{{short description|Human gene}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{infobox gene}} '''Tet methylcytosine dioxygenase 2''' ('''''TET2''''') is a human gene.<ref name="entrez">{{cite web |title = Entrez Gene: Tet methylcytosine dioxygenase 1|url = https://www.ncbi.nlm.nih.gov/gene?db=gene&cmd=retrieve&list_uids=54790|access-date = 1 September 2012}}</ref> It resides at chromosome 4q24, in a region showing recurrent microdeletions and copy-neutral loss of heterozygosity (CN-LOH) in patients with diverse myeloid malignancies.
== Function == ''TET2'' encodes a protein that catalyzes the conversion of the modified DNA base methylcytosine to 5-hydroxymethylcytosine.
The first mechanistic reports showed tissue-specific accumulation of 5-hydroxymethylcytosine (5hmC) and the conversion of 5mC to 5hmC by TET1 in humans in 2009.<ref name=":1">{{cite journal | vauthors = Kriaucionis S, Heintz N | title = The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain | journal = Science | volume = 324 | issue = 5929 | pages = 929–30 | date = May 2009 | pmid = 19372393 | pmc = 3263819 | doi = 10.1126/science.1169786 | bibcode = 2009Sci...324..929K | url = }}</ref><ref name=":2">{{cite journal | vauthors = Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L, Rao A | title = Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1 | journal = Science | volume = 324 | issue = 5929 | pages = 930–5 | date = May 2009 | pmid = 19372391 | pmc = 2715015 | doi = 10.1126/science.1170116 | bibcode = 2009Sci...324..930T | url = }}</ref> In these two papers, Kriaucionis and Heintz <ref name=":1" /> provided evidence that a high abundance of 5hmC can be found in specific tissues and Tahiliani et al.<ref name=":2" /> demonstrated the TET1-dependent conversion of 5mC to 5hmC. A role for TET1 in cancer was reported in 2003 showing that it acted as a complex with MLL (myeloid/lymphoid or mixed-lineage leukaemia 1) (KMT2A),<ref>{{cite journal | vauthors = Lorsbach RB, Moore J, Mathew S, Raimondi SC, Mukatira ST, Downing JR | title = TET1, a member of a novel protein family, is fused to MLL in acute myeloid leukemia containing the t(10;11)(q22;q23) | journal = Leukemia | volume = 17 | issue = 3 | pages = 637–41 | date = March 2003 | pmid = 12646957 | doi = 10.1038/sj.leu.2402834 | doi-access = | s2cid = 1202064 }}</ref><ref>{{cite journal | vauthors = Ono R, Taki T, Taketani T, Taniwaki M, Kobayashi H, Hayashi Y | title = 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) | journal = Cancer Research | volume = 62 | issue = 14 | pages = 4075–80 | date = July 2002 | pmid = 12124344 }}</ref> a positive global regulator of gene transcription that is named after its role cancer regulation. An explanation for protein function was provided in 2009 <ref>{{cite journal | vauthors = Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L, Rao A | title = Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1 | journal = Science | volume = 324 | issue = 5929 | pages = 930–5 | date = May 2009 | pmid = 19372391 | doi = 10.1126/science.1170116 | url= | pmc = 2715015 | bibcode = 2009Sci...324..930T }}</ref> via computational search for enzymes that could modify 5mC. At this time, methylation was known to be crucial for gene silencing, mammalian development, and retrotransposon silencing. The mammalian TET proteins were found to be orthologues of ''Trypanosoma brucei'' base J-binding protein 1 (JBP1) and JBP2. Base J was the first hypermodified base that was known in eukaryotic DNA and had been found in ''T. brucei'' DNA in the early 1990s,<ref>{{cite journal | vauthors = Gommers-Ampt JH, Van Leeuwen F, de Beer AL, Vliegenthart JF, Dizdaroglu M, Kowalak JA, Crain PF, Borst P | title = beta-D-glucosyl-hydroxymethyluracil: a novel modified base present in the DNA of the parasitic protozoan T. brucei | journal = Cell | volume = 75 | issue = 6 | pages = 1129–36 | date = December 1993 | pmid = 8261512 | doi = 10.1016/0092-8674(93)90322-h | hdl = 1874/5219 | s2cid = 24801094 | hdl-access = free }}</ref> although the evidence of an unusual form of DNA modification goes back to at least the mid 1980s.<ref>{{cite journal | vauthors = Bernards A, van Harten-Loosbroek N, Borst P | title = Modification of telomeric DNA in Trypanosoma brucei; a role in antigenic variation? | journal = Nucleic Acids Research | volume = 12 | issue = 10 | pages = 4153–70 | date = May 1984 | pmid = 6328412 | doi = 10.1093/nar/12.10.4153 | pmc = 318823 }}</ref>
In two articles published back-to-back in ''Science'' journal in 2011, firstly<ref name=":3">{{cite journal | vauthors = He YF, Li BZ, Li Z, Liu P, Wang Y, Tang Q, Ding J, Jia Y, Chen Z, Li L, Sun Y, Li X, Dai Q, Song CX, Zhang K, He C, Xu GL | title = Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA | journal = Science | volume = 333 | issue = 6047 | pages = 1303–7 | date = September 2011 | pmid = 21817016 | pmc = 3462231 | doi = 10.1126/science.1210944 | bibcode = 2011Sci...333.1303H | url = }}</ref> it was demonstrated that (1) TET converts 5mC to 5fC and 5caC, and (2) 5fC and 5caC are both present in mouse embryonic stem cells and organs, and secondly<ref name=":4">{{cite journal | vauthors = Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, He C, Zhang Y | title = Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine | journal = Science | volume = 333 | issue = 6047 | pages = 1300–3 | date = September 2011 | pmid = 21778364 | pmc = 3495246 | doi = 10.1126/science.1210597 | bibcode = 2011Sci...333.1300I | url = }}</ref> that (1) TET converts 5mC and 5hmC to 5caC, (2) the 5caC can then be excised by thymine DNA glycosylase (TDG), and (3) depleting TDG causes 5caC accumulation in mouse embryonic stem cells.
In general terms, DNA methylation causes specific sequences to become inaccessible for gene expression. The process of demethylation is initiated through modification of the 5mC to 5hmC, 5fC, etc. To return to the unmodified form of cytosine (C), the site is targeted for TDG-dependent base excision repair (TET–TDG–BER).<ref name=":3" /><ref name=":5">{{cite journal | vauthors = Maiti A, Drohat AC | title = Thymine DNA glycosylase can rapidly excise 5-formylcytosine and 5-carboxylcytosine: potential implications for active demethylation of CpG sites | journal = The Journal of Biological Chemistry | volume = 286 | issue = 41 | pages = 35334–8 | date = October 2011 | pmid = 21862836 | doi = 10.1074/jbc.c111.284620 | pmc = 3195571 | doi-access = free }}</ref><ref name=":6">{{cite journal | vauthors = Weber AR, Krawczyk C, Robertson AB, Kuśnierczyk A, Vågbø CB, Schuermann D, Klungland A, Schär P | title = Biochemical reconstitution of TET1-TDG-BER-dependent active DNA demethylation reveals a highly coordinated mechanism | journal = Nature Communications | volume = 7 | issue = 1 | article-number = 10806 | date = March 2016 | pmid = 26932196 | doi = 10.1038/ncomms10806 | pmc = 4778062 | bibcode = 2016NatCo...710806W | doi-access = free }}</ref> The “thymine” in TDG (thymine DNA glycosylase) might be considered a misnomer; TDG was previously known for removing thymine moieties from G/T mismatches.
The process involves hydrolysing the carbon-nitrogen bond between the sugar-phosphate DNA backbone and the mismatched thymine. Only in 2011, two publications <ref name=":3" /><ref name=":4" /> demonstrated the activity for TDG as also excising the oxidation products of 5-methylcytosine. Furthermore, in the same year <ref name=":5" /> it was shown that TDG excises both 5fC and 5caC. The site left behind remains abasic until it is repaired by the base excision repair system. The biochemical process was further described in 2016 <ref name=":6" /> by evidence of base excision repair coupled with TET and TDG.
In simple terms, TET–TDG–BER produces demethylation; TET proteins oxidise 5mC to create the substrate for TDG-dependent excision. Base excision repair then replaces 5mC with C.
== Clinical significance == The most striking outcome of aberrant TET activity is its association with the development of cancer.
Mutations in this gene were first identified in myeloid neoplasms with deletion or uniparental disomy at 4q24.<ref name="PMID 19483684">{{cite journal | vauthors = 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 | title = Acquired mutations in TET2 are common in myelodysplastic syndromes | journal = Nature Genetics | volume = 41 | issue = 7 | pages = 838–42 | date = July 2009 | pmid = 19483684 | doi = 10.1038/ng.391 | s2cid = 9859570 }}</ref> TET2 may also be a candidate for active DNA demethylation, the catalytic removal of the methyl group added to the fifth carbon on the cytosine base.
Damaging variants in TET2 were attributed as the cause of several myeloid malignancies around the same time as the protein’s function was reported for TET-dependent oxidation.<ref>{{cite journal | vauthors = Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Massé A, Kosmider O, Le Couedic JP, Robert F, Alberdi A, Lécluse Y, Plo I, Dreyfus FJ, Marzac C, Casadevall N, Lacombe C, Romana SP, Dessen P, Soulier J, Viguié F, Fontenay M, Vainchenker W, Bernard OA | title = Mutation in TET2 in myeloid cancers | journal = The New England Journal of Medicine | volume = 360 | issue = 22 | pages = 2289–301 | date = May 2009 | pmid = 19474426 | doi = 10.1056/NEJMoa0810069 | doi-access = free }}</ref><ref>{{cite journal | vauthors = 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 | title = Acquired mutations in TET2 are common in myelodysplastic syndromes | journal = Nature Genetics | volume = 41 | issue = 7 | pages = 838–42 | date = July 2009 | pmid = 19483684 | doi = 10.1038/ng.391 | s2cid = 9859570 | url = http://www.nature.com/articles/ng.391 | url-access = subscription }}</ref><ref>{{cite journal | vauthors = Abdel-Wahab O, Mullally A, Hedvat C, Garcia-Manero G, Patel J, Wadleigh M, Malinge S, Yao J, Kilpivaara O, Bhat R, Huberman K, Thomas S, Dolgalev I, Heguy A, Paietta E, Le Beau MM, Beran M, Tallman MS, Ebert BL, Kantarjian HM, Stone RM, Gilliland DG, Crispino JD, Levine RL | title = Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies | journal = Blood | volume = 114 | issue = 1 | pages = 144–7 | date = July 2009 | pmid = 19420352 | doi = 10.1182/blood-2009-03-210039 | url= | pmc = 2710942 }}</ref><ref>{{cite journal | vauthors = Jankowska AM, Szpurka H, Tiu RV, Makishima H, Afable M, Huh J, O'Keefe CL, Ganetzky R, McDevitt MA, Maciejewski JP | title = Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms | journal = Blood | volume = 113 | issue = 25 | pages = 6403–10 | date = June 2009 | pmid = 19372255 | doi = 10.1182/blood-2009-02-205690 | url= | pmc = 2710933 }}</ref><ref>{{cite journal | vauthors = 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 | title = TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis | journal = Leukemia | volume = 23 | issue = 5 | pages = 905–11 | date = May 2009 | pmid = 19262601 | pmc = 4654629 | doi = 10.1038/leu.2009.47 | url = }}</ref><ref>{{cite journal | vauthors = Tefferi A, Levine RL, Lim KH, Abdel-Wahab O, Lasho TL, Patel J, Finke CM, Mullally A, Li CY, Pardanani A, Gilliland DG | title = Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates | journal = Leukemia | volume = 23 | issue = 5 | pages = 900–4 | date = May 2009 | pmid = 19262599 | doi = 10.1038/leu.2009.37 | pmc = 4654631 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Tefferi A, Lim KH, Abdel-Wahab O, Lasho TL, Patel J, Patnaik MM, Hanson CA, Pardanani A, Gilliland DG, Levine RL | title = Detection of mutant TET2 in myeloid malignancies other than myeloproliferative neoplasms: CMML, MDS, MDS/MPN and AML | journal = Leukemia | volume = 23 | issue = 7 | pages = 1343–5 | date = July 2009 | pmid = 19295549 | doi = 10.1038/leu.2009.59 | pmc = 4654626 | doi-access = free }}</ref> Not only were damaging TET2 mutations found in disease, but the levels of 5hmC were also affected, linking the molecular mechanism of impaired demethylation with disease [75].<ref name=":0">{{cite journal | vauthors = Ko M, Huang Y, Jankowska AM, Pape UJ, Tahiliani M, Bandukwala HS, An J, Lamperti ED, Koh KP, Ganetzky R, Liu XS, Aravind L, Agarwal S, Maciejewski JP, Rao A | title = Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2 | journal = Nature | volume = 468 | issue = 7325 | pages = 839–43 | date = December 2010 | pmid = 21057493 | pmc = 3003755 | doi = 10.1038/nature09586 | bibcode = 2010Natur.468..839K | url = }}</ref> In mice the depletion of TET2 skewed the differentiation of haematopoietic precursors,<ref name=":0" /> as well as amplifying the rate of haematopoietic or progenitor cell renewal.<ref>{{cite journal | vauthors = Moran-Crusio K, Reavie L, Shih A, Abdel-Wahab O, Ndiaye-Lobry D, Lobry C, Figueroa ME, Vasanthakumar A, Patel J, Zhao X, Perna F, Pandey S, Madzo J, Song C, Dai Q, He C, Ibrahim S, Beran M, Zavadil J, Nimer SD, Melnick A, Godley LA, Aifantis I, Levine RL | title = Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation | journal = Cancer Cell | volume = 20 | issue = 1 | pages = 11–24 | date = July 2011 | pmid = 21723200 | pmc = 3194039 | doi = 10.1016/j.ccr.2011.06.001 }}</ref><ref>{{cite journal | vauthors = Quivoron C, Couronné 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 | title = TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis | journal = Cancer Cell | volume = 20 | issue = 1 | pages = 25–38 | date = July 2011 | pmid = 21723201 | doi = 10.1016/j.ccr.2011.06.003 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Ko M, Bandukwala HS, An J, Lamperti ED, Thompson EC, Hastie R, Tsangaratou A, Rajewsky K, Koralov SB, Rao A | title = Ten-Eleven-Translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 35 | pages = 14566–71 | date = August 2011 | pmid = 21873190 | pmc = 3167529 | doi = 10.1073/pnas.1112317108 | bibcode = 2011PNAS..10814566K | doi-access = free }}</ref><ref>{{cite journal | vauthors = Li Z, Cai X, Cai CL, Wang J, Zhang W, Petersen BE, Yang FC, Xu M | title = Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies | journal = Blood | volume = 118 | issue = 17 | pages = 4509–18 | date = October 2011 | pmid = 21803851 | pmc = 3952630 | doi = 10.1182/blood-2010-12-325241 | url = https://ashpublications.org/blood/article/118/17/4509/29053/Deletion-of-Tet2-in-mice-leads-to-dysregulated }}</ref> It has also been reported that 5mC oxidation by TET2 of RNA rather than DNA affects chromatin towards an open state.<ref>{{cite journal | vauthors = Zou Z, Dou X, Li Y, Zhang Z, Wang J, Gao B, Xiao Y, Wang Y, Zhao L, Sun C, Liu Q, Yu X, Wang H, Hong J, Dai Q, Yang FC, Xu M, He C | title = RNA m<sup>5</sup>C oxidation by TET2 regulates chromatin state and leukaemogenesis | journal = Nature | date = October 2024 | volume = 634 | issue = 8035 | pages = 986–994 | pmid = 39358506 | doi = 10.1038/s41586-024-07969-x | pmc = 11499264 | bibcode = 2024Natur.634..986Z }}</ref><ref>{{Cite web | vauthors = Nield D |date=2024-10-08 |title=Study Reveals How Major Cancer-Causing Mutation Triggers Disease |url=https://www.sciencealert.com/study-reveals-how-major-cancer-causing-mutation-triggers-disease |access-date=2024-10-12 |website=ScienceAlert |language=en-US}}</ref>
Somatic TET2 mutations are frequently observed in myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap syndromes including chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemias (AML) and secondary AML (sAML).<ref name="PMID 21057493">{{cite journal | vauthors = Ko M, Huang Y, Jankowska AM, Pape UJ, Tahiliani M, Bandukwala HS, An J, Lamperti ED, Koh KP, Ganetzky R, Liu XS, Aravind L, Agarwal S, Maciejewski JP, Rao A | title = Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2 | journal = Nature | volume = 468 | issue = 7325 | pages = 839–43 | date = December 2010 | pmid = 21057493 | pmc = 3003755 | doi = 10.1038/nature09586 | bibcode = 2010Natur.468..839K }}</ref>
''TET2'' mutations have prognostic value in cytogenetically normal acute myeloid leukemia (CN-AML). "Nonsense" and "frameshift" mutations in this gene are associated with poor outcome on standard therapies in this otherwise favorable-risk patient subset.<ref name="PMID 21343549">{{cite journal | vauthors = Metzeler KH, Maharry K, Radmacher MD, Mrózek 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 | title = TET2 mutations improve the new European LeukemiaNet risk classification of acute myeloid leukemia: a Cancer and Leukemia Group B study | journal = Journal of Clinical Oncology | volume = 29 | issue = 10 | pages = 1373–81 | date = April 2011 | pmid = 21343549 | pmc = 3084003 | doi = 10.1200/JCO.2010.32.7742 }}</ref>
Loss-of-function ''TET2'' mutations may also have a possible causal role in atherogenesis as reported by Jaiswal S. et al, as a consequence of clonal hematopoiesis.<ref name="PMID 28636844">{{cite journal | vauthors = Jaiswal S, Natarajan P, Silver AJ, Gibson CJ, Bick AG, Shvartz E, McConkey M, Gupta N, Gabriel S, Ardissino D, Baber U, Mehran R, Fuster V, Danesh J, Frossard P, Saleheen D, Melander O, Sukhova GK, Neuberg D, Libby P, Kathiresan S, Ebert BL | title = Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease | journal = The New England Journal of Medicine | volume = 377 | issue = 2 | pages = 111–121 | date = July 2017 | pmid = 28636844 | pmc = 6717509 | doi = 10.1056/NEJMoa1701719 }}</ref> Loss-of-function due to somatic variants are frequently reported in cancer, however homozygous germline loss-of-function has been shown in humans, causing childhood immunodeficiency and lymphoma.<ref>{{cite journal |vauthors=Stremenova Spegarova J, Lawless D, Mohamad SM, Engelhardt KR, Doody GM, Shrimpton J, Rensing-Ehl A, Ehl S, Rieux-Laucat F, Cargo C, Griffin H, Mikulasova A, Acres M, Morgan NV, Poulter JA, Sheridan E, Chetcuti P, O'Riordan S, Anwar R, Carter CR, Przyborski S, Windebank K, Cant AJ, Lako M, Bacon C, Savic S, Hambleton S|date=June 2020|title=Germline TET2 Loss-Of-Function Causes Childhood Immunodeficiency And Lymphoma|journal=Blood|volume=136|issue=9|pages=1055–1066|doi=10.1182/blood.2020005844|pmid=32518946|s2cid=219564194|doi-access=free}}</ref> The phenotype of immunodeficiency, autoimmunity and lymphoproliferation highlights requisite roles of TET2 in the human immune system.
== WIT pathway == ''TET2'' is mutated in 7%–23% of acute myeloid leukemia (AML) patients.<ref name="sardina">{{cite journal | vauthors = Sardina JL, Graf T | title = A new path to leukemia with WIT | journal = Molecular Cell | volume = 57 | issue = 4 | pages = 573–574 | date = February 2015 | pmid = 25699704 | doi = 10.1016/j.molcel.2015.02.005 | doi-access = free }}</ref> Importantly, ''TET2'' is mutated in a mutually exclusive manner with ''WT1'', ''IDH1'', and ''IDH2''.<ref name="pmid25482556">{{cite journal | vauthors = Rampal R, Alkalin A, Madzo J, Vasanthakumar A, Pronier E, Patel J, Li Y, Ahn J, Abdel-Wahab O, Shih A, Lu C, Ward PS, Tsai JJ, Hricik T, Tosello V, Tallman JE, Zhao X, Daniels D, Dai Q, Ciminio L, Aifantis I, He C, Fuks F, Tallman MS, Ferrando A, Nimer S, Paietta E, Thompson CB, Licht JD, Mason CE, Godley LA, Melnick A, Figueroa ME, Levine RL | title = DNA hydroxymethylation profiling reveals that WT1 mutations result in loss of TET2 function in acute myeloid leukemia | journal = Cell Reports | volume = 9 | issue = 5 | pages = 1841–1855 | date = December 2014 | pmid = 25482556 | pmc = 4267494 | doi = 10.1016/j.celrep.2014.11.004 }}</ref><ref name="pmid25601757">{{cite journal | vauthors = Wang Y, Xiao M, Chen X, Chen L, Xu Y, Lv L, Wang P, Yang H, Ma S, Lin H, Jiao B, Ren R, Ye D, Guan KL, Xiong Y | title = WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation | journal = Molecular Cell | volume = 57 | issue = 4 | pages = 662–673 | date = February 2015 | pmid = 25601757 | pmc = 4336627 | doi = 10.1016/j.molcel.2014.12.023 }}</ref> TET2 can be recruited by WT1, a sequence-specific zinc finger transcription factor, to WT1-target genes, which it then activates by converting methylcytosine into 5-hydroxymethylcytosine at the genes’ promoters.<ref name="pmid25601757" /> Additionally, isocitrate dehydrogenases 1 and 2, encoded by ''IDH1'' and ''IDH2'', respectively, can inhibit the activity of TET proteins when present in mutant forms that produce the TET inhibitor <small>D</small>-2-hydroxyglutarate.<ref>{{cite journal | vauthors = Liu S, Cadoux-Hudson T, Schofield CJ | title = Isocitrate dehydrogenase variants in cancer - Cellular consequences and therapeutic opportunities | journal = Current Opinion in Chemical Biology | volume = 57 | pages = 122–134 | date = August 2020 | pmid = 32777735 | pmc = 7487778 | doi = 10.1016/j.cbpa.2020.06.012 | doi-access = free }}</ref> Together, ''WT1'', ''IDH1/2'' and ''TET2'' define the WIT pathway in AML.<ref name="sardina" /><ref name="pmid25601757" /> The WIT pathway might also be more broadly involved in suppressing tumor formation, as a number of non-hematopoietic malignancies appear to harbor mutations of WIT genes in a non-exclusive manner.<ref name="sardina" />
== References == {{reflist}}
== Further reading == {{refbegin | 2}} * {{cite journal | vauthors = 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 | title = Acquired mutations in TET2 are common in myelodysplastic syndromes | journal = Nature Genetics | volume = 41 | issue = 7 | pages = 838–42 | date = July 2009 | pmid = 19483684 | doi = 10.1038/ng.391 | s2cid = 9859570 }} * {{cite journal | vauthors = Ko M, Huang Y, Jankowska AM, Pape UJ, Tahiliani M, Bandukwala HS, An J, Lamperti ED, Koh KP, Ganetzky R, Liu XS, Aravind L, Agarwal S, Maciejewski JP, Rao A | title = Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2 | journal = Nature | volume = 468 | issue = 7325 | pages = 839–43 | date = December 2010 | pmid = 21057493 | pmc = 3003755 | doi = 10.1038/nature09586 | bibcode = 2010Natur.468..839K }} * {{cite journal | vauthors = Metzeler KH, Maharry K, Radmacher MD, Mrózek 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 | title = TET2 mutations improve the new European LeukemiaNet risk classification of acute myeloid leukemia: a Cancer and Leukemia Group B study | journal = Journal of Clinical Oncology | volume = 29 | issue = 10 | pages = 1373–81 | date = April 2011 | pmid = 21343549 | pmc = 3084003 | doi = 10.1200/JCO.2010.32.7742 }} {{refend}} {{Use dmy dates|date=April 2017}}
Category:Genes on human chromosome 4 Category:Genes associated with cancer