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Entity | Ph negative myeloproliferative neoplasms (MPN) |
Note | Frequency: mutated in 10-16% of polycythemia vera, 4-11% of essential thrombocytemia, 7-17% of idiopathic myelofibrosis, 14% of myelofibrosis post PV or ET, 29% of mastocytosis. TET2 mutation is a very early event, preceding JAK2 mutation in the major part of cases with JAK2 V617F mutation. It is associated with the expansion of the mutated clone (Delhommeau et al., 2009; Tefferi et al., 2009b). However there is no notable correlation with prognosis. TET2 mutations were also observed during the progression from MPN to AML, appearing as a later event. |
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Entity | Ph positive chronic myeloproliferative leukemia (CML) |
Note | No TET2 mutation detected in chronic phase. In contrast mutations were detected in 8-12% of accelerated or blastic phase (Makishima et al., 2011; Roche-Lestienne et al., 2011). |
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Entity | Chronic myelomonocytic leukemia (CMML) |
Note | Frequency : TET2 mutated in 42-50%, being by far the most frequent molecular event in CMML. |
Prognosis | Controversial. In some clinical studies CMML with TET2 mutated have a shorter overall survival and a higher monocyte rate compared to wt CMML. However other studies show less genomic alterations and a better prognosis in TET2 mutated patients (Tefferi et al., 2009a; Smith et al., 2010). Genome-wide DNA methylation studies show that TET2 mutated CMML express a lower level of hypermethylation than wt CMML and constitute a subtype with distinct epigenetic characteristics. |
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Entity | Myelodysplastic syndrome (MDS) |
Note | Frequency : TET2 mutated in 12-26%. As in CMML, TET2 mutation is the most frequent molecular event, before ASXL1 (~ 14%) and RUNX1 (~ 8%) mutations. There is no significant association with either sub-type of MDS. However there is a correlation between TET2 mutation and MDS with a normal karyotype (Tefferi et al., 2009a; Langemeijer et al., 2009; Smith et al., 2010). |
Prognosis | So far, no independent prognosis value. |
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Entity | Acute myeloid leukemia (AML) |
Note | Frequency : from 7 to 27% of primary AML. |
Prognosis | The impact of TET2 mutations on AML prognosis is controversial. TET2 mutations are significantly associated with normal karyotype, older medium age, hyperleucocytosis and blasts rate more elevated. According to European Leukemia Net criteria, TET2 mutation impairs the prognosis of cytogenetically normal AML with favourable risk (NPM1 and/or CEBPA mutated, FLT3-ITD negative), in comparison with wt-TET2 patients (Metzeler et al., 2011). A more recent study from the EORTC group in AML patients<60 years, shows that a TET2 mutation is an independent factor of poor prognosis. TET2 mutations confer an even worse prognosis when associated with other bad prognosis factors (FLT3-ITD(+), -5, -7, complex). The same worse prognosis is observed when associated with a DNMT3A mutation. They also show that patients with low TET2 mRNA expression, albeit without mutation, have also a decrease of their overall survival (Aslanyan et al., 2014). |
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Entity | Blastic plasmacytoid dendritic cell neoplasm |
Note | One study of 13 cases of this rare haematopoietic neoplasm of uncertain lineage showed TET2 frame shift, nonsense or missense mutations in 7 cases (53%). In 3 cases at least the mutations were biallelic (Jardin et al., 2011). |
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Entity | Lymphoproliferative disease |
Note | Frequency: TET2 mutations were observed largely more frequently in T-cell lymphomas than in B-cell lymphomas (12% vs 2%). One to 3 TET2 mutations were found in 47 to 76% of angioimmunoblastic T-cell lymphoma (AITL), often associated with mutations of DNMT3A, a gene involved in cytosine methylation. In peripheral not otherwise specified T-cell lymphoma (PTCL-NOS), 38% harboured a TET2 mutation (Odejide et al., 2014). TET2 mutations can occur in early or advanced stages of lymphoid differentiation. Some patients have a concomitant or previous myelodysplastic syndrome, and the same TET2 mutation is found in both cell lineages, favouring a common origin from an early stem cell (Viguié et al., 2005; Delhommeau et al., 2009). More recently TET2 mutations were observed in12% of diffuse large B-cell lymphomas, composed of 5% missense and 7% nonsense mutations (Asmar et al., 2013). |
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Entity | Low grade diffuse glioma |
Note | More than 85% of low grade diffuse glioma have an IDH1/2 mutation. TET2 gene was explored in those lacking one of these two mutations. No TET2 mutation was found but TET2 promoter methylation was detected in 5 of 35 cases (14%). No TET2 alteration was observed in all cases with IDH1/2 mutation (Kim et al., 2011). |
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Entity | Other cancer types |
Note | Some studies show that 5hmc reduction is significantly associated with tumorigenesis in a great variety of tumours, and that 5hmC depletion is frequently linked to a TET2 mutation or transcriptional inactivation, in cancers of breast, lung, pancreas, liver and probably colon and prostate (Yang et al., 2013). |
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Clinical and biological impact of TET2 mutations and expression in younger adult AML patients treated within the EORTC/GIMEMA AML-12 clinical trial. |
Aslanyan MG, Kroeze LI, Langemeijer SM, Koorenhof-Scheele TN, Massop M, van Hoogen P, Stevens-Linders E, van de Locht LT, Tonnissen E, van der Heijden A, da Silva-Coelho P, Cilloni D, Saglio G, Marie JP, Tang R, Labar B, Amadori S, Muus P, Willemze R, Marijt EW, de Witte T, van der Reijden BA, Suciu S, Jansen JH. |
Ann Hematol. 2014 Aug;93(8):1401-12. doi: 10.1007/s00277-014-2055-7. Epub 2014 Mar 29. |
PMID 24994606 |
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Genome-wide profiling identifies a DNA methylation signature that associates with TET2 mutations in diffuse large B-cell lymphoma. |
Asmar F, Punj V, Christensen J, Pedersen MT, Pedersen A, Nielsen AB, Hother C, Ralfkiaer U, Brown P, Ralfkiaer E, Helin K, Gronbaek K. |
Haematologica. 2013 Dec;98(12):1912-20. doi: 10.3324/haematol.2013.088740. Epub 2013 Jul 5. |
PMID 23831920 |
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Uncovering the role of 5-hydroxymethylcytosine in the epigenome. |
Branco MR, Ficz G, Reik W. |
Nat Rev Genet. 2011 Nov 15;13(1):7-13. doi: 10.1038/nrg3080. (REVIEW) |
PMID 22083101 |
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Mutation in TET2 in myeloid cancers. |
Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Masse A, Kosmider O, Le Couedic JP, Robert F, Alberdi A, Lecluse Y, Plo I, Dreyfus FJ, Marzac C, Casadevall N, Lacombe C, Romana SP, Dessen P, Soulier J, Viguie F, Fontenay M, Vainchenker W, Bernard OA. |
N Engl J Med. 2009 May 28;360(22):2289-301. doi: 10.1056/NEJMoa0810069. |
PMID 19474426 |
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Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2. |
Doege CA, Inoue K, Yamashita T, Rhee DB, Travis S, Fujita R, Guarnieri P, Bhagat G, Vanti WB, Shih A, Levine RL, Nik S, Chen EI, Abeliovich A. |
Nature. 2012 Aug 30;488(7413):652-5. doi: 10.1038/nature11333. |
PMID 22902501 |
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TET2 and TP53 mutations are frequently observed in blastic plasmacytoid dendritic cell neoplasm. |
Jardin F, Ruminy P, Parmentier F, Troussard X, Vaida I, Stamatoullas A, Lepretre S, Penther D, Duval AB, Picquenot JM, Courville P, Capiod JC, Tilly H, Bastard C, Marolleau JP. |
Br J Haematol. 2011 May;153(3):413-6. doi: 10.1111/j.1365-2141.2010.08556.x. Epub 2011 Jan 31. |
PMID 21275969 |
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TET2 promoter methylation in low-grade diffuse gliomas lacking IDH1/2 mutations. |
Kim YH, Pierscianek D, Mittelbronn M, Vital A, Mariani L, Hasselblatt M, Ohgaki H. |
J Clin Pathol. 2011 Oct;64(10):850-2. doi: 10.1136/jclinpath-2011-200133. Epub 2011 Jun 20. |
PMID 21690245 |
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Modulation of TET2 expression and 5-methylcytosine oxidation by the CXXC domain protein IDAX. |
Ko M, An J, Bandukwala HS, Chavez L, Aijo T, Pastor WA, Segal MF, Li H, Koh KP, Lahdesmaki H, Hogan PG, Aravind L, Rao A. |
Nature. 2013 May 2;497(7447):122-6. doi: 10.1038/nature12052. Epub 2013 Apr 7. |
PMID 23563267 |
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Ten-Eleven-Translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice. |
Ko M, Bandukwala HS, An J, Lamperti ED, Thompson EC, Hastie R, Tsangaratou A, Rajewsky K, Koralov SB, Rao A. |
Proc Natl Acad Sci U S A. 2011 Aug 30;108(35):14566-71. doi: 10.1073/pnas.1112317108. Epub 2011 Aug 22. |
PMID 21873190 |
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TET enzymes, TDG and the dynamics of DNA demethylation. |
Kohli RM, Zhang Y. |
Nature. 2013 Oct 24;502(7472):472-9. doi: 10.1038/nature12750. (REVIEW) |
PMID 24153300 |
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Acquired mutations in TET2 are common in myelodysplastic syndromes. |
Langemeijer SM, Kuiper RP, Berends M, Knops R, Aslanyan MG, Massop M, Stevens-Linders E, van Hoogen P, van Kessel AG, Raymakers RA, Kamping EJ, Verhoef GE, Verburgh E, Hagemeijer A, Vandenberghe P, de Witte T, van der Reijden BA, Jansen JH. |
Nat Genet. 2009 Jul;41(7):838-42. doi: 10.1038/ng.391. Epub 2009 May 31. |
PMID 19483684 |
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CBL, CBLB, TET2, ASXL1, and IDH1/2 mutations and additional chromosomal aberrations constitute molecular events in chronic myelogenous leukemia. |
Makishima H, Jankowska AM, McDevitt MA, O'Keefe C, Dujardin S, Cazzolli H, Przychodzen B, Prince C, Nicoll J, Siddaiah H, Shaik M, Szpurka H, Hsi E, Advani A, Paquette R, Maciejewski JP. |
Blood. 2011 May 26;117(21):e198-206. doi: 10.1182/blood-2010-06-292433. Epub 2011 Feb 23. |
PMID 21346257 |
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TET2 mutations improve the new European LeukemiaNet risk classification of acute myeloid leukemia: a Cancer and Leukemia Group B study. |
Metzeler KH, Maharry K, Radmacher MD, Mrozek K, Margeson D, Becker H, Curfman J, Holland KB, Schwind S, Whitman SP, Wu YZ, Blum W, Powell BL, Carter TH, Wetzler M, Moore JO, Kolitz JE, Baer MR, Carroll AJ, Larson RA, Caligiuri MA, Marcucci G, Bloomfield CD. |
J Clin Oncol. 2011 Apr 1;29(10):1373-81. doi: 10.1200/JCO.2010.32.7742. Epub 2011 Feb 22. |
PMID 21343549 |
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A targeted mutational landscape of angioimmunoblastic T-cell lymphoma. |
Odejide O, Weigert O, Lane AA, Toscano D, Lunning MA, Kopp N, Kim S, van Bodegom D, Bolla S, Schatz JH, Teruya-Feldstein J, Hochberg E, Louissaint A, Dorfman D, Stevenson K, Rodig SJ, Piccaluga PP, Jacobsen E, Pileri SA, Harris NL, Ferrero S, Inghirami G, Horwitz SM, Weinstock DM. |
Blood. 2014 Feb 27;123(9):1293-6. doi: 10.1182/blood-2013-10-531509. Epub 2013 Dec 17. |
PMID 24345752 |
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Inhibition of TET2-mediated conversion of 5-methylcytosine to 5-hydroxymethylcytosine disturbs erythroid and granulomonocytic differentiation of human hematopoietic progenitors. |
Pronier E, Almire C, Mokrani H, Vasanthakumar A, Simon A, da Costa Reis Monte Mor B, Masse A, Le Couedic JP, Pendino F, Carbonne B, Larghero J, Ravanat JL, Casadevall N, Bernard OA, Droin N, Solary E, Godley LA, Vainchenker W, Plo I, Delhommeau F. |
Blood. 2011 Sep 1;118(9):2551-5. doi: 10.1182/blood-2010-12-324707. Epub 2011 Jul 6. |
PMID 21734233 |
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TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. |
Quivoron C, Couronne L, Della Valle V, Lopez CK, Plo I, Wagner-Ballon O, Do Cruzeiro M, Delhommeau F, Arnulf B, Stern MH, Godley L, Opolon P, Tilly H, Solary E, Duffourd Y, Dessen P, Merle-Beral H, Nguyen-Khac F, Fontenay M, Vainchenker W, Bastard C, Mercher T, Bernard OA. |
Cancer Cell. 2011 Jul 12;20(1):25-38. doi: 10.1016/j.ccr.2011.06.003. Epub 2011 Jun 30. |
PMID 21723201 |
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Mutation analysis of TET2, IDH1, IDH2 and ASXL1 in chronic myeloid leukemia. |
Roche-Lestienne C, Marceau A, Labis E, Nibourel O, Coiteux V, Guilhot J, Legros L, Nicolini F, Rousselot P, Gardembas M, Helevaut N, Frimat C, Mahon FX, Guilhot F, Preudhomme C; Fi-LMC group. |
Leukemia. 2011 Oct;25(10):1661-4. doi: 10.1038/leu.2011.139. Epub 2011 Jun 3. |
PMID 21637286 |
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Next-generation sequencing of the TET2 gene in 355 MDS and CMML patients reveals low-abundance mutant clones with early origins, but indicates no definite prognostic value. |
Smith AE, Mohamedali AM, Kulasekararaj A, Lim Z, Gaken J, Lea NC, Przychodzen B, Mian SA, Nasser EE, Shooter C, Westwood NB, Strupp C, Gattermann N, Maciejewski JP, Germing U, Mufti GJ. |
Blood. 2010 Nov 11;116(19):3923-32. doi: 10.1182/blood-2010-03-274704. Epub 2010 Aug 6. |
PMID 20693430 |
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The Ten-Eleven Translocation-2 (TET2) gene in hematopoiesis and hematopoietic diseases. |
Solary E, Bernard OA, Tefferi A, Fuks F, Vainchenker W. |
Leukemia. 2014 Mar;28(3):485-96. doi: 10.1038/leu.2013.337. Epub 2013 Nov 13. (REVIEW) |
PMID 24220273 |
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Detection of mutant TET2 in myeloid malignancies other than myeloproliferative neoplasms: CMML, MDS, MDS/MPN and AML. |
Tefferi A, Lim KH, Abdel-Wahab O, Lasho TL, Patel J, Patnaik MM, Hanson CA, Pardanani A, Gilliland DG, Levine RL. |
Leukemia. 2009a Jul;23(7):1343-5. doi: 10.1038/leu.2009.59. Epub 2009 Mar 19. |
PMID 19295549 |
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TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis. |
Tefferi A, Pardanani A, Lim KH, Abdel-Wahab O, Lasho TL, Patel J, Gangat N, Finke CM, Schwager S, Mullally A, Li CY, Hanson CA, Mesa R, Bernard O, Delhommeau F, Vainchenker W, Gilliland DG, Levine RL. |
Leukemia. 2009b May;23(5):905-11. doi: 10.1038/leu.2009.47. Epub 2009 Mar 5. |
PMID 19262601 |
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Common 4q24 deletion in four cases of hematopoietic malignancy: early stem cell involvement? |
Viguie F, Aboura A, Bouscary D, Ramond S, Delmer A, Tachdjian G, Marie JP, Casadevall N. |
Leukemia. 2005 Aug;19(8):1411-5. |
PMID 15920487 |
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Tumor development is associated with decrease of TET gene expression and 5-methylcytosine hydroxylation. |
Yang H, Liu Y, Bai F, Zhang JY, Ma SH, Liu J, Xu ZD, Zhu HG, Ling ZQ, Ye D, Guan KL, Xiong Y. |
Oncogene. 2013 Jan 31;32(5):663-9. doi: 10.1038/onc.2012.67. Epub 2012 Mar 5. |
PMID 22391558 |
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