Expression and prognosis analysis of TET family in acute myeloid leukemia

Zhang, Ting‐Juan; Zhao, Yangli; Zhao, Yangjing; Zhou, Jing‐Dong

doi:10.18632/aging.102928

Cited by 20 publications

(25 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This heterogeneity in 5-hmC levels may be due to either compensation of TET2-deficiency by up-modulation of TET3 or by factors other than mutations which influence 5-hmC in WT cases, as previously reported. 33 Our results indicate that elevated TET3 levels compensated TET2-deficiency in terms of clinical outcomes in both univariate and multivariate settings (Fig. 2F-G, TableS2-3).…”

Section: Resultssupporting

confidence: 53%

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

et al. 2022

View full text Add to dashboard Cite

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.

show abstract

Section: Resultssupporting

confidence: 53%

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

et al. 2022

View full text Add to dashboard Cite

show abstract

“…in vitro 91 high expression of TET3 may be in cell culture 53,92 a positive prognostic marker. 97 in vitro 71 correlated with adverse outcome in cell culture 70 in male AML patients. Mutations in KDM6A associated with cytarabine resistance.…”

Section: Context 1 Heterozygous Mutations In Tet2mentioning

confidence: 92%

“…These molecules are intermediates in the pathway of in vitro 51,91 and in MLL-rearranged leukemia 96 . cell culture 50,51,53,[92][93][94] Reduced expression in AML 97 Increased expression in MLL-rearranged leukemia 96 TET2 KIAA1546, Nbla00191 Methylcytosine 5mC, 5hmC and 5fC Increased activity Tumor suppressor in AML, MDS, dioxygenase TET2…”

Section: Context 1 Heterozygous Mutations In Tet2mentioning

confidence: 99%

See 1 more Smart Citation

Emerging epigenetic therapeutics for myeloid leukemia: modulating demethylase activity with ascorbate

2020

View full text Add to dashboard Cite

The past decade has seen a proliferation of drugs that target epigenetic pathways. Many of these drugs were developed to treat acute myeloid leukemia, a condition in which dysregulation of the epigenetic landscape is well established. While these drugs have shown promise, critical issues persist. Specifically, patients with the same mutations respond quite differently to treatment. This is true even with highly specific drugs that are designed to target the underlying oncogenic driver mutations. Furthermore, patients who do respond may eventually develop resistance. There is now evidence that epigenetic heterogeneity contributes, in part, to these issues. Cancer cells also have a remarkable capacity to ‘rewire’ themselves at the epigenetic level in response to drug treatment, and thereby maintain expression of key oncogenes. This epigenetic plasticity is a promising new target for drug development. It is therefore important to consider combination therapy in cases in which both driver mutations and epigenetic plasticity are targeted. Using ascorbate as an example of an emerging epigenetic therapeutic, we review the evidence for its potential use in both of these modes. We provide an overview of 2-oxoglutarate dependent dioxygenases with DNA, histone and RNA demethylase activity, focusing on those which require ascorbate as a cofactor. We also evaluate their role in the development and maintenance of acute myeloid leukemia. Using this information, we highlight situations in which the use of ascorbate to restore 2-oxoglutarate dependent dioxygenase activity could prove beneficial, in contrast to contexts in which targeted inhibition of specific enzymes might be preferred. Finally, we discuss how these insights could be incorporated into the rational design of future clinical trials.

show abstract

“…Conversely, higher expression of TET1 at diagnosis was associated with poor clinical outcomes in a cohort of 360 CN-AML patients [ 43 ]. Finally, a recent study demonstrated that high TET3 expression was an independent factor for better OS and disease-free survival (DFS) in AML [ 44 ]. Of note, patients with lower TET3 expression undergoing hematopoietic stem cell transplant (HSCT) showed better OS and DFS than those who did not proceed to HSCT [ 44 ].…”

Section: The Metabolomics Of Tet Family Of Genesmentioning

confidence: 99%

The Interactome between Metabolism and Gene Mutations in Myeloid Malignancies

Gurnari

Pagliuca

Visconte

2021

IJMS

View full text Add to dashboard Cite

The study of metabolic deregulation in myeloid malignancies has led to the investigation of metabolic-targeted therapies considering that cells undergoing leukemic transformation have excessive energy demands for growth and proliferation. However, the most difficult challenge in agents targeting metabolism is to determine a window of therapeutic opportunities between normal and neoplastic cells, considering that all or most of the metabolic pathways important for cancer ontogeny may also regulate physiological cell functions. Targeted therapies have used the properties of leukemic cells to produce altered metabolic products when mutated. This is the case of IDH1/2 mutations generating the abnormal conversion of α-ketoglutarate (KG) to 2-hydroxyglutarate, an oncometabolite inhibiting KG-dependent enzymes, such as the TET family of genes (pivotal in characterizing leukemia cells either by mutations, e.g., TET2, or by altered expression, e.g., TET1/2/3). Additional observations derive from the high sensitivity of leukemic cells to oxidative phosphorylation and its amelioration using BCL-2 inhibitors (Venetoclax) or by disrupting the mitochondrial respiration. More recently, nicotinamide metabolism has been described to mediate resistance to Venetoclax in patients with acute myeloid leukemia. Herein, we will provide an overview of the latest research on the link between metabolic pathways interactome and leukemogenesis with a comprehensive analysis of the metabolic consequences of driver genetic lesions and exemplificative druggable pathways.

show abstract

Expression and prognosis analysis of TET family in acute myeloid leukemia

Cited by 20 publications

References 40 publications

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

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

Emerging epigenetic therapeutics for myeloid leukemia: modulating demethylase activity with ascorbate

The Interactome between Metabolism and Gene Mutations in Myeloid Malignancies

Contact Info

Product

Resources

About