Ten-eleven translocation methylcytosine dioxygenase 2 (TET2)

Ten-eleven translocation methylcytosine dioxygenase 2 (TET2) is a member of the TET family of alpha-ketoglutarate/Fe(II)-dependent dioxygenases responsible for catalyzing the sequential oxidation of 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine in DNA. These conversions are crucial steps in active DNA demethylation, an epigenetic process regulating gene expression. TET2 is highly expressed in hematopoietic tissues and plays a significant role in the regulation of hematopoiesis, acting as a tumor suppressor whose loss is frequently observed in myeloid malignancies. Mutations in TET2 are among the most common genetic alterations in myelodysplastic syndromes and acute myeloid leukemia, driving aberrant self-renewal and impaired differentiation of hematopoietic cells. The structure of TET2 comprises a carboxy-terminal catalytic domain formed by a cysteine-rich region and a double-stranded β-helix domain, and its enzymatic activity requires α-ketoglutarate, Fe(II), and is enhanced by ascorbic acid. While no specific TET2-targeted drugs are clinically available, the enzyme's function is relevant to the mechanism of action of hypomethylating agents and can be influenced by metabolic derangements such as those caused by IDH mutations. TET2 status (mutation, expression, functional activity) is a significant biomarker in several hematological malignancies.

Other names

Tet methylcytosine dioxygenase 2Tet Methylcytosine Dioxygenase 2TET methylcytosine dioxygenase 2TET2 proteinTET protein 2

Enhancers (e.g., ascorbic acid): Stimulate TET2 dioxygenase activity through cofactor availability (ascorbic acid enhances Fe(II)-dependent catalysis). Indirect inhibitors: 2-hydroxyglutarate (from mutant IDH1/2) competitively inhibits TET2 by mimicking its α-ketoglutarate cofactor, leading to DNA hypermethylation. General epigenetic therapy: Hypomethylating agents reverse DNA hypermethylation associated with TET2 deficiency by inhibiting DNA methyltransferases.