TET2 regulates extranodal NK/T cell lymphoma progression through regulation of DNA methylation

IF 3.3 4区 医学 Q2 HEMATOLOGY
Chunxiang Xiang, Limin Gao, Qing Tao, Zihang Chen, Sha Zhao, Weiping Liu
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引用次数: 0

Abstract

The biological role of Ten-11 translocation 2 (TET2) and the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in the development of extra-nodal natural killer/T-cell lymphoma (ENKTL) remains unclear. The level of 5mC and 5hmC was detected in 112 cases of ENKTL tissue specimens by immunohistochemical (IHC) staining. Subsequently, TET2 knockdown and the overexpression cell models were constructed in ENKTL cell lines. Biochemical analyses were used to assess proliferation, apoptosis, cell cycle and monoclonal formation in cells treated or untreated with L-Ascorbic acid sodium salt (LAASS). Dot-Blots were used to detect levels of genome 5mC and 5hmC. Additionally, the ILLUMINA 850k methylation chip was used to analyze the changes of TET2 regulatory genes. RNA-Seq was used to profile differentially expressed genes regulated by TET2. The global level of 5hmC was significantly decreased, while 5mC was highly expressed in ENKTL tissue. TET2 protein expression was negatively correlated with the ratio of 5mC/5hmC (p < 0.0001). The 5mC/5hmC status were related to the site of disease, clinical stage, PINK score and Ki-67 index, as well as the 5-year OS. TET2 knockdown prolonged the DNA synthesis period, increased the cloning ability of tumor cells, increased the level of 5mC and decreased the level of 5hmC in ENKTL cells. While overexpression of TET2 presented the opposite effect. Furthermore, treatment of ENKTL cells with LAASS significantly induced ENKTL cell apoptosis. These results suggest that TET2 plays an important role in ENKTL development via regulation of 5mC and 5hmC and may serve as a novel therapeutic target for ENKTL.

TET2通过调节DNA甲基化调控结节外NK/T细胞淋巴瘤的发展。
Ten-11易位2(TET2)和5-甲基胞嘧啶(5mC)转化为5-羟甲基胞嘧啶(5hmC)在结外自然杀伤/T细胞淋巴瘤(ENKTL)发病过程中的生物学作用尚不清楚。通过免疫组化(IHC)染色法检测了112例ENKTL组织标本中5mC和5hmC的水平。随后,在ENKTL细胞系中构建了TET2敲除和过表达细胞模型。生化分析用于评估经左旋抗坏血酸钠盐(LAASS)处理或未处理的细胞的增殖、凋亡、细胞周期和单克隆形成。点阵图用于检测基因组 5mC 和 5hmC 的水平。此外,还使用 ILLUMINA 850k 甲基化芯片分析 TET2 调控基因的变化。RNA-Seq 用于分析受 TET2 调控的差异表达基因。在ENKTL组织中,5hmC的整体水平明显下降,而5mC则高表达。TET2 蛋白表达与 5mC/5hmC 的比值呈负相关(p
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来源期刊
Hematological Oncology
Hematological Oncology 医学-血液学
CiteScore
4.20
自引率
6.10%
发文量
147
审稿时长
>12 weeks
期刊介绍: Hematological Oncology considers for publication articles dealing with experimental and clinical aspects of neoplastic diseases of the hemopoietic and lymphoid systems and relevant related matters. Translational studies applying basic science to clinical issues are particularly welcomed. Manuscripts dealing with the following areas are encouraged: -Clinical practice and management of hematological neoplasia, including: acute and chronic leukemias, malignant lymphomas, myeloproliferative disorders -Diagnostic investigations, including imaging and laboratory assays -Epidemiology, pathology and pathobiology of hematological neoplasia of hematological diseases -Therapeutic issues including Phase 1, 2 or 3 trials as well as allogeneic and autologous stem cell transplantation studies -Aspects of the cell biology, molecular biology, molecular genetics and cytogenetics of normal or diseased hematopoeisis and lymphopoiesis, including stem cells and cytokines and other regulatory systems. Concise, topical review material is welcomed, especially if it makes new concepts and ideas accessible to a wider community. Proposals for review material may be discussed with the Editor-in-Chief. Collections of case material and case reports will be considered only if they have broader scientific or clinical relevance.
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