TET2

TET2 (Ten-Eleven Translocation 2)

一行要約

TET2 は α-ketoglutarate / Fe2+ 依存性 dioxygenase で、5-methylcytosine (5mC) を 5-hydroxymethylcytosine (5hmC) → 5fC → 5caC に逐次酸化し、active DNA demethylation を駆動する epigenetic regulator。Hematological malignancy で frequent loss-of-function mutation (clonal hematopoiesis of indeterminate potential, CHIP の major driver), AML / MDS / T-cell lymphoma で確立した tumor suppressor。固形腫瘍では CHIP-derived TET2 loss が inflammatory myeloid expansion → cancer-promoting inflammation に寄与し、肺癌 含む solid tumor の predisposition / progression / IO 応答性に影響する経路として注目。

主要エビデンス

• CHIP and cancer risk: TET2 / DNMT3A / ASXL1 driven CHIP が aging / inflammatory disease / cancer risk の独立予測因子 (Jaiswal 2014 NEJM, 2017 NEJM)
• AML / MDS: TET2 loss-of-function は AML driver, hypomethylating agent (azacitidine / decitabine) 応答 biomarker
• Vitamin C と TET2 reactivation: 高用量 vitamin C が TET2 dioxygenase activity を回復、AML xenograft で differentiation 誘導 (Cimmino 2017 Cell)
• CAR-T persistence: lentivirus integration による TET2 disruption が稀な long-term CR を駆動 (Fraietta 2018 Nature)
• Solid tumor: lung / colorectal / pancreas で CHIP-derived TET2 mutant myeloid 浸潤が tumor-promoting inflammation を加速

メカニズム

TET2 は CXXC ドメインなしで CG-rich region に結合 (DNMT3A / IDAX 等の partner 経由)、5mC を α-KG / Fe²⁺ / O₂ 依存的に酸化。生成物 5hmC は (1) thymine DNA glycosylase (TDG) → BER で active demethylation 完結、(2) 安定 epigenetic mark として gene body / enhancer で活性 chromatin と associate。TET2 loss → hypermethylation 増加、HSC self-renewal advantage、myeloid differentiation 異常、inflammatory cytokine (IL-6, IL-1β, TNF-α) 過剰産生。固形腫瘍 TME で TET2-mutant myeloid が NLRP3 inflammasome 活性化 → tumor-promoting inflammation 増幅。

臨床位置づけ

血液悪性腫瘍では HMA (azacitidine, decitabine) 応答 biomarker / TKI 開発標的として確立。固形腫瘍では (1) CHIP screening で CV / cancer risk stratification, (2) CHIP-positive 患者の IO 応答性 / irAE 頻度との関連 (preliminary)、(3) lung cancer / NSCLC で CHIP 共存と治療応答 / 予後の研究進行中。Vitamin C の clinical use は乳/胃/大腸で trial 段階、固形腫瘍 IO combination の rationale 検討。

Open Questions

• Solid tumor outcome での CHIP-TET2 の predictive value: prospective validation
• TET2 reactivation 戦略 (vitamin C, α-KG analog) の clinical translation
• TET2 mutant myeloid と IO 応答性 / irAE の因果性検証
• Immune cell TET2 編集 (CAR-T persistence 強化) の安全性 / efficacy

関連エンティティ

• 関連経路: Epigenetic-chromatin-remodeling-pathway / NF-kB-pathway / Pyroptosis-inflammasome-pathway
• 関連遺伝子: EZH2 / ARID1A / SMARCA4 / CREBBP / SETD2
• 関連薬剤: Hypomethylating-agent / CAR-T-therapy / PD-1-inhibitor
• 関連概念: Tumor-promoting-inflammation / Clonal-evolution-ITH / Epigenetic-therapy-resistance / Emergency-granulopoiesis

関連論文

直近 30 件のみ表示中 (関連 35 件)。 全件は MOC ページ または Obsidian (source Markdown) から辿れます。

Basic-Immunotherapy

• Hogg et al. NatRevDrugDiscov 2020 — Targeting the epigenetic regulation of antitumour immunity
• Khan et al. Nature 2019 — TOX transcriptionally and epigenetically programs CD8 T cell exhaustion
• Nicola et al. Nature 2026 — Polyclonal selection of immune checkpoint mutations in thyroid autoimmunity
• Slater et al. TrendsCancer 2026 — Epigenetic, epitranscriptomic, and metabolic control of t cell exhaustion

Basic-Liquid-biopsy

• Merker et al. JClinOncol 2018 — Circulating tumor DNA analysis in patients with cancer american society of clinical oncology and college of american
• Corcoran et al. NEnglJMed 2018 — Application of cell-free DNA analysis to cancer treatment
• Bruhm et al. NatRevCancer 2025 — Genomic and fragmentomic landscapes of cell-free DNA for early cancer detection
• Aggarwal et al. NatRevClinOncol 2021 — Strategies for the successful implementation of plasma-based NSCLC genotyping in clinical practice
• Chabon et al. Nature 2020 — Integrating genomic features for non-invasive early lung cancer detection

Basic-Neutrophil and myeloid cell

• Nogales-Pons et al. JExpMed 2021 — Myeloid diversity in tumors shaped by genes, location, and time
• Wigerblad et al. JImmunol 2022 — Single-cell analysis reveals the range of transcriptional states of circulating human neutrophils
• Cerezo-Wallis et al. Nature 2026 — Architecture of the neutrophil compartment

Basic-Oncogene and genetics

• McGranahan et al. Cell 2017 — Clonal heterogeneity and tumor evolution past, present, and the future
• Ma et al. MolCell 2023 — SRSF2 plays an unexpected role as reader of m5c on mRNA, linking epitranscriptomics to cancer
• Pich et al. NEnglJMed 2025 — Tumor-infiltrating clonal hematopoiesis
• Cheek et al. NatGenet 2026 — Age distinguishes selection from causation in cancer genomes
• Kakiuchi et al. NatRevCancer 2021 — Clonal expansion in non-cancer tissues
• Michalak et al. NatRevMolCellBiol 2019 — The roles of DNA, RNA and histone methylation in ageing and cancer

Basic-Others

• DiNardo et al. NEnglJMed 2018 — Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML
• Laisne et al. NatRevCancer 2025 — Epigenomic heterogeneity as a source of tumour evolution
• Gerhardt et al. Nature 2026 — Mutation-dependent responses to sleep and exercise in clonal haematopoiesis
• Zeng et al. Nature 2026 — Human haematopoietic stem cells remember inflammatory stress

Clinical-NSCLC-Driver-Other

• Caswell et al. TrendsCancer 2026 — Lung cancer in never smokers from early detection to prevention

Clinical-NSCLC-EGFR

• Yang et al. ClinCancerRes 2018 — Investigating novel resistance mechanisms to third-generation EGFR tyrosine kinase inhibitor osimertinib in non-small

Clinical-Novel modalities

• Li et al. JHematolOncol 2026 — Nanotechnology-enhanced CAR-T therapy strategies in cancer, aging, and autoimmune diseases
• Milone et al. NatCancer 2021 — Engineering enhanced CAR T-cells for improved cancer therapy

Clinical-Others

• Chu et al. NatCancer 2026 — Integrated proteogenomic and metabolomic profiling of acute myeloid leukemias to identify molecular subtypes and

Clinical-Thymic

• Saito et al. Carcinogenesis 2017 — The genomic and epigenomic landscape in thymic carcinoma
• He et al. CellRepMed 2021 — Molecular predictors of response to pembrolizumab in thymic carcinoma
• Mohrmann et al. Med 2025 — Genomic landscape and molecularly informed therapy in thymic carcinoma and other advanced thymic epithelial tumors