The Potential Equivalents of TET2 Mutations

Abstract

TET2 is a dioxygenase dependent on Fe2+ and α-ketoglutarate which oxidizes 5-methylcytosine (5meC) to 5-hydroxymethylcytosine (5hmeC). TET proteins successively oxidize 5mC to yield 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). Among these oxidized methylcytosines, 5fC and 5caC are directly excised by thymine DNA glycosylase (TDG) and ultimately replaced with unmethylated cytosine. Mutations in TET2 have been shown to lead to a hypermethylated state of the genome and to be responsible for the initiation of the oncogenetic process, especially in myeloid and lymphoid malignancies. Nonetheless, this was also shown to be the case in other cancers. In AML, TET2 mutations have been observed to be mutually exclusive with IDH1, IDH2, and WT1 mutations, all of them showing a similar impact on the transcription profile of the affected cell. Because of this, it is possible that TET2/IDH1/2/WT1 mutated AML could be considered as having similar characteristics between each other. Nonetheless, other genes also interact with TET2 and influence its effect, thus making it possible that other signatures exist that would mimic the effect of TET2 mutations. Thus, in this review, we searched the literature for the genes that were observed to interact with TET2 and classified them in the following manner: transcription alteration, miRs, direct interaction, posttranslational changes, and substrate reduction. What we propose in the present review is the potential extension of the TET2/IDH1/2/WT1 entity with the addition of certain expression signatures that would be able to induce a similar phenotype with that induced by TET2 mutations. Nonetheless, we recommend that this approach be taken on a disease by disease basis.

Deciphering the link between Diabetes mellitus and SARS-CoV-2 infection through differential targeting of microRNAs in the human pancreas

“…hsa-mir-3123 is downregulated in insulin receptor haploinsufficient hepatic stellate cells [ 83 ]. hsa-miR-4775 is associated with diabetic nephropathy and its role in targeting apoptotic pathway’s core genes [ 84 , 85 ]. hsa-miR-1236-3p is reported to be involved in apoptosis induction [ 86 ].…”

Rationale for a Combination Therapy with the STAT5 Inhibitor AC-4-130 and the MCL1 Inhibitor S63845 in the Treatment of FLT3-Mutated or TET2-Mutated Acute Myeloid Leukemia

“…Leukemic IDH1 and IDH2 mutations disrupt TET2 function and impair hematopoietic differentiation [ 30 , 31 ]. As TET2 function is dependent on the metabolites produced by the IDH proteins [ 21 , 32 ], susceptibility to STAT5 and MCL1 inhibitors may be similar in AML cells with IDH mutations, as in TET2 mutated cells.…”

“…Hematopoietic cytokine receptor signaling is largely mediated by JAKs and their downstream transcription factors, the STATs [ 7 ]. Mutations in the tumor suppressors IDH1/2 and TET2 may be functionally equivalent [ 21 ]. The tumor suppressor FoxP3 may inhibit AKT and its downstream target MCL-1 [ 22 , 23 ].…”

Effects of hypoxia on DNA hydroxymethylase Tet methylcytosine dioxygenase 2 in a KG‑1 human acute myeloid leukemia cell line and its mechanism

“…As an important tumor suppressor gene related to epigenetic modification, the mechanism of TET2 gene regulation remains unclear ( 36 ). At the pre-mRNA level, multiple studies have confirmed that microRNAs [miR-22, miR-29, miR-101 and miR-125] negatively regulate TET2 expression ( 37 , 38 ).…”

“…The findings of the present study suggested that cell metabolism was accelerated under hypoxic conditions and that hypoxia may serve certain roles, such as promoting proliferation and inducing apoptosis in the pathogenesis of AML. As an important tumor suppressor gene related to epigenetic modification, the mechanism of TET2 gene regulation remains unclear (36). At the pre-mRNA level, multiple studies have confirmed that microRNAs [miR-22, miR-29, miR-101 and miR-125] negatively regulate TET2 expression (37,38).…”