F, et al. Histone deacetylases: a common molecular target for differentiation treatment of acute myeloid leukemias? Oncogene. 2001; 20(24): 3110–3115.
  70. Castelli G, Pelosi E, Testa U. Targeting histone methyltransferase and demethylase in acute myeloid leukemia therapy. Onco Targets Ther. 2018; 11: 131–155.
  71. Esteller M. Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet. 2007; 8(4): 286–298.
  72. Cheung N, So CW. Transcriptional and epigenetic networks in haematological malignancy. FEBS Lett. 2011; 585(13): 2100–2111.
  73. Kuzmichev A, Jenuwein T, Tempst P, et al. Different EZH2-containing complexes target methylation of histone H1 or nucleosomal histone H3. Mol Cell. 2004; 14(2): 183–193.
  74. Ernst T, Chase AJ, Score J, et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet. 2010; 42(8): 722–726.
  75. Nikoloski G, Langemeijer SMC, Kuiper RP, et al. Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat Genet. 2010; 42(8): 665–667.
  76. Tanaka S, Miyagi S, Sashida G, et al. Ezh2 augments leukemogenicity by reinforcing differentiation blockage in acute myeloid leukemia. Blood. 2012; 120(5): 1107–1117.
  77. Herrera-Merchan A, Arranz L, Ligos JM, et al. Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease. Nat Commun. 2012; 3: 623.
  78. Simon JA, Lange CA. Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat Res. 2008; 647(1-2): 21–29.
  79. Morin RD, Johnson NA, Severson TM, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet. 2010; 42(2): 181–185.
  80. Wang X, Dai H, Wang Q, 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. 2013; 8(4): e61341.
  81. Göllner S, Oellerich T, Agrawal-Singh S, et al. Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia. Nat Med. 2017; 23(1): 69–78.
  82. Le Beau MM, Espinosa R, Davis EM, et al. Cytogenetic and molecular delineation of a region of chromosome 7 commonly deleted in malignant myeloid diseases. Blood. 1996; 88(6): 1930–1935.
  83. Ringrose L, Paro R. Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins. Annu Rev Genet. 2004; 38: 413–443.
  84. Hess JL. MLL: a histone methyltransferase disrupted in leukemia. Trends Mol Med. 2004; 10(10): 500–507.
  85. Krivtsov AV, Armstrong SA. MLL translocations, histone modifications and leukaemia stem-cell development. Nat Rev Cancer. 2007; 7(11): 823–833.
  86. Marschalek R. Mixed lineage leukemia: roles in human malignancies and potential therapy. FEBS J. 2010; 277(8): 1822–1831.
  87. Zeisig BB, So CW. Cellular and molecular basis of KMT2A/MLL leukaemias: from transformation mechanisms to novel therapeutic strategies. In: Rowley JD, Le Beau MM, Rabbitts TH. ed. Chromosomal translocations and genome rearrangements in cancer. Springer, New York 2016: 223–250.
  88. Döhner K, Tobis K, Ulrich R, et al. Prognostic significance of partial tandem duplications of the MLL gene in adult patients 16 to 60 years old with acute myeloid leukemia and normal cytogenetics: a study of the Acute Myeloid Leukemia Study Group Ulm. J Clin Oncol. 2002; 20(15): 3254–3261.
  89. Harrison CJ, Griffiths M, Moorman F, et al. A multicenter evaluation of comprehensive analysis of MLL translocations and fusion gene partners in acute leukemia using the MLL FusionChip device. Cancer Genet Cytogenet. 2007; 173(1): 17–22.
  90. Abdel-Wahab O, Adli M, LaFave LM, et al. ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression. Cancer Cell. 2012; 22(2): 180–193.
  91. Patel JP, Gönen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012; 366(12): 1079–1089.
  92. Boultwood J, Perry J, Pellagatti A, et al. Frequent mutation of the polycomb-associated gene ASXL1 in the myelodysplastic syndromes and in acute myeloid leukemia. Leukemia. 2010; 24(5): 1062–1065.
  93. Rocquain J, Carbuccia N, Trouplin V, et al. Combined mutations of ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 and WT1 genes in myelodysplastic syndromes and acute myeloid leukemias. BMC Cancer. 2010; 10: 401.
  94. Metzeler KH, Becker H, Maharry K, et al. ASXL1 mutations identify a high-risk subgroup of older patients with primary cytogenetically normal AML within the ELN Favorable genetic category. Blood. 2011; 118(26): 6920–6929.
  95. Schnittger S, Eder C, Jeromin S, et al. ASXL1 exon 12 mutations are frequent in AML with intermediate risk karyotype and are independently associated with an adverse outcome. Leukemia. 2013; 27(1): 82–91.
  96. Paschka P, Schlenk RF, Gaidzik VI, et al. ASXL1 mutations in younger adult patients with acute myeloid leukemia: a study by the German-Austrian Acute Myeloid Leukemia Study Group. Haematologica. 2015; 100(3): 324–330.
  97. Abdel-Wahab O, Levine RL. Mutations in epigenetic modifiers in the pathogenesis and therapy of acute myeloid leukemia. Blood. 2013; 121(18): 3563–3572.
  98. Katoh M. Functional and cancer genomics of ASXL family members. Br J Cancer. 2013; 109(2): 299–306.
  99. Pratcorona M, Abbas S, Sanders MA, et al. Acquired mutations in ASXL1 in acute myeloid leukemia: prevalence and prognostic value. Haematologica. 2012; 97(3): 388–392.
  100. Abdel-Wahab O, Kilpivaara O, Patel J, et al. The most commonly reported variant in ASXL1 (c.1934dupG;p.Gly646TrpfsX12) is not a somatic alteration. Leukemia. 2010; 24(9): 1656–1657.
  101. Abdel-Wahab O, Manshouri T, Patel J, et al. Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias. Cancer Res. 2010; 70(2): 447–452.
  102. Bejar R, Stevenson K, Stojanov P, et al. O-024 Next-generation sequencing of 213 MDS patient samples identifies mutation profiles associated with response to hypomethylating agents and overall survival. Leuk Res. 2013; 37: S19–S20.
  103. Itzykson R, Kosmider O, Cluzeau T, et al. Groupe Francophone des Myelodysplasies (GFM). Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias. Leukemia. 2011; 25(7): 1147–1152.
  104. Reitman ZJ, Yan H. Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. J Natl Cancer Inst. 2010; 102(13): 932–941.
  105. Dang L, White DW, Gross S, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009; 462(7274): 739–744.
  106. Ward PS, Patel J, Wise DR, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010; 17(3): 225–234.
  107. Gross S, Cairns RA, Minden MD, et al. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med. 2010; 207(2): 339–344.
  108. Reitman ZJ, Parsons DW, Yan H. IDH1 and IDH2: not your typical oncogenes. Cancer Cell. 2010; 17(3): 215–216.
  109. Shen Y, Zhu YM, Fan X, et al. Gene mutation patterns and their prognostic impact in a cohort of 1185 patients with acute myeloid leukemia. Blood. 2011; 118(20): 5593–5603.
  110. Abbas S, Lugthart S, Kavelaars FG, et al. Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: prevalence and prognostic value. Blood. 2010; 116(12): 2122–2126.
  111. Paschka P, Schlenk RF, Gaidzik VI, 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. J Clin Oncol. 2010; 28(22): 3636–3643.
  112. Marcucci G, Maharry K, Wu YZ, 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. J Clin Oncol. 2010; 28(14): 2348–2355.
  113. Xu W, Yang H, Liu Y, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011; 19(1): 17–30.
  114. DiNardo CD, Propert KJ, Loren AW, et al. Serum 2-hydroxyglutarate levels predict isocitrate dehydrogenase mutations and clinical outcome in acute myeloid leukemia. Blood. 2013; 121(24): 4917–4924.
  115. DiNardo CD, de Botton S, Stein EM, et al. Ivosidenib (AG-120) in mutant IDH1 AML and advanced hematologic malignancies: results of a phase 1 dose escalation and expansion study. Blood. 2017; 130: 725.
  116. Nassereddine S, Lap CJ, Haroun F, et al. The role of mutant IDH1 and IDH2 inhibitors in the treatment of acute myeloid leukemia. Ann Hematol. 2017; 96(12): 1983–1991.
  117. Vasilatou D, Papageorgiou S, Pappa V, et al. The role of microRNAs in normal and malignant hematopoiesis. Eur J Haematol. 2010; 84(1): 1–16.
  118. Jongen-Lavrencic M, Sun SuM, Dijkstra MK, et al. MicroRNA expression profiling in relation to the genetic heterogeneity of acute myeloid leukemia. Blood. 2008; 111(10): 5078–5085.
  119. Garzon R, Liu S, Fabbri M, et al. MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1. Blood. 2009; 113(25): 6411–6418.
  120. Ufkin ML, Peterson S, Yang X, et al. miR-125a regulates cell cycle, proliferation, and apoptosis by targeting the ErbB pathway in acute myeloid leukemia. Leuk Res. 2014; 38(3): 402–410.
  121. Winter J, Diederichs S. MicroRNA biogenesis and cancer. Methods Mol Biol. 2011; 676: 3–22.
  122. Li Z, Lu J, Sun M, et al. Distinct microRNA expression profiles in acute myeloid leukemia with common translocations. Proc Natl Acad Sci U S A. 2008; 105(40): 15535–15540.
  123. Mendler JH, Maharry K, Radmacher MD, et al. MicroRNA expression in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008; 358(18): 1919–1928.
  124. Gong JN, Yu J, Lin HS, et al. The role, mechanism and potentially therapeutic application of microRNA-29 family in acute myeloid leukemia. Cell Death Differ. 2014; 21(1): 100–112.
  125. Su R, Lin HS, Zhang XH, et al. MiR-181 family: regulators of myeloid differentiation and acute myeloid leukemia as well as potential therapeutic targets. Oncogene. 2015; 34(25): 3226–3239.
  126. Chung SS, Park CY. MicroRNA dysregulation in the myelodysplastic syndromes. Microrna. 2014; 2(3): 174–186.



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