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Mutations in epigenetic regulators in myelodysplastic syndromes

  • Progress in Hematology
  • Dysplastic myelopoiesis—from the second JSH International Symposium
  • Published:
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Abstract

Until recently, the genetic aberrations that are causally linked to the pathogenesis of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms were largely unknown. Using novel technologies like high-resolution SNP-array analysis and next generation sequencing, various genes have now been identified that are recurrently mutated. Strikingly, several of the newly identified genes (ASXL1, DNMT3A, EZH2, IDH1 and IDH2, and TET2) are involved in the epigenetic regulation of gene expression. Aberrant epigenetic modifications have been described in many types of cancer, including myeloid malignancies. It has been proposed that repression of genes that are crucial for the cessation of the cell cycle and induction of differentiation might contribute to the malignant transformation of normal hematopoietic cells. Several therapies that aim to re-express silenced genes are currently being tested in MDS, like histone deacetylase inhibitors and hypomethylating agents. It will be interesting to assess whether patients carrying mutations in epigenetic regulators respond differently to these novel forms of epigenetic therapies.

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References

  1. Cazzola M, Della Porta MG, Travaglino E, Malcovati L. Classification and prognostic evaluation of myelodysplastic syndromes. Semin Oncol. 2011;38(5):627–34.

    Article  PubMed  CAS  Google Scholar 

  2. Tefferi A, Vardiman JW. Myelodysplastic syndromes. N Engl J Med. 2009;361:1872–85.

    Article  PubMed  CAS  Google Scholar 

  3. Nimer SD. Myelodysplastic syndromes. Blood. 2008;111:4841–51.

    Article  PubMed  CAS  Google Scholar 

  4. Haase D, Germing U, Schanz J, Pfeilstöcker M, Nösslinger T, Hildebrandt B, et al. New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients. Blood. 2007;110:4385–95.

    Article  PubMed  CAS  Google Scholar 

  5. Bejar R, Stevenson K, Abdel-Wahab O, Galili N, Nilsson B, Garcia-Manero G, et al. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med. 2011;364(26):2496–506.

    Article  PubMed  CAS  Google Scholar 

  6. Walter MJ, Ding L, Shen D, Shao J, Grillot M, McLellan M, et al. Recurrent DNMT3A mutations in patients with myelodysplastic syndromes. Leukemia. 2011;25(7):1153–8.

    Article  PubMed  CAS  Google Scholar 

  7. Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R, et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature. 2011;478(7367):64–9.

    Article  PubMed  CAS  Google Scholar 

  8. Qiu J. Epigenetics: unfinished symphony. Nature. 2006;441(7090):143–5.

    Article  PubMed  CAS  Google Scholar 

  9. Figueroa ME, Skrabanek L, Li Y, Jiemjit A, Fandy TE, Paietta E, et al. MDS and secondary AML display unique patterns and abundance of aberrant DNA methylation. Blood. 2009;114(16):3448–58.

    Article  PubMed  CAS  Google Scholar 

  10. Shen L, Kantarjian H, Guo Y, Lin E, Shan J, Huang X, et al. DNA methylation predicts survival and response to therapy in patients with myelodysplastic syndromes. J Clin Oncol. 2010;28(4):605–13.

    Article  PubMed  CAS  Google Scholar 

  11. Garcia-Manero G, Fenaux P. Hypomethylating agents and other novel strategies in myelodysplastic syndromes. J Clin Oncol. 2011;29(5):516–23.

    Article  PubMed  CAS  Google Scholar 

  12. Blum W. How much? How frequent? How long? A clinical guide to new therapies in myelodysplastic syndromes. Hematology Am Soc Hematol Educ Program. 2010;2010:314–21.

    Article  PubMed  Google Scholar 

  13. Lee SW, Cho YS, Na JM, Park UH, Kang M, Kim EJ, et al. ASXL1 represses retinoic acid receptor-mediated transcription through associating with HP1 and LSD1. J Biol Chem. 2010;285(1):18–29.

    Article  PubMed  CAS  Google Scholar 

  14. Park UH, Yoon SK, Park T, Kim EJ, Um SJ. Additional Sex Comb-like (ASXL) proteins 1 and 2 play opposite roles in adipogenesis via reciprocal regulation of peroxisome proliferator-activated receptor γ. J Biol Chem. 2011;286(2):1354–63.

    Article  PubMed  CAS  Google Scholar 

  15. Cho YS, Kim EJ, Park UH, Sin HS, Um SJ. Additional Sex Comb-like 1 (ASXL1), in cooperation with SRC-1, acts as a ligand-dependent coactivator for retinoic acid receptor. J Biol Chem. 2006;281(26):17588–98.

    Article  PubMed  CAS  Google Scholar 

  16. Huh J, Tiu RV, Gondek LP, O’Keefe CL, Jasek M, Makishima H, et al. Characterization of chromosome arm 20q abnormalities in myeloid malignancies using genome-wide single nucleotide polymorphism array analysis. Genes Chromosomes Cancer. 2010;49(4):390–9.

    PubMed  CAS  Google Scholar 

  17. Gelsi-Boyer V, Trouplin V, Adélaïde J, Bonansea J, Cervera N, Carbuccia N, et al. Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. Br J Haematol. 2009;145(6):788–800.

    Article  PubMed  CAS  Google Scholar 

  18. Boultwood J, Perry J, Pellagatti A, Fernandez-Mercado M, Fernandez-Santamaria C, Calasanz MJ, et al. Frequent mutation of the polycomb-associated gene ASXL1 in the myelodysplastic syndromes and in acute myeloid leukemia. Leukemia. 2010;24(5):1062–5.

    Article  PubMed  CAS  Google Scholar 

  19. Rocquain J, Carbuccia N, Trouplin V, Raynaud S, Murati A, Nezri M, 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.

    Article  PubMed  Google Scholar 

  20. Thol F, Friesen I, Damm F, Yun H, Weissinger EM, Krauter J, et al. Prognostic significance of ASXL1 mutations in patients with myelodysplastic syndromes. J Clin Oncol. 2011;29(18):2499–506.

    Article  PubMed  CAS  Google Scholar 

  21. Abdel-Wahab O, Kilpivaara O, Patel J, Busque L, Levine RL. The most commonly reported variant in ASXL1 (c.1934dupG;p.Gly646TrpfsX12) is not a somatic alteration. Leukemia. 2010;24(9):1656–7.

    Article  PubMed  CAS  Google Scholar 

  22. Jurkowska RZ, Jurkowski TP, Jeltsch A. Structure and function of mammalian DNA methyltransferases. Chembiochem. 2011;12(2):206–22.

    Article  PubMed  CAS  Google Scholar 

  23. Cheng X, Blumenthal RM. Mammalian DNA methyltransferases: a structural perspective. Structure. 2008;16(3):341–50.

    Article  PubMed  Google Scholar 

  24. Tadokoro Y, Ema H, Okano M, Li E, Nakauchi H. De novo DNA methyltransferase is essential for self-renewal, but not for differentiation, in hematopoietic stem cells. J Exp Med. 2007;204(4):715–22.

    Article  PubMed  CAS  Google Scholar 

  25. Wu H, Coskun V, Tao J, Xie W, Ge W, Yoshikawa K, et al. Dnmt3a-dependent nonpromoter DNA methylation facilitates transcription of neurogenic genes. Science. 2010;329(5990):444–8.

    Article  PubMed  CAS  Google Scholar 

  26. Irizarry RA, Ladd-Acosta C, Wen B, Wu Z, Montano C, Onyango P, et al. The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet. 2009;41(2):178–86.

    Article  PubMed  CAS  Google Scholar 

  27. Esteller M. Aberrant DNA methylation as a cancer-inducing mechanism. Annu Rev Pharmacol Toxicol. 2005;45:629–56.

    Article  PubMed  CAS  Google Scholar 

  28. Lin J, Yao DM, Qian J, Chen Q, Qian W, Li Y, et al. Recurrent DNMT3A R882 mutations in Chinese patients with acute myeloid leukemia and myelodysplastic syndrome. PLoS One. 2011;6(10):e26906.

    Article  PubMed  CAS  Google Scholar 

  29. Thol F, Winschel C, Ludeking A, Yun H, Friesen I, Damm F, et al. Rare occurence of DNMT3A mutations in myelodysplastic syndromes. Haematologica. 2011. doi:10.3324/haematol.2011.045559.

  30. Shen Y, Zhu YM, Fan X, Shi JY, Wang QR, Yan XJ, et al. Gene mutation patterns and their prognostic impact in a cohort of 1185 patients with acute myeloid leukemia. Blood. 2011;118(20):5593–603.

    Article  PubMed  CAS  Google Scholar 

  31. Yan XJ, Xu J, Gu ZH, Pan CM, Lu G, Shen Y, et al. Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat Genet. 2011;43(4):309–15.

    Article  PubMed  CAS  Google Scholar 

  32. Suetake I, Mishima Y, Kimura H, Lee YH, Goto Y, Takeshima H, et al. Characterization of DNA- binding activity in the N-terminal domain of the DNA methyltransferase Dnmt3a. Biochem J. 2011;437(1):141–8.

    Article  PubMed  CAS  Google Scholar 

  33. Galetzka D, Tralau T, Stein R, Haaf T. Expression of DNMT3A transcripts and nucleolar localization of DNMT3A protein in human testicular and fibroblast cells suggest a role for de novo DNA methylation in nucleolar inactivation. J Cell Biochem. 2006;98(4):885–94.

    Article  PubMed  CAS  Google Scholar 

  34. Galetzka D, Weis E, Tralau T, Seidmann L, Haaf T. Sex-specific windows for high mRNA expression of DNA methyltransferases 1 and 3A and methyl-CpG-binding domain proteins 2 and 4 in human fetal gonads. Mol Reprod Dev. 2007;74(2):233–41.

    Article  PubMed  CAS  Google Scholar 

  35. Moarefi AH, Chédin F. ICF syndrome mutations cause a broad spectrum of biochemical defects in DNMT3B-mediated de novo DNA methylation. J Mol Biol. 2011;409(5):758–72.

    Article  PubMed  CAS  Google Scholar 

  36. Brun ME, Lana E, Rivals I, Lefranc G, Sarda P, Claustres M, et al. Heterochromatic genes undergo epigenetic changes and escape silencing in immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome. PLoS One. 2011;6(4):e19464.

    Article  PubMed  CAS  Google Scholar 

  37. Sneeringer CJ, Scott MP, Kuntz KW, Knutson SK, Pollock RM, Richon VM, et al. Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc Natl Acad Sci USA. 2010;107(49):20980–5.

    Article  PubMed  CAS  Google Scholar 

  38. Chase A, Cross NC. Aberrations of EZH2 in cancer. Clin Cancer Res. 2011;17(9):2613–8.

    Article  PubMed  CAS  Google Scholar 

  39. Cui K, Zang C, Roh TY, Schones DE, Childs RW, Peng W, et al. Chromatin signatures in multipotent human hematopoietic stem cells indicate the fate of bivalent genes during differentiation. Cell Stem Cell. 2009;4(1):80–93.

    Article  PubMed  CAS  Google Scholar 

  40. Nikoloski G, Langemeijer SMC, Kuiper RP, Knops R, Massop M, Tönnissen ERLTM, et al. Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat Genet. 2010;42:665–7.

    Article  PubMed  CAS  Google Scholar 

  41. Ernst T, Chase AJ, Score J, Hidalgo-Curtis CE, Bryant C, Jones AV, et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet. 2010;42:722–6.

    Article  PubMed  CAS  Google Scholar 

  42. Makishima H, Jankowska AM, Tiu RV, Szpurka H, Sugimoto Y, Hu Z, et al. Novel homo- and hemizygous mutations in EZH2 in myeloid malignancies. Leukemia. 2010;24(10):1799–804.

    Article  PubMed  CAS  Google Scholar 

  43. 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):932–41.

    Article  PubMed  CAS  Google Scholar 

  44. Fu Y, Huang R, Du J, Yang R, An N, Liang A. Glioma-derived mutations in IDH: from mechanism to potential therapy. Biochem Biophys Res Commun. 2010;397(2):127–30.

    Article  PubMed  CAS  Google Scholar 

  45. Bourne TD, Schiff D. Update on molecular findings management and outcome in low-grade gliomas. Nat Rev Neurol. 2010;6(12):695–701.

    Article  PubMed  Google Scholar 

  46. Kosmider O, Gelsi-Boyer V, Slama L, Dreyfus F, Beyne-Rauzy O, Quesnel B, et al. Mutations of IDH1 and IDH2 genes in early and accelerated phases of myelodysplastic syndromes and MDS/myeloproliferative neoplasms. Leukemia. 2010;24(5):1094–6.

    Article  PubMed  CAS  Google Scholar 

  47. Thol F, Weissinger EM, Krauter J, Wagner K, Damm F, Wichmann M, et al. IDH1 mutations in patients with myelodysplastic syndromes are associated with an unfavorable prognosis. Haematologica. 2010;95(10):1668–74.

    Article  PubMed  CAS  Google Scholar 

  48. Yoshida K, Sanada M, Kato M, Kawahata R, Matsubara A, Takita J, et al. A nonsense mutation of IDH1 in myelodysplastic syndromes and related disorders. Leukemia. 2011;25(1):184–6.

    Article  PubMed  CAS  Google Scholar 

  49. Patnaik MM, Hanson CA, Hodnefield JM, Lasho TL, Finke CM, Knudson RA, et al. Differential prognostic effect of IDH1 versus IDH2 mutations in myelodysplastic syndromes: a Mayo Clinic Study of 277 patients. Leukemia. 2011. doi: 10.1038/leu.2011.298.

  50. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462(7274):739–44.

    Article  PubMed  CAS  Google Scholar 

  51. Gross S, Cairns RA, Minden MD, Driggers EM, Bittinger MA, Jang HG, 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):339–44.

    Article  PubMed  CAS  Google Scholar 

  52. Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18(6):553–67.

    Article  PubMed  CAS  Google Scholar 

  53. Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011;19(1):17–30.

    Article  PubMed  CAS  Google Scholar 

  54. Chowdhury R, Yeoh KK, Tian YM, Hillringhaus L, Bagg EA, Rose NR, et al. The oncometabolite 2- hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 2011;12(5):463–9.

    Article  PubMed  CAS  Google Scholar 

  55. Caramazza D, Lasho TL, Finke CM, Gangat N, Dingli D, Knudson RA, et al. IDH mutations and trisomy 8 in myelodysplastic syndromes and acute myeloid leukemia. Leukemia. 2010;24(12):2120–2.

    Article  PubMed  CAS  Google Scholar 

  56. Pardanani A, Patnaik MM, Lasho TL, Mai M, Knudson RA, Finke C, et al. Recurrent IDH mutations in high-risk myelodysplastic syndrome or acute myeloid leukemia with isolated del(5q). Leukemia. 2010;24(7):1370–2.

    Article  PubMed  CAS  Google Scholar 

  57. Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, et al. Conversion of 5- methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009;324(5929):930–5.

    Article  PubMed  CAS  Google Scholar 

  58. He YF, Li BZ, Li Z, Liu P, Wang Y, Tang Q, et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science. 2011;333(6047):1303–7.

    Article  PubMed  CAS  Google Scholar 

  59. Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, et al. Tet proteins can convert 5- methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science. 2011;333(6047):1300–3.

    Article  PubMed  CAS  Google Scholar 

  60. Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Massé A, et al. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009;360(22):2289–301.

    Article  PubMed  Google Scholar 

  61. Langemeijer SM, Kuiper RP, Berends M, Knops R, Aslanyan MG, Massop M, et al. Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet. 2009;41(7):838–42.

    Article  PubMed  CAS  Google Scholar 

  62. Quivoron C, Couronné L, Della Valle V, Lopez CK, Plo I, Wagner-Ballon O, et al. TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. Cancer Cell. 2011;20(1):25–38.

    Article  PubMed  CAS  Google Scholar 

  63. Moran-Crusio K, Reavie L, Shih A, Abdel-Wahab O, Ndiaye-Lobry D, Lobry C, et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell. 2011;20(1):11–24.

    Article  PubMed  CAS  Google Scholar 

  64. Li Z, Cai X, Cai CL, Wang J, Zhang W, Petersen BE, et al. Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. Blood. 2011;118(17):4509–18.

    Article  PubMed  CAS  Google Scholar 

  65. Ko M, Huang Y, Jankowska AM, Pape UJ, Tahiliani M, Bandukwala HS, et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature. 2010;468(7325):839–43.

    Article  PubMed  CAS  Google Scholar 

  66. Pollyea DA, Raval A, Kusler B, Gotlib JR, Alizadeh AA, Mitchell BS. Impact of TET2 mutations on mRNA expression and clinical outcomes in MDS patients treated with DNA methyltransferase inhibitors. Hematol Oncol. 2011;29(3):157–60.

    Article  PubMed  CAS  Google Scholar 

  67. Itzykson R, Kosmider O, Cluzeau T, Mansat-De Mas V, Dreyfus F, Beyne-Rauzy O, et al. Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias. Leukemia. 2011;25(7):1147–52.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Gorica Nikoloski.

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Nikoloski, G., van der Reijden, B.A. & Jansen, J.H. Mutations in epigenetic regulators in myelodysplastic syndromes. Int J Hematol 95, 8–16 (2012). https://doi.org/10.1007/s12185-011-0996-3

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  • DOI: https://doi.org/10.1007/s12185-011-0996-3

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