TET2 mutations as a part of DNA dioxygenase deficiency in myelodysplastic syndromes

Abstract

Decrease in DNA dioxygease activity generated by TET2 gene family is crucial in myelodysplastic syndromes (MDS). The general down-regulation of 5-hydroxymethylcytosine (5-hmC) argues for a role of DNA demethylation in MDS beyond TET2 mutations, which albeit frequent, do not convey any prognostic significance. We investigated TETs expression to identify factors which can modulate the impact of mutations and thus 5-hmC levels on clinical phenotypes and prognosis of MDS patients. DNA/RNA-sequencing and 5-hmC data were collected from 1,665 patients with MDS and 91 controls. Irrespective of mutations, a significant fraction of MDS patients exhibited lower TET2 expression, while 5-hmC levels were not uniformly decreased. In searching for factors explaining compensatory mechanisms, we discovered that TET3 was up-regulated in MDS and inversely correlated with TET2 expression in wild-type cases. While TET2 was reduced across all age-groups, TET3 levels were increased in a likely feedback mechanism induced by TET2 dysfunction. This inverse relationship of TET2 and TET3 expression also corresponded to the expression of L-2-hydroxyglutarate dehydrogenase, involved in agonist/antagonist substrate metabolism. Importantly, elevated TET3 levels influenced the clinical phenotype of TET2-deficiency whereby the lack of compensation by TET3 (low TET3 expression) was associated with poor outcomes of TET2 mutant carriers.

Diagnostic and Prognostic Power of Active DNA Demethylation Pathway Intermediates in Acute Myelogenous Leukemia and Myelodysplastic Syndromes

“…Products of this process can be used to assess the extent to which TET2 mutations are responsible for the impairment of the TET2 demethylating activity. In concordance with the previous studies, we observed a significant decrease in the 5-hmdC levels in the genome of the MDS and AML patients compared to healthy subjects ( Figure 1 b) [ 20 ]. Surprisingly, levels of two other TETs products, i.e., 5-fdC and 5-cadC, increased significantly in both patient groups ( Figure 1 c,d).…”

“…Therefore, it is likely that in the cases of the TET2 mutation/inactivation compensatory overexpression of the TET1/3 enzymatic activity, may restore/improve hydroxymethylation, and potentially reverse the epigenetic consequences caused by the TET2 deficiency, in the case of 5-fdC and 5-cadC. Indeed, just recently it was found that MDS patients reveal the decrease in the TET2 expression (and 5-hmdC level), while TET3 was up-regulated and inversely correlated with the TET2 expression [ 20 ].…”

“…In 7% to 10% of AML patients, loss-of-function mutations in TET2 were described; moreover, 10% to 20% of people with AML have heterozygous mutations in IDH1 and IDH2 that are mutually exclusive with mutations in TET2 [ 19 ]. More recently, Gurnari et al found that the depletion of 5-hmCyt and TET2 mRNA are common in MDS irrespective of the TET2 mutation [ 20 ]. In the light of this research “TETopathy”, defined as various factors causing abnormalities in TETs expression, activity, or specificity, appears a common feature of MDS/AML patients.…”

Vitamin C Deficiency in Patients With Acute Myeloid Leukemia

“…Zhao et al, demonstrated that combination of vitamin C and decitabine activates TET2 in leukemia cells, improving OS in elderly patients. In particular, several authors showed that vitamin C may be a useful anti-leukemic agent able to restore the dioxygenase activity, thereby attenuating the effects of TET2 dysfunction, a widespread feature of hematological malignancies beyond the mere presence of mutations (25,27,29,(47)(48)(49). However, the degree of vitamin C absorption by leukemic cells is unknown.…”

The Anti-Leukemia Effect of Ascorbic Acid: From the Pro-Oxidant Potential to the Epigenetic Role in Acute Myeloid Leukemia

“…These findings provide the evidence of decreased TET2 activity in both context of IDH and WT1 mutations, and are in line with a recent study reporting TET2 deficiency in up to 74% of patients with myeloid disorders, a result that goes beyond the mere presence of TET2 mutations. Indeed, loss of TET2 functions by mutations or down-modulation due to various mechanisms have been identified as a common lynchpin of myeloid malignancies, as also indicated by the meta-analysis performed in the above-mentioned study (Gurnari et al, 2022). The implications of this are obvious, and suggest the potential application of ascorbate in settings beyond the disruption of TET2-IDH-WT1 pathway, which is the scenario where we would expect its maximal therapeutic efficacy, as also demonstrated by anecdotal case reports (Das et al, 2019).…”