Tet methylcytosine dioxygenase 2

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Tet methylcytosine dioxygenase 2 (TET2) is a human gene.[1] 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[edit]

TET2 encodes a protein that catalyzes the conversion of the modified DNA base methylcytosine to 5-hydroxymethylcytosine.

Clinical significance[edit]

Mutations in this gene were first identified in myeloid neoplasms with deletion or uniparental disomy at 4q24.[2] 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.

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).[3]

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.[4]

Loss of function TET2 mutations may also have a possible causal role in atherogenesis as reported by Jaiswal S. et al. [5]

WIT pathway[edit]

TET2 is mutated in 7%–23% of AML patients. Importantly, TET2 is mutated in a mutually exclusive manner with WT1, IDH1, and IDH2.[6] TET2 can be recruited by WT1, a sequence-specific zinc finger transcription factor, to its target genes and activates WT1-target genes by converting methylcytosine into 5-hydroxymethylcytosine at the genes’ promoters.[7] 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.[8]

References[edit]

  1. ^ "Entrez Gene: Tet methylcytosine dioxygenase 1". Retrieved September 2012. Check date values in: |accessdate= (help)
  2. ^ Langemeijer, S. M. C.; Kuiper, R. P.; Berends, M.; Knops, R.; Aslanyan, M. G.; Massop, M.; Stevens-Linders, E.; Van Hoogen, P.; Van Kessel, A. G.; Raymakers, R. A. P.; Kamping, E. J.; Verhoef, G. E.; Verburgh, E.; Hagemeijer, A.; Vandenberghe, P.; De Witte, T.; Van Der Reijden, B. A.; Jansen, J. H. (2009). "Acquired mutations in TET2 are common in myelodysplastic syndromes". Nature Genetics. 41 (7): 838–842. doi:10.1038/ng.391. PMID 19483684.
  3. ^ Ko, M.; Huang, Y.; Jankowska, A. M.; Pape, U. J.; Tahiliani, M.; Bandukwala, H. S.; An, J.; Lamperti, E. D.; Koh, K. P.; Ganetzky, R.; Liu, X. S.; Aravind, L.; Agarwal, S.; MacIejewski, J. P.; Rao, A. (2010). "Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2". Nature. 468 (7325): 839–843. doi:10.1038/nature09586. PMC 3003755. PMID 21057493.
  4. ^ Metzeler, K. H.; Maharry, K.; Radmacher, M. D.; Mrózek, K.; Margeson, D.; Becker, H.; Curfman, J.; Holland, K. B.; Schwind, S.; Whitman, S. P.; Wu, Y. -Z.; Blum, W.; Powell, B. L.; Carter, T. H.; Wetzler, M.; Moore, J. O.; Kolitz, J. E.; Baer, M. R.; Carroll, A. J.; Larson, R. A.; Caligiuri, M. A.; Marcucci, G.; Bloomfield, C. D. (2011). "TET2 Mutations Improve the New European LeukemiaNet Risk Classification of Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study". Journal of Clinical Oncology. 29 (10): 1373–1381. doi:10.1200/JCO.2010.32.7742. PMC 3084003. PMID 21343549.
  5. ^ Jaiswal, S.; et al. (2017). "Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease". New England Journal of Medicine. 377 (2): 111–121. doi:10.1056/NEJMoa1701719. PMID 28636844.
  6. ^ 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 (December 2014). "DNA Hydroxymethylation Profiling Reveals that WT1 Mutations Result in Loss of TET2 Function in Acute Myeloid Leukemia". Cell Rep. 9 (5): 1841–56. doi:10.1016/j.celrep.2014.11.004. PMC 4267494. PMID 25482556.
  7. ^ 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 (February 2015). "WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation". Mol Cell. 57 (4): 662–73. doi:10.1016/j.molcel.2014.12.023. PMC 4336627. PMID 25601757.
  8. ^ Sardina JL, Graf T (February 2015). "A new path to leukemia with WIT". Mol Cell. 57: 573–4. doi:10.1016/j.molcel.2015.02.005. PMID 25699704.

Further reading[edit]