Loss of TET2 in hematopoietic cells leads to DNA hypermethylation of active enhancers and induction of leukemogenesis

Genes and Development

Volumn 29, Issue 9, 2015, Pages 910-922

  Rasmussen, Kasper D ^a,b   Jia, Guangshuai ^a,b   Johansen, Jens V ^a   Pedersen, Marianne T ^a,b   Rapin, Nicolas ^a,b,c,d   Bagger, Frederik O ^a,b,c,d   Porse, Bo T ^a,b,c,d   Bernard, Olivier A ^e   Christensen, Jesper ^a,b   Helin, Kristian ^a,b,c  

^a UNIVERSITY OF COPENHAGEN   (Denmark)

^b UNIVERSITY OF COPENHAGEN   (Denmark)

^c University of Copenhagen   (Denmark)

^d FINSEN LABORATORY   (Denmark)

^e INSTITUT GUSTAVE ROUSSY   (France)

Author keywords

DNA methylation; Enhancer; Leukemia; TET2

Indexed keywords

DIOXYGENASE; METHYLCYTOSINE DIOXYGENASE TET2; UNCLASSIFIED DRUG; DNA BINDING PROTEIN; ONCOPROTEIN; TET2 PROTEIN, MOUSE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CARCINOGENESIS; CELL PROLIFERATION; CONTROLLED STUDY; CPG ISLAND; DEREGULATION; DNA METHYLATION; ENHANCER REGION; GENE; GENE EXPRESSION; GENE MUTATION; HEMATOPOIETIC CELL; HUMAN; LEUKEMIA; LEUKEMOGENESIS; MOUSE; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; STEM CELL; TUMOR SUPPRESSOR GENE; ANIMAL; CYTOLOGY; GENE EXPRESSION REGULATION; GENE TRANSLOCATION; GENETICS; HEMATOPOIETIC STEM CELL; MUTATION; PATHOLOGY;

MAMMALIA;

ANIMALS; CARCINOGENESIS; CELL PROLIFERATION; DNA METHYLATION; DNA-BINDING PROTEINS; ENHANCER ELEMENTS, GENETIC; GENE EXPRESSION REGULATION, NEOPLASTIC; HEMATOPOIETIC STEM CELLS; HUMANS; MICE; MUTATION; PROTO-ONCOGENE PROTEINS; TRANSLOCATION, GENETIC;

EID: 84929461859     PISSN: 08909369     EISSN: 15495477     Source Type: Journal    
DOI: 10.1101/gad.260174.115     Document Type: Article

References (53)

1. Akalin A, Garrett-Bakelman FE, Kormaksson M, Busuttil J, Zhang L, Khrebtukova I, Milne TA, Huang Y, Biswas D, Hess JL, et al. 2012. Base-pair resolutionDNAmethylation sequencing reveals profoundly divergent epigenetic landscapes in acute myeloid leukemia. PLoS Genet 8: e1002781.
2. Andersson R, Gebhard C, Miguel-Escalada I, Hoof I, Bornholdt J, Boyd M, Chen Y, Zhao X, Schmidl C, Suzuki T, et al. 2014. An atlas of active enhancers across human cell types and tissues. Nature 507: 455–461.
3. Aran D, Sabato S, Hellman A. 2013. DNA methylation of distal regulatory sites characterizes dysregulation of cancer genes. Genome Biol 14: R21.
4. Asmar F, Punj V, Christensen J, Pedersen MT, Pedersen A, Nielsen AB, Hother C, Ralfkiaer U, Brown P, Ralfkiaer E, et al. 2013. Genome-wide profiling identifies a DNA methylation signature that associates with TET2 mutations in diffuse large B-cell lymphoma. Haematologica 98: 1912–1920.
5. Baylin SB, Jones PA. 2011. A decade of exploring the cancer epigenome— biological and translational implications. Nat Rev Cancer 11: 726–734.
6. Busque L, Patel JP, Figueroa ME, Vasanthakumar A, Provost S, Hamilou Z, Mollica L, Li J, Viale A, Heguy A, et al. 2012. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat Genet 44: 1179–1181.
7. The Cancer Genome Atlas Research Network. 2013. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 368: 2059–2074.
8. Delhommeau F, Dupont S, Valle Della V, James C, Trannoy S, Massé A, Kosmider O, Le Couédic J-P, Robert F, Alberdi A, et al. 2009. Mutation in TET2 in myeloid cancers. N Engl J Med 360: 2289–2301.
9. Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, Li Y, Bhagwat N, Vasanthakumar A, Fernandez HF, et al. 2010. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18: 553–567.
10. Haferlach T, Kohlmann A, Wieczorek L, Basso G, Kronnie GT, Béné M-C, De Vos J, Hernández JM, Hofmann W-K, Mills KI, et al. 2010. Clinical utility of microarray-based gene expression profiling in the diagnosis and subclassification of leukemia: report from the International Microarray Innovations in Leukemia Study Group. J Clin Oncol 28: 2529–2537.
11. Hon GC, Song C-X, Du T, Jin F, Selvaraj S, Lee AY, Yen C-A, Ye Z, Mao S-Q, Wang B-A, et al. 2014. 5mC oxidation by Tet2 modulates enhancer activity and timing of transcriptome reprogramming during differentiation. Mol Cell 56: 286–297.
12. Issa J-P. 2014. Aging and epigenetic drift: a vicious cycle. J Clin Invest 124: 24–29.
13. Itzykson R, Kosmider O, Renneville A, Morabito M, Preudhomme C, Berthon C, Adès L, Fenaux P, Platzbecker U, Gagey O, et al. 2013. Clonal architecture of chronic myelomonocytic leukemias. Blood 121: 2186–2198.
14. Jan M, Snyder TM, Corces-Zimmerman MR, Vyas P, Weissman IL, Quake SR, Majeti R. 2012. Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Sci Transl Med 4: 149-118.
15. Kasowski M, Kyriazopoulou-Panagiotopoulou S, Grubert F, Zaugg JB, Kundaje A, Liu Y, Boyle AP, Zhang QC, Zakharia F, Spacek DV, et al. 2013. Extensive variation in chromatin states across humans. Science 342: 750–752.
16. Ko M, Huang Y, Jankowska AM, Pape UJ, Tahiliani M, Bandukwala HS, An J, Lamperti ED, Koh KP, Ganetzky R, et al. 2010. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 468: 839–843.
17. Kosmider O, Gelsi-Boyer V, Ciudad M, Racoeur C, Jooste V, Vey N, Quesnel B, Fenaux P, Bastie J-N, Beyne-Rauzy O, et al. 2009. TET2 gene mutation is a frequent and adverse event in chronic myelomonocytic leukemia. Haematologica 94: 1676–1681.
18. Landan G, Cohen NM, Mukamel Z, Bar A, Molchadsky A, Brosh R, Horn-Saban S, Zalcenstein DA, Goldfinger N, Zundelevich A, et al. 2012. Epigenetic polymorphism and the stochastic formation of differentially methylated regions in normal and cancerous tissues. Nat Genet 44: 1207–1214.
19. Langemeijer SMC, Kuiper RP, Berends M, Knops R, Aslanyan MG, Massop M, Stevens-Linders E, van Hoogen P, van Kessel AG, Raymakers RAP, et al. 2009. Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet 41: 838–842.
20. Li Z, Cai X, Cai CL, Wang J, Zhang W, Petersen BE, Yang FC, Xu M. 2011. Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. Blood 118: 4509–4518.
21. Lo M-C, Peterson LF, Yan M, Cong X, Jin F, Shia W-J, Matsuura S, Ahn E-Y, Komeno Y, Ly M, et al. 2012. Combined gene expression and DNA occupancy profiling identifies potential therapeutic targets of t(8;21) AML. Blood 120: 1473–1484.
22. Lobry C, Ntziachristos P, Ndiaye-Lobry D, Oh P, Cimmino L, Zhu N, Araldi E, Hu W, Freund J, Abdel-Wahab O, et al. 2013. Notch pathway activation targets AML-initiating cell homeostasis and differentiation. J Exp Med 210: 301–319.
23. Lu F, Liu Y, Jiang L, Yamaguchi S, Zhang Y. 2014. Role of Tet proteins in enhancer activity and telomere elongation. Genes Dev 28: 2103–2119.
24. Maegawa S, Gough SM, Watanabe-Okochi N, Lu Y, Zhang N, Castoro RJ, Estecio MRH, Jelinek J, Liang S, Kitamura T, et al. 2014. Age-related epigenetic drift in the pathogenesis of MDS and AML. Genome Res 24: 580–591.
25. Martens JHA, Mandoli A, Simmer F, Wierenga B-J, Saeed S, Singh AA, Altucci L, Vellenga E, Stunnenberg HG. 2012. ERG and FLI1 binding sites demarcate targets for aberrant epigenetic regulation by AML1-ETO in acute myeloid leukemia. Blood 120: 4038–4048.
26. Meissner A, Mikkelsen TS, Gu H, Wernig M, Hanna J, Sivachenko A, Zhang X, Bernstein BE, Nusbaum C, Jaffe DB, et al. 2008. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454: 766–770.
27. Messerschmidt DM, Knowles BB, Solter D. 2014. DNA methylation dynamics during epigenetic reprogramming in the germline and preimplantation embryos. Genes Dev 28: 812–828.
28. Moran-Crusio K, Reavie L, Shih A, Abdel-Wahab O, Ndiaye- Lobry D, Lobry C, Figueroa ME, Vasanthakumar A, Patel J, Zhao X, et al. 2011. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 20: 11–24.
29. Pastor WA, Pape UJ, Huang Y, Henderson HR, Lister R, Ko M, McLoughlin EM, Brudno Y, Mahapatra S, Kapranov P, et al. 2011. Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells. Nature 473: 394–397.
30. Pastor WA, Aravind L, Rao A. 2013. TETonic shift: biological roles of TET proteins in DNA demethylation and transcription. Nat Rev Mol Cell Biol 14: 341–356.
31. Pérez C, Martínez-Calle N, Martín-Subero JI, Segura V, Delabesse E, Fernandez-Mercado M, Garate L, Alvarez S, Rifon J, Varea S, et al. 2012. TET2 mutations are associated with specific 5- methylcytosine and 5-hydroxymethylcytosine profiles in patients with chronic myelomonocytic leukemia. PLoS One 7: e31605.
32. Plank JL, Dean A. 2014. Enhancer function: mechanistic and genome- wide insights come together. Mol Cell 55: 5–14.
33. Ptasinska A, Assi SA, Mannari D, James SR, Williamson D, Dunne J, Hoogenkamp M, Wu M, Care M, McNeill H, et al. 2012. Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding. Leukemia 26: 1829–1841.
34. Quivoron C, Couronné L, Valle Della V, Lopez CK, Plo I, Wagner-Ballon O, Do Cruzeiro M, Delhommeau F, Arnulf B, Stern MTH, et al. 2011. TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. Cancer Cell 20: 25–38.
35. Schoofs T, Berdel WE, Müller-Tidow C. 2014. Origins of aberrant DNA methylation in acute myeloid leukemia. Leukemia 28: 1–14.
36. Schübeler D. 2015. Function and information content of DNA methylation. Nature 517: 321–326.
37. Shide K, Kameda T, Shimoda H, Yamaji T, Abe H, Kamiunten A, Sekine M, Hidaka T, Katayose K, Kubuki Y, et al. 2012. TET2 is essential for survival and hematopoietic stem cell homeostasis. Leukemia 26: 2216–2223.
38. Shih AH, Abdel-Wahab O, Patel JP, Levine RL. 2012. The role of mutations in epigenetic regulators in myeloid malignancies. Nat Rev Cancer 12: 599–612.
39. Solary E, Bernard OA, Tefferi A, Fuks F, Vainchenker W. 2014. The ten-eleven translocation-2 (TET2) gene in hematopoiesis and hematopoietic diseases. Leukemia 28: 485–496.
40. Somervaille TCP, Cleary ML. 2006. Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia. Cancer Cell 10: 257–268.
41. Soucie E, Hanssens K, Mercher T, Georgin-Lavialle S, Damaj G, Livideanu C, Chandesris MO, Acin Y, Létard S, de Sepulveda P, et al. 2012. In aggressive forms of mastocytosis, TET2 loss cooperates with c-KITD816V to transform mast cells. Blood 120: 4846–4849.
42. Stadler MB, Murr R, Burger L, Ivanek R, Lienert F, Schöler A, van Nimwegen E, Wirbelauer C, Oakeley EJ, Gaidatzis D, et al. 2011. DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature 480: 490–495.
43. Stroud H, Feng S, Morey Kinney S, Pradhan S, Jacobsen SE. 2011. 5-Hydroxymethylcytosine is associated with enhancers and gene bodies in human embryonic stem cells. Genome Biol 12: R54.
44. Teschendorff AE, West J, Beck S. 2013. Age-associated epigenetic drift: implications, and a case of epigenetic thrift? Hum Mol Genet 22: R7–R15.
45. Thurman RE, Rynes E, Humbert R, Vierstra J, Maurano MT, Haugen E, Sheffield NC, Stergachis AB, Wang H, Vernot B, et al. 2012. The accessible chromatin landscape of the human genome. Nature 489: 75–82.
46. Tsumura A, Hayakawa T, Kumaki Y, Takebayashi S-I, Sakaue M, Matsuoka C, Shimotohno K, Ishikawa F, Li E, Ueda HR, et al. 2006. Maintenance of self-renewal ability of mouse embryonic stem cells in the absence of DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b. Genes Cells 11: 805–814.
47. Weissmann S, Alpermann T, Grossmann V, Kowarsch A, Nadarajah N, Eder C, Dicker F, Fasan A, Haferlach C, Haferlach T, et al. 2012. Landscape of TET2 mutations in acute myeloid leukemia. Leukemia 26: 934–942.
48. Wiench M, John S, Baek S, Johnson TA, Sung M-H, Escobar T, Simmons CA, Pearce KH, Biddie SC, Sabo PJ, et al. 2011. DNA methylation status predicts cell type-specific enhancer activity. EMBO J 30: 3028–3039.
49. Williams K, Christensen J, Pedersen MT, Johansen JV, Cloos PAC, Rappsilber J, Helin K. 2011. TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature 473: 343–348.
50. Wu H, Zhang Y. 2011. Tet1 and 5-hydroxymethylation: a genome- wide view in mouse embryonic stem cells. Cell Cycle 10: 2428–2436.
51. Yamazaki J, Taby R, Vasanthakumar A, Macrae T, Ostler KR, Shen L, Kantarjian HM, Estecio MR, Jelinek J, Godley LA, et al. 2012. Effects of TET2 mutations on DNA methylation in chronic myelomonocytic leukemia. Epigenetics 7: 201–207.
52. Yan M, Kanbe E, Peterson LF, Boyapati A, Miao Y, Wang Y, Chen I-M, Chen Z, Rowley JD, Willman CL, et al. 2006. A previously unidentified alternatively spliced isoform of t(8;21) transcript promotes leukemogenesis. Nat Med 12: 945–949.
53. Yu M, Hon GC, Szulwach KE, Song C-X, Zhang L, Kim A, Li X, Dai Q, Shen Y, Park B, et al. 2012. Base-resolution analysis of 5-hydroxymethylcytosine in the mammalian genome. Cell 149: 1368–1380.