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Acquired, inactivating mutations in Tet methylcytosine dioxygenase 2 (TET2) are detected in peripheral blood cells of a remarkable 5%–10% of adults greater than 65 years of age. They impart a hematopoietic stem cell advantage and resultant clonal hematopoiesis of indeterminate potential (CHIP) with skewed myelomonocytic differentiation. CHIP is associated with an overall increased risk of transformation to a hematological malignancy, especially myeloproliferative and myelodysplastic neoplasms (MPN, MDS) and acute myeloid leukemia (AML), of approximately 0.5% to 1% per year. However, it is becoming increasingly possible to identify individuals at greatest risk, based on CHIP mutational characteristics. CHIP, and particularly TET2-mutant CHIP, is also a novel, significant risk factor for cardiovascular diseases, related in part to hyper-inflammatory, progeny macrophages carrying TET2 mutations. Therefore, somatic TET2 mutations contribute to myeloid expansion and innate immune dysregulation with age and contribute to prevalent diseases in the developed world—cancer and cardiovascular disease. Herein, we describe the impact of detecting TET2 mutations in the clinical setting. We also present the rationale and promise for targeting TET2-mutant and other CHIP clones, and their inflammatory environment, as potential means of lessening risk of myeloid cancer development and dampening CHIP-comorbid inflammatory diseases.

Background Increasing germline gene mutations have been discovered in haematological malignancies with the development of next-generation sequencing (NGS), which is critical for proper clinical management and long-term follow-up of affected individuals. Tet methylcytosine dioxygenase 2 ( TET2 ) is one of the most common mutations in haematological neoplasms. We aimed to compare the clinical characteristics of patients with germline and somatic TET2 mutations in haematological diseases and to analyse whether germline TET2 mutations have a family aggregation and tumour predisposition. Methods Out of 612 patients who underwent NGS of 34 recurrently mutated genes in haematological diseases, 100 haematological patients with TET2 mutations were selected for further study. Somatic mutations were detected by NGS in bone marrow/peripheral blood genomic DNA (gDNA). Germline TET2 mutations were validated in nail/hair gDNA by Sanger sequencing. Digital data were extracted from the haematology department of the West China Hospital of Sichuan University. TET2 mutation results were analysed by referencing online public databases (COSMIC and ClinVar). Results One hundred patients were studied, including 33 patients with germline and 67 patients with somatic TET2 mutations. For germline TET2 mutations, the variant allele frequency (VAF) was more stable (50.58% [40.5–55], P  < 0.0001), and mutation sites recurrently occurred in three sites, unlike somatic TET2 mutations. Patients with germline TET2 mutations were younger (median age 48, 16–82 years) ( P  = 0.0058) and mainly suffered from myelodysplastic syndromes (MDS) ( n  = 13, 39.4%), while patients with somatic TET2 mutations were mainly affected by acute myeloid leukemia (AML) ( n  = 26, 38.8%) ( P  = 0.0004). Germline TET2 mutation affected the distribution of cell counts in the peripheral blood and bone marrow ( P  < 0.05); it was a poor prognostic factor for MDS patients via univariate analysis (HR = 5.3, 95% CI: 0.89–32.2, P  = 0.0209) but not in multivariate analysis using the Cox regression model ( P  = 0.062). Conclusions Germline TET2 mutation might have a family aggregation, and TET2 may be a predisposition gene for haematological malignancy under the other gene mutations as the second hit. Germline TET2 mutation may play a role in the proportion of blood and bone marrow cells and, most importantly, may be an adverse factor for MDS patients.

Clonal hematopoiesis is a proposed marker of aging. Clonal hematopoiesis of indeterminate potential (CHIP) is a candidate risk factor for atherosclerotic cardiovascular diseases, hematological malignancies, and all-cause mortality, while its associations with the diseases of other systems and cause-specific mortality remain inconclusive. We estimated the longitudinal risk for CHIP with 70 common diseases, all-cause, and cause-specific mortality among 431,546 participants in the UK Biobank. Two-sample MR analyses were performed to test the causal associations of CHIP with incident diseases. Cox proportional hazard regression model was used to generate the hazard ratio [HR] and 95% confidence interval [CI] for each CHIP phenotype with the common health-related outcomes. Also evaluated the joint associations between CHIP and TL for diseases and mortalities. This study included 431,546 participants (mean age, 56.49 years; 45.7% male), of whom 20,274 had CHIP. CHIP at baseline was associated with increased risk of cancers (HR = 1.14, 95% CI 1.10-1.17), infections (HR = 1.12, 95% CI 1.07-1.16), ischemic heart diseases (HR = 1.07, 95% CI 1.02-1.12), diseases of the blood (HR = 1.31, 95% CI 1.26-1.37), nervous (HR = 1.05, 95% CI 1.01-1.10), respiratory (HR = 1.10, 95% CI 1.06-1.13), and genitourinary systems (HR = 1.10, 95% CI 1.07-1.14), and related mortality (false discovery rate <0.05). CHIP carriers were also at elevated risk of incident mental (HR = 1.07, 95% CI 1.03-1.12) and dermatological (HR = 1.07 95% CI 1.03-1.11) disorders and mortality due to circulatory system (HR = 1.19, 95% CI 1.11-1.28). Most of the associations between CHIP and diseases or mortalities were robust after adjustment for inflammatory parameters. Large clone size CHIP had higher longitudinal risks compared with small clone size or overall CHIP. CHIP due to TET2 mutation was associated with more outcomes than other common CHIP driver genes. Significant interactions were observed between CHIP and short telomere length, the additive and multiplicative effects on the risk of diseases and mortalities were more obvious among large clone size CHIP. This study showed that CHIP was associated with diseases and mortalities of multiple systems, suggesting CHIP was a candidate risk factor for human health.

As a kind of human unique benign skin tumour, keloid has caused great trouble to the physical and mental health of patients and is unfavourable for beautiful. The abnormal proliferation of fibroblasts is one of the main causes of keloid formation. TET2 (Ten eleven translocation 2) catalyzes the oxidation of cytosine 5mC to 5hmC which process plays important role in cell proliferation. However, the molecular mechanism of TET2 in keloids is not well-researched. qPCR was used to detect the mRNA levels and Western blot was used to detect the protein level. DNA Dot blot was used to detect the level of 5hmC. CCK8 was used to examine the cell proliferation rate. EDU/DAPI staining was used to evaluate the living cells' proliferation rate. DNA IP and PCR were used to detect the accumulation of DNA at the target site after 5hmC enrichment. We found that TET2 was highly expressed in keloid tissue. Interestingly, TET2 expression was increased in fibroblasts that were isolated and cultured in vitro compared to the tissue of origin. Knocking down TET2 expression can effectively decrease the modification level of 5hmC and inhibit the proliferation of fibroblasts. Notably, overexpression of DNMT3A inhibited fibroblast proliferation by decreasing 5hmC. The 5hmC-IP assay showed that TET2 could affect the expression of TGFβ by regulating the 5hmC modification level in the promoter region. And by this way, TET2 regulates the proliferation of fibroblasts. This study found new epigenetic mechanisms for keloid formation.

This meta-analysis aims to concisely summarize the genetic landscape of splenic, nodal and extranodal marginal zone lymphomas (MZL) in the dura mater, salivary glands, thyroid, ocular adnexa, lung, stomach and skin with respect to somatic variants. A systematic PubMed search for sequencing studies of MZL was executed. All somatic mutations of the organs mentioned above were combined, uniformly annotated, and a dataset containing 25 publications comprising 6016 variants from 1663 patients was created. In splenic MZL, KLF2 (18%, 103/567) and NOTCH2 (16%, 118/725) were the most frequently mutated genes. Pulmonary and nodal MZL displayed recurrent mutations in chromatin-modifier-encoding genes, especially KMT2D (25%, 13/51, and 20%, 20/98, respectively). In contrast, ocular adnexal, gastric, and dura mater MZL had mutations in genes encoding for NF-κB pathway compounds, in particular TNFAIP3, with 39% (113/293), 15% (8/55), and 45% (5/11), respectively. Cutaneous MZL frequently had FAS mutations (63%, 24/38), while MZL of the thyroid had a higher prevalence for TET2 variants (61%, 11/18). Finally, TBL1XR1 (24%, 14/58) was the most commonly mutated gene in MZL of the salivary glands. Mutations of distinct genes show origin-preferential distribution among nodal and splenic MZL as well as extranodal MZL at/from different anatomic locations. Recognition of such mutational distribution patterns may help assigning MZL origin in difficult cases and possibly pave the way for novel more tailored treatment concepts.

TET2, a member of ten-eleven translocation (TET) family as α-ketoglutarate- and Fe 2+-dependent dioxygenase catalyzing the iterative oxidation of 5-methylcytosine (5mC), has been widely recognized to be an important regulator for normal hematopoiesis especially myelopoiesis. Mutation and dysregulation of TET2 contribute to the development of multiple hematological malignancies. Recent studies reveal that TET2 also plays an important role in innate immune homeostasis by promoting DNA demethylation or independent of its enzymatic activity. Here, we focus on the functions of TET2 in the initiation and resolution of inflammation through epigenetic regulation and signaling network. In addition, we highlight regulation of TET2 at various molecular levels as well as the correlated inflammatory diseases, which will provide the insight to intervene in the pathological process caused by TET2 dysregulation.

Mutations in IDH1, IDH2, and TET2 are recurrently observed in myeloid neoplasms. IDH1 and IDH2 encode isocitrate dehydrogenase isoforms, which normally catalyze the conversion of isocitrate to α-ketoglutarate (α-KG). Oncogenic IDH1/2 mutations confer neomorphic activity, leading to the production of D-2-hydroxyglutarate (D-2-HG), a potent inhibitor of α-KG-dependent enzymes which include the TET methylcytosine dioxygenases. Given their mutual exclusivity in myeloid neoplasms, IDH1, IDH2, and TET2 mutations may converge on a common oncogenic mechanism. Contrary to this expectation, we observed that they have distinct, and even opposite, effects on hematopoietic stem and progenitor cells in genetically engineered mice. Epigenetic and single-cell transcriptomic analyses revealed that Idh2R172K and Tet2 loss-of-function have divergent consequences on the expression and activity of key hematopoietic and leukemogenic regulators. Notably, chromatin accessibility and transcriptional deregulation in Idh2R172K cells were partially disconnected from DNA methylation alterations. These results highlight unanticipated divergent effects of IDH1/2 and TET2 mutations, providing support for the optimization of genotype-specific therapies.

Recent studies have linked atopic dermatitis (AD) to colorectal cancer (CRC) risk. Their causality and potential molecular mechanisms remain unclear. We performed Mendelian randomization (MR) analysis to evaluate the causality between AD and CRC. Summary statistic data-based Mendelian randomization (SMR) analysis was used to identify CRC-related causal genes. Transcriptome analyses and immunohistochemical methods were applied to investigate the shared gene signature and potential mechanisms that contribute to the pathogenesis of both AD and CRC. A predictive analysis was performed to examine the shared gene signature associated with immunotherapy response in CRC. MR analysis indicated a causal association between AD and a decreased risk of CRC. SMR analysis uncovered TET2 as a CRC-related causal gene, showing an inverse relationship with the risk of CRC. Transcriptome analyses identified TET2 as a shared gene signature between AD and CRC. Decreased TET2 expression is associated with impaired demethylation and worse prognosis in CRC patients. We observed ten pathways related to the inflammatory response and immune regulation that may be shared mechanisms underlying both AD and CRC. These findings were validated through single-cell analysis. TET2 shows promise as a powerful predictive biomarker for cancer prognosis and immunotherapy response in CRC. There is a causal association between AD and a decreased risk of CRC. AD may influence the occurrence of CRC by modulating immune and inflammatory responses. TET2 could serve as a potential biomarker for prognosis and may be considered a novel therapeutic target for methylation and immune-related interventions.

Pediatric T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy resulting from overproduction of immature T-cells in the thymus and is typified by widespread alterations in DNA methylation. As survival rates for relapsed T-ALL remain dismal (10 to 25%), development of targeted therapies to prevent relapse is key to improving prognosis. Whereas mutations in the DNA demethylating enzyme TET2 are frequent in adult T-cell malignancies, TET2 mutations in T-ALL are rare. Here, we analyzed RNA-sequencing data of 321 primary T-ALLs, 20 T-ALL cell lines, and 25 normal human tissues, revealing that TET2 is transcriptionally repressed or silenced in 71% and 17% of T-ALL, respectively. Furthermore, we show that TET2 silencing is often associated with hypermethylation of the TET2 promoter in primary T-ALL. Importantly, treatment with the DNA demethylating agent, 5-azacytidine (5-aza), was significantly more toxic to TET2-silenced T-ALL cells and resulted in stable re-expression of the TET2 gene. Additionally, 5-aza led to up-regulation of methylated genes and human endogenous retroviruses (HERVs), which was further enhanced by the addition of physiological levels of vitamin C, a potent enhancer of TET activity. Together, our results clearly identify 5-aza as a potential targeted therapy for TET2-silenced T-ALL.

Ten-Eleven Translocation-2 ( TET2 ) inactivation through loss-of-function mutation, deletion and IDH1/2 (Isocitrate Dehydrogenase 1 and 2) gene mutation is a common event in myeloid and lymphoid malignancies. TET2 gene mutations similar to those observed in myeloid and lymphoid malignancies also accumulate with age in otherwise healthy subjects with clonal hematopoiesis. TET2 is one of the three proteins of the TET (Ten-Eleven Translocation) family, which are evolutionarily conserved dioxygenases that catalyze the conversion of 5-methyl-cytosine (5-mC) to 5-hydroxymethyl-cytosine (5-hmC) and promote DNA demethylation. TET dioxygenases require 2-oxoglutarate, oxygen and Fe(II) for their activity, which is enhanced in the presence of ascorbic acid. TET2 is the most expressed TET gene in the hematopoietic tissue, especially in hematopoietic stem cells. In addition to their hydroxylase activity, TET proteins recruit the O-linked β-D-N-acetylglucosamine (O-GlcNAc) transferase (OGT) enzyme to chromatin, which promotes post-transcriptional modifications of histones and facilitates gene expression. The TET2 level is regulated by interaction with IDAX, originating from TET2 gene fission during evolution, and by the microRNA miR-22. TET2 has pleiotropic roles during hematopoiesis, including stem-cell self-renewal, lineage commitment and terminal differentiation of monocytes. Analysis of Tet2 knockout mice, which are viable and fertile, demonstrated that Tet2 functions as a tumor suppressor whose haploinsufficiency initiates myeloid and lymphoid transformations. This review summarizes the recently identified TET2 physiological and pathological functions and discusses how this knowledge influences our therapeutic approaches in hematological malignancies and possibly other tumor types.