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  • Spotlight Review
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Spotlight on Epigenetics in Hematologic Malignancies

The Ten-Eleven Translocation-2 (TET2) gene in hematopoiesis and hematopoietic diseases

Leukemia volume 28, pages 485–496 (2014)Cite this article

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Abstract

Ten-Eleven Translocation-2 (TET2) inactivation through loss-of-function mutation, deletion and IDH1/2 (Isocitrate Dehydrogenase 1 and 2) gene mutation is a common event in myeloid and lymphoid malignancies. TET2 gene mutations similar to those observed in myeloid and lymphoid malignancies also accumulate with age in otherwise healthy subjects with clonal hematopoiesis. TET2 is one of the three proteins of the TET (Ten-Eleven Translocation) family, which are evolutionarily conserved dioxygenases that catalyze the conversion of 5-methyl-cytosine (5-mC) to 5-hydroxymethyl-cytosine (5-hmC) and promote DNA demethylation. TET dioxygenases require 2-oxoglutarate, oxygen and Fe(II) for their activity, which is enhanced in the presence of ascorbic acid. TET2 is the most expressed TET gene in the hematopoietic tissue, especially in hematopoietic stem cells. In addition to their hydroxylase activity, TET proteins recruit the O-linked β-D-N-acetylglucosamine (O-GlcNAc) transferase (OGT) enzyme to chromatin, which promotes post-transcriptional modifications of histones and facilitates gene expression. The TET2 level is regulated by interaction with IDAX, originating from TET2 gene fission during evolution, and by the microRNA miR-22. TET2 has pleiotropic roles during hematopoiesis, including stem-cell self-renewal, lineage commitment and terminal differentiation of monocytes. Analysis of Tet2 knockout mice, which are viable and fertile, demonstrated that Tet2 functions as a tumor suppressor whose haploinsufficiency initiates myeloid and lymphoid transformations. This review summarizes the recently identified TET2 physiological and pathological functions and discusses how this knowledge influences our therapeutic approaches in hematological malignancies and possibly other tumor types.

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References

  1. 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: 2289–2301.

    Article  PubMed  Google Scholar 

  2. 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: 838–842.

    Article  CAS  PubMed  Google Scholar 

  3. 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: 930–935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ono R, Taki T, Taketani T, Taniwaki M, Kobayashi H, Hayashi Y . LCX, leukemia-associated protein with a CXXC domain, is fused to MLL in acute myeloid leukemia with trilineage dysplasia having t(10;11)(q22;q23). Cancer Res 2002; 62: 4075–4080.

    CAS  PubMed  Google Scholar 

  5. Lorsbach RB, Moore J, Mathew S, Raimondi SC, Mukatira ST, Downing JR . TET1, a member of a novel protein family, is fused to MLL in acute myeloid leukemia containing the t(10;11)(q22;q23). Leukemia 2003; 17: 637–641.

    Article  CAS  PubMed  Google Scholar 

  6. Ko M, An J, Bandukwala HS, Chavez L, Aijö T, Pastor WA et al. Modulation of TET2 expression and 5-methylcytosine oxidation by the CXXC domain protein IDAX. Nature 2013; 497: 122–126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Xu Y, Xu C, Kato A, Tempel W, Abreu JG, Bian C et al. Tet3 CXXC domain and dioxygenase activity cooperatively regulate key genes for Xenopus eye and neural development. Cell 2012; 151: 1200–1213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kaelin WG Jr, McKnight SL . Influence of metabolism on epigenetics and disease. Cell 2013; 153: 56–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yin R, Mao SQ, Zhao B, Chong Z, Yang Y, Zhao C et al. Ascorbic Acid enhances tet-mediated 5-methylcytosine oxidation and promotes DNA demethylation in mammals. J Am Chem Soc 2013; 135: 10396–10403.

    Article  CAS  PubMed  Google Scholar 

  10. Blaschke K, Ebata KT, Karimi MM, Zepeda-Martínez JA, Goyal P, Mahapatra S et al. Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. Nature 2013; 500: 222–226.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kovaleva EG, Lipscomb JD . Versatility of biological non-heme Fe(II) centers in oxygen activation reactions. Nat Chem Biol 2008; 4: 186–193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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: 553–567.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Coulter JB, O'Driscoll CM, Bressler JP . Hydroquinone increases 5-hydroxymethylcytosine formation through Ten Eleven Translocation 1 (Tet1) 5-methylcytosine dioxygenase. J Biol Chem 2013; 288: 28792–28800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ito S, D’Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y . Role of Tet proteins in 5mC to 5-hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 2010; 466: 1129–1133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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: 839–843.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Guo JU, Su Y, Zhong C, Ming GL, Song H . Emerging roles of TET proteins and 5-hydroxymethylcytosines in active DNA demethylation and beyond. Cell Cycle 2011; 10: 2662–2668.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bhutani N, Burns DM, Blau HM . DNA demethylation dynamics. Cell 2011; 146: 866–872.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Nabel CS, Manning SA, Kohli RM . The curious chemical biology of cytosine: deamination, methylation, and oxidation as modulators of genomic potential. ACS Chem Biol 2012; 7: 20–30.

    Article  CAS  PubMed  Google Scholar 

  19. 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: 1300–1303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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: 1303–1307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Maiti A, Drohat AC, Thymine DNA . glycosylase can rapidly excise 5-formylcytosine and 5 carboxylcytosine: potential implications for active demethylation of CpG sites. J Biol Chem 2011; 286: 35334–35338.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cortellino S, Xu J, Sannai M, Moore R, Caretti E, Cigliano A et al. Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair. Cell 2011; 146: 67–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Shen L, Wu H, Diep D, Yamaguchi S, D'Alessio AC, Fung HL et al. Genome-wide analysis reveals TET- and TDG-dependent 5-methylcytosine oxidation dynamics. Cell 2013; 153: 692–706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Frauer C, Hoffmann T, Bultmann S, Casa V, Cardoso MC, Antes I et al. Recognition of 5-hydroxymethylcytosine by the Uhrf1 SRA domain. PLoS One 2011; 6: e21306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yildirim O, Li R, Hung JH, Chen PB, Dong X, Ee LS et al. Mbd3/NURD complex regulates expression of 5-hydroxymethylcytosine marked genes in embryonic stem cells. Cell 2011; 147: 1498–1510.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mellén M, Ayata P, Dewell S, Kriaucionis S, Heintz N . MeCP2 binds to 5-hmC enriched within active genes and accessible chromatin in the nervous system. Cell 2012; 151: 1417–1430.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Spruijt CG, Gnerlich F, Smits AH, Pfaffeneder T, Jansen PW, Bauer C et al. Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives. Cell 2013; 152: 1146–1159.

    Article  CAS  PubMed  Google Scholar 

  28. Hanover JA, Krause MW, Love DC . Bittersweet memories: linking metabolism to epigenetics through O-GlcNAcylation. Nat Rev Mol Cell Biol 2012; 13: 312–321.

    Article  CAS  PubMed  Google Scholar 

  29. Deplus R, Delatte B, Schwinn MK, Defrance M, Méndez J, Murphy N et al. TET2 and TET3 regulate GlcNAcylation and H3K4 methylation through OGT and SET1/COMPASS. EMBO J 2013; 32: 645–655.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Chen Q, Chen Y, Bian C, Fujiki R, Yu X . TET2 promotes histone O-GlcNAcylation during gene transcription. Nature 2013; 493: 561–564.

    Article  CAS  PubMed  Google Scholar 

  31. Vella P, Scelfo A, Jammula S, Chiacchiera F, Williams K, Cuomo A et al. Tet proteins connect the O-linked N-acetylglucosamine transferase Ogt to chromatin in embryonic stem cells. Mol Cell 2013; 49: 645–656.

    Article  CAS  PubMed  Google Scholar 

  32. Pendino F, Nguyen E, Jonassen I, Dysvik B, Azouz A, Lanotte M et al. Functional involvement of RINF, retinoid-inducible nuclear factor (CXXC5), in normal and tumoral human myelopoiesis. Blood 2009; 113: 3172–3181.

    Article  CAS  PubMed  Google Scholar 

  33. Kojima T, Shimazui T, Hinotsu S, Joraku A, Oikawa T, Kawai K et al. Decreased expression of CXXC4 promotes a malignant phenotype in renal cell carcinoma by activating Wnt signaling. Oncogene 2009; 28: 297–305.

    Article  CAS  PubMed  Google Scholar 

  34. Hino S, Kishida S, Michiue T, Fukui A, Sakamoto I, Takada S et al. Inhibition of the Wnt signaling pathway by Idax, a novel Dvl-binding protein. Mol Cell Biol 2001; 21: 330–342.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Guilhamon P, Eskandarpour M, Halai D, Wilson GA, Feber A, Teschendorff AE et al. Meta-analysis of IDH-mutant cancers identifies EBF1 as an interaction partner for TET2. Nat Commun 2013; 4: 2166.

    Article  PubMed  CAS  Google Scholar 

  36. Arioka Y, Watanabe A, Saito K, Yamada Y . Activation-induced cytidine deaminase alters the subcellular localization of Tet family proteins. PLoS One 2012; 7: e45031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Song SJ, Ito K, Ala U, Kats L, Webster K, Sun SM et al. The oncogenic microRNA miR-22 targets the TET2 tumor suppressor to promote hematopoietic stem cell self-renewal and transformation. Cell Stem Cell 2013; 13: 87–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ficz G, Branco MR, Seisenberger S, Santos F, Krueger F, Hore TA et al. Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation. Nature 2011; 473: 398–402.

    Article  CAS  PubMed  Google Scholar 

  39. Koh KP, Yabuuchi A, Rao S, Huang Y, Cunniff K, Nardone J et al. Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells. Cell Stem Cell 2011; 8: 200–213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Doege CA, Inoue K, Yamashita T, Rhee DB, Travis S, Fujita R et al. Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2. Nature 2012; 488: 652–655.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Piccolo FM, Bagci H, Brown KE, Landeira D, Soza-Ried J, Feytout A et al. Different roles for Tet1 and Tet2 proteins in reprogramming-mediated erasure of imprints induced by EGC fusion. Mol Cell 2013; 49: 1023–1033.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Xu Y, Wu F, Tan L, Kong L, Xiong L, Deng J et al. Genome-wide regulation of 5-hmC, 5mC, and gene expression by Tet1 hydroxylase in mouse embryonic stem cells. Mol Cell 2011; 42: 451–464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Williams K, Christensen J, Pedersen MT, Johansen JV, Cloos PA, Rappsilber J et al. TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature 2011; 473: 343–348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Pastor WA, Pape UJ, Huang Y, Henderson HR, Lister R, Ko M et al. Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells. Nature 2011; 473: 394–397.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wu H, D'Alessio AC, Ito S, Wang Z, Cui K, Zhao K et al. Genome-wide analysis of 5-hydroxymethylcytosine distribution reveals its dual function in transcriptional regulation in mouse embryonic stem cells. Genes Dev 2011; 25: 679–684.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wu H, Zhang Y . Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. Genes Dev 2011; 25: 2436–2452.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Williams K, Christensen J, Helin K . DNA methylation: TET proteins-guardians of CpG islands? EMBO Rep 2011; 13: 28–35.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Wu Y, Guo Z, Liu Y, Tang B, Wang Y, Yang L et al. Oct4 and the small molecule inhibitor, SC1, regulates Tet2 expression in mouse embryonic stem cells. Mol Biol Rep 2013; 40: 2897–2906.

    Article  CAS  PubMed  Google Scholar 

  49. Costa Y, Ding J, Theunissen TW, Faiola F, Hore TA, Shliaha PV et al. NANOG-dependent function of TET1 and TET2 in establishment of pluripotency. Nature 2013; 495: 370–374.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Wang T, Wu H, Li Y, Szulwach KE, Lin L, Li X et al. Subtelomeric hotspots of aberrant 5-hydroxymethylcytosine-mediated epigenetic modifications during reprogramming to pluripotency. Nat Cell Biol 2013; 15: 700–711.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Dawlaty MM, Ganz K, Powell BE, Hu YC, Markoulaki S, Cheng AW et al. Tet1 is dispensable for maintaining pluripotency and its loss is compatible with embryonic and postnatal development. Cell Stem Cell 2011; 9: 166–175.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Dawlaty MM, Breiling A, Le T, Raddatz G, Barrasa MI, Cheng AW et al. Combined deficiency of Tet1 and Tet2 causes epigenetic abnormalities but is compatible with postnatal development. Dev Cell 2013; 24: 310–323.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Figueroa ME, Lugthart S, Li Y, Erpelinck-Verschueren C, Deng X, Christos PJ et al. DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell 2010; 17: 13–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 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: 11–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bocker MT, Tuorto F, Raddatz G, Musch T, Yang FC, Xu M et al. Hydroxylation of 5-methylcytosine by TET2 maintains the active state of the mammalian HOXA cluster. Nat Commun 2012; 3: 818.

    Article  PubMed  CAS  Google Scholar 

  56. Ko M, Bandukwala HS, An J, Lamperti ED, Thompson EC, Hastie R et al. Ten-Eleven-Translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice. Proc Natl Acad Sci USA 2011; 108: 14566–14571.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Pronier E, Almire C, Mokrani H, Vasanthakumar A, Simon A, da Costa Reis Monte Mor B et al. Inhibition of TET2-mediated conversion of 5-methylcytosine to 5-hydroxymethylcytosine disturbs erythroid and granulomonocytic differentiation of human hematopoietic progenitors. Blood 2011; 118: 2551–2555.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Itzykson R, Kosmider O, Renneville A, Gelsi-Boyer V, Meggendorfer M, Morabito M et al. Prognostic score including gene mutations in chronic myelomonocytic leukemia. J Clin Oncol 2013; 31: 2428–2436.

    Article  CAS  PubMed  Google Scholar 

  59. Itzykson R, Kosmider O, Renneville A, Morabito M, Preudhomme C, Berthon C et al. Clonal architecture of chronic myelomonocytic leukemias. Blood 2013; 121: 2186–2198.

    Article  CAS  PubMed  Google Scholar 

  60. Itzykson R, Solary E . An evolutionary perspective on chronic myelomonocytic leukemia. Leukemia 2013; 27: 1441–1450.

    Article  CAS  PubMed  Google Scholar 

  61. Kallin EM, Rodríguez-Ubreva J, Christensen J, Cimmino L, Aifantis I, Helin K et al. Tet2 facilitates the derepression of myeloid target genes during CEBPα-induced transdifferentiation of pre-B cells. Mol Cell 2012; 48: 266–276.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Klug M, Schmidhofer S, Gebhard C, Andreesen R, Rehli M . 5-Hydroxymethylcytosine is an essential intermediate of active DNA demethylation processes in primary human monocytes. Genome Biol 2013; 14: R46.

    Article  PubMed  PubMed Central  Google Scholar 

  63. 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: 4509–4518.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. 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: 25–38.

    Article  CAS  PubMed  Google Scholar 

  65. Lobry C, Ntziachristos P, Ndiaye-Lobry D, Oh P, Cimmino L, Zhu N et al. Notch pathway activation targets AML-initiating cell homeostasis and differentiation. J Exp Med 2013; 210: 301–319.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Aucagne R, Droin N, Paggetti J, Lagrange B, Largeot A, Hammann A et al. Transcription intermediary factor 1γ is a tumor suppressor in mouse and human chronic myelomonocytic leukemia. J Clin Invest 2011; 121: 2361–2370.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA 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: 225–234.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Koivunen P, Lee S, Duncan CG, Lopez G, Lu G, Ramkissoon S et al. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature 2012; 483: 484–488.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Lian CG, Xu Y, Ceol C, Wu F, Larson A, Dresser K et al. Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma. Cell 2012; 50: 1135–1146.

    Article  CAS  Google Scholar 

  70. Gambichler T, Sand M, Skrygan M . Loss of 5-hydroxymethylcytosine and ten-eleven translocation 2 protein expression in malignant melanoma. Melanoma Res 2013; 23: 218–220.

    Article  CAS  PubMed  Google Scholar 

  71. Busque L, Patel JP, Figueroa ME, Vasanthakumar A, Provost S, Hamilou Z et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat Genet 2012; 44: 1179–1181.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Sakaguchi H, Okuno Y, Muramatsu H, Yoshida K, Shiraishi Y, Takahashi M et al. Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia. Nat Genet 2013; 45: 937–941.

    Article  CAS  PubMed  Google Scholar 

  73. Langemeijer SM, Jansen JH, Hooijer J, van Hoogen P, Stevens-Linders E, Massop M et al. TET2 mutations in childhood leukemia. Leukemia 2011; 25: 189–192.

    Article  CAS  PubMed  Google Scholar 

  74. Metzeler KH, Maharry K, Radmacher MD, Mrózek K, Margeson D, Becker H 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: 1373–1381.

    Article  PubMed  PubMed Central  Google Scholar 

  75. 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: 648–657.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Jan M, Snyder TM, Corces-Zimmerman MR, Vyas P, Weissman IL, Quake SR et al. Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Sci Transl Med 2012; 4: 149ra118.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. 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: 2496–2506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Tefferi A, Pardanani A, Lim KH, Abdel-Wahab O, Lasho TL, Patel J et al. TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis. Leukemia 2009; 23: 905–911.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Vannucchi AM, Lasho TL, Guglielmelli P, Biamonte F, Pardanani A, Pereira A et al. Mutations and prognosis in primary myelofibrosis. Leukemia 2013; 27: 1861–1869.

    Article  CAS  PubMed  Google Scholar 

  80. Beer PA, Delhommeau F, LeCouédic JP, Dawson MA, Chen E, Bareford D et al. Two routes to leukemic transformation after a JAK2 mutation-positive myeloproliferative neoplasm. Blood 2010; 115: 2891–2900.

    Article  CAS  PubMed  Google Scholar 

  81. Schaub FX, Looser R, Li S, Hao-Shen H, Lehmann T, Tichelli A et al. Clonal analysis of TET2 and JAK2 mutations suggests that TET2 can be a late event in the progression of myeloproliferative neoplasms. Blood 2010; 115: 2003–2007.

    Article  CAS  PubMed  Google Scholar 

  82. Roche-Lestienne C, Marceau A, Labis E, Nibourel O, Coiteux V, Guilhot J et alFi-LMC group. Mutation analysis of TET2, IDH1, IDH2 and ASXL1 in chronic myeloid leukemia. Leukemia 2011; 25: 1661–1664.

    Article  CAS  PubMed  Google Scholar 

  83. Tefferi A, Lim KH, Abdel-Wahab O, Lasho TL, Patel J, Patnaik MM et al. Detection of mutant TET2 in myeloid malignancies other than myeloproliferative neoplasms: CMML, MDS, MDS/MPN and AML. Leukemia 2009; 23: 1343–1345.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Kosmider O, Gelsi-Boyer V, Cheok M, Grabar S, Della-Valle V, Picard F et al. TET2 mutation is an independent favorable prognostic factor in myelodysplastic syndromes (MDSs). Blood 2009; 114: 3285–3291.

    Article  CAS  PubMed  Google Scholar 

  85. 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: 1147–1152.

    Article  CAS  PubMed  Google Scholar 

  86. Grossmann V, Kohlmann A, Eder C, Haferlach C, Kern W, Cross NC et al. Molecular profiling of chronic myelomonocytic leukemia reveals diverse mutations in >80% of patients with TET2 and EZH2 being of high prognostic relevance. Leukemia 2011; 25: 877–879.

    Article  CAS  PubMed  Google Scholar 

  87. Kohlmann A, Grossmann V, Klein HU, Schindela S, Weiss T, Kazak B et al. Next-generation sequencing technology reveals a characteristic pattern of molecular mutations in 72.8% of chronic myelomonocytic leukemia by detecting frequent alterations in TET2, CBL, RAS, and RUNX1. J Clin Oncol 2010; 28: 3858–3865.

    Article  CAS  PubMed  Google Scholar 

  88. Flach J, Dicker F, Schnittger S, Kohlmann A, Haferlach T, Haferlach C . Mutations of JAK2 and TET2, but not CBL are detectable in a high portion of patients with refractory anemia with ring sideroblasts and thrombocytosis. Haematologica 2010; 95: 518–519.

    Article  PubMed  Google Scholar 

  89. Nibourel O, Kosmider O, Cheok M, Boissel N, Renneville A, Philippe N et al. Incidence and prognostic value of TET2 alterations in de novo acute myeloid leukemia achieving complete remission. Blood 2010; 116: 1132–1135.

    Article  CAS  PubMed  Google Scholar 

  90. Weissmann S, Alpermann T, Grossmann V, Kowarsch A, Nadarajah N, Eder C et al. Landscape of TET2 mutations in acute myeloid leukemia. Leukemia 2012; 26: 934–942.

    Article  CAS  PubMed  Google Scholar 

  91. Konstandin N, Bultmann S, Szwagierczak A, Dufour A, Ksienzyk B, Schneider F et al. Genomic 5-hydroxymethylcytosine levels correlate with TET2 mutations and a distinct global gene expression pattern in secondary acute myeloid leukemia. Leukemia 2011; 25: 1649–1652.

    Article  CAS  PubMed  Google Scholar 

  92. Kosmider O, Delabesse E, de Mas VM, Cornillet-Lefebvre P, Blanchet O, Delmer A et al. GOELAMS Investigators. TET2 mutations in secondary acute myeloid leukemias: a French retrospective study. Haematologica 2011; 96: 1059–1063.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Chou WC, Chou SC, Liu CY, Chen CY, Hou HA, Kuo YY et al. TET2 mutation is an unfavorable prognostic factor in acute myeloid leukemia patients with intermediate-risk cytogenetics. Blood 2011; 118: 3803–3810.

    Article  CAS  PubMed  Google Scholar 

  94. Tefferi A, Levine RL, Lim KH, Abdel-Wahab O, Lasho TL, Patel J et al. Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates. Leukemia 2009; 23: 900–904.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Soucie E, Hanssens K, Mercher T, Georgin-Lavialle S, Damaj G, Livideanu C et al. In aggressive forms of mastocytosis, TET2 loss cooperates with c-KITD816V to transform mast cells. Blood 2012; 120: 4846–4849.

    Article  CAS  PubMed  Google Scholar 

  96. Jardin F, Ruminy P, Parmentier F, Troussard X, Vaida I, Stamatoullas A et al. TET2 and TP53 mutations are frequently observed in blastic plasmacytoid dendritic cell neoplasm. Br J Haematol 2011; 153: 413–416.

    Article  CAS  PubMed  Google Scholar 

  97. Menezes J, Acquadro F, Wiseman M, Gonzalo Gómez-López G, Salgado RN, Talavera-Casañas JG et al. Exome sequencing reveals novel and recurrent mutations with clinical impact in Blastic Plasmacytoid Dendritic Cell Neoplasm. Leukemia 2013; e-pub ahead of print 27 September 2013 doi:10.1038/leu.2013.283.

    Article  PubMed  CAS  Google Scholar 

  98. Marcucci G, Maharry K, Wu YZ, Radmacher MD, Mrózek K, Margeson D 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: 2348–2355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Tefferi A, Lasho TL, Abdel-Wahab O, Guglielmelli P, Patel J, Caramazza D et al. IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis. Leukemia 2010; 24: 1302–1309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. McKenney AS, Levine RL . Isocitrate dehydrogenase mutations in leukemia. J Clin Invest 2013; 123: 3672–3677.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Losman JA, Looper RE, Koivunen P, Lee S, Schneider RK, McMahon C et al. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science 2013; 339: 1621–1625.

    Article  CAS  PubMed  Google Scholar 

  102. Wang F, Travins J, DeLaBarre B, Penard-Lacronique V, Schalm S, Hansen E et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 2013; 340: 622–626.

    Article  CAS  PubMed  Google Scholar 

  103. Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 2012; 483: 474–478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Janin M, Mylonas E, Saada V, Micol JB, Renneville A, Quivoron C et al. Serum 2-HG production in IDH1 and IDH2 mutated de novo acute myeloid leukemia: A Study by the Acute Leukemia French Association Group. J Clin Oncol 2014; 32: 297–305.

    Article  CAS  PubMed  Google Scholar 

  105. Jankowska AM, Makishima H, Tiu RV, Szpurka H, Huang Y, Traina F et al. Mutational spectrum analysis of chronic myelomonocytic leukemia includes genes associated with epigenetic regulation: UTX, EZH2, and DNMT3A. Blood 2011; 118: 3932–3941.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Abdel-Wahab O, Adli M, LaFave LM, Gao J, Hricik T, Shih AH et al. ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression. Cancer Cell 2012; 22: 180–193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Lemonnier F, Couronné L, Parrens M, Jaïs JP, Travert M, Lamant L et al. Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters. Blood 2012; 120: 1466–1469.

    Article  CAS  PubMed  Google Scholar 

  108. Couronné L, Bastard C, Bernard OA . TET2 and DNMT3A mutations in human T-cell lymphoma. N Engl J Med 2012; 366: 95–96.

    Article  PubMed  Google Scholar 

  109. Cairns RA, Iqbal J, Lemonnier F, Kucuk C, de Leval L, Jais JP et al. IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma. Blood 2012; 119: 1901–1903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Meissner B, Kridel R, Lim RS, Rogic S, Tse K, Scott DW et al. The E3 ubiquitin ligase UBR5 is recurrently mutated in mantle cell lymphoma. Blood 2013; 121: 3161–3164.

    Article  CAS  PubMed  Google Scholar 

  111. Asmar F, Punj V, Christensen J, Pedersen MT, Pedersen A, Nielsen AB et al. Genome-wide profiling identifies a DNA methylation signature that associates with TET2 mutations in diffuse large B-cell lymphoma. Haematologica 2013; e-pub ahead of print 12 July 2013.

  112. Nickerson ML, Im KM, Misner KJ, Tan W, Lou H, Gold B et al. Somatic alterations contributing to metastasis of a castration-resistant prostate cancer. Hum Mutat 2013; 34: 1231–1241.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Yang H, Liu Y, Bai F, Zhang JY, Ma SH, Liu J et al. Tumor development is associated with decrease of TET gene expression and 5-methylcytosine hydroxylation. Oncogene 2013; 32: 663–669.

    Article  CAS  PubMed  Google Scholar 

  114. 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: 157–160.

    Article  CAS  PubMed  Google Scholar 

  115. Voso MT, Fabiani E, Piciocchi A, Matteucci C, Brandimarte L, Finelli C et al. Role of BCL2L10 methylation and TET2 mutations in higher risk myelodysplastic syndromes treated with 5-azacytidine. Leukemia 2011; 25: 1910–1913.

    Article  CAS  PubMed  Google Scholar 

  116. Braun T, Itzykson R, Renneville A, de Renzis B, Dreyfus F, Laribi K et al. Molecular predictors of response to decitabine in advanced chronic myelomonocytic leukemia: a phase 2 trial. Blood 2011; 118: 3824–3831.

    Article  CAS  PubMed  Google Scholar 

  117. 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: 2499–2506.

    Article  CAS  PubMed  Google Scholar 

  118. Zuber J, Shi J, Wang E, Rappaport AR, Herrmann H, Sison EA et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 2011; 478: 524–528.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Chen L, Deshpande AJ, Banka D, Bernt KM, Dias S, Buske C et al. Abrogation of MLL-AF10 and CALM-AF10-mediated transformation through genetic inactivation or pharmacological inhibition of the H3K79 methyltransferase Dot1l. Leukemia 2013; 27: 813–822.

    Article  CAS  PubMed  Google Scholar 

  120. Papaemmanuil E, Gerstung M, Malcovati L, Tauro S, Gundem G, Van Loo P et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood 2013; 122: 3616–3627.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

ES, OAB and WV are heading teams independently supported by the Ligue Nationale Contre le Cancer (Equipes labellisées) and receive grants from Inserm, Agence National de la Recherche and Institut National du Cancer. We are grateful to all members of Inserm UMR895 and UMR1009 who were involved in cited works or provided helpful comments. We apologize to all colleagues whose work was not cited because of space restrictions.

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Authors and Affiliations

  1. Hematology Department, Gustave Roussy, Villejuif, France

    E Solary, O A Bernard & W Vainchenker

  2. Inserm UMR1009, Gustave Roussy, Villejuif cedex, France

    E Solary & W Vainchenker

  3. Faculty of Medicine, University Paris-Sud, Le Kremlin-Bicêtre, France

    E Solary, O A Bernard & W Vainchenker

  4. Inserm UMR985, Gustave Roussy, Villejuif, France

    O A Bernard

  5. Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA

    A Tefferi

  6. Faculty of Medicine, Laboratory of Cancer Epigenetics, Université Libre de Bruxelles, Brussels, Belgium

    F Fuks

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  1. E Solary
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Solary, E., Bernard, O., Tefferi, A. et al. The Ten-Eleven Translocation-2 (TET2) gene in hematopoiesis and hematopoietic diseases. Leukemia 28, 485–496 (2014). https://doi.org/10.1038/leu.2013.337

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