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DOI	10.1073/pnas.2110758118
	TET2 as a tumor suppressor and therapeutic target in T-cell acute lymphoblastic leukemia
	Bensberg M.; Rundquist O.; Selimovic A.; Lagerwall C.; Benson M.; Gustafsson M.; Vogt H.; Lentini A.; Nestor C.E.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:34
英文摘要	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. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	5-azacytidine; HERV; T-ALL; TET2; Vitamin C
语种	英语
scopus关键词	antineoplastic antimetabolite; antioxidant; ascorbic acid; azacitidine; dioxygenase; DNA binding protein; TET2 protein, human; tumor marker; acute lymphoblastic leukemia; apoptosis; cell proliferation; combination drug therapy; DNA methylation; gene expression regulation; genetics; human; metabolism; pathology; promoter region; tumor cell culture; Antimetabolites, Antineoplastic; Antioxidants; Apoptosis; Ascorbic Acid; Azacitidine; Biomarkers, Tumor; Cell Proliferation; Dioxygenases; DNA Methylation; DNA-Binding Proteins; Drug Therapy, Combination; Gene Expression Regulation, Neoplastic; Humans; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Promoter Regions, Genetic; RNA-Seq; Tumor Cells, Cultured
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251043
作者单位	Crown Princess Victoria Children’s Hospital, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, 581 83, Sweden; Bioinformatics, Department of Physics, Chemistry and Biology, Linköping University, Linköping, 581 83, Sweden; Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, 171 77, Sweden
推荐引用方式 GB/T 7714	Bensberg M.,Rundquist O.,Selimovic A.,et al. TET2 as a tumor suppressor and therapeutic target in T-cell acute lymphoblastic leukemia[J],2021,118(34).
APA	Bensberg M..,Rundquist O..,Selimovic A..,Lagerwall C..,Benson M..,...&Nestor C.E..(2021).TET2 as a tumor suppressor and therapeutic target in T-cell acute lymphoblastic leukemia.Proceedings of the National Academy of Sciences of the United States of America,118(34).
MLA	Bensberg M.,et al."TET2 as a tumor suppressor and therapeutic target in T-cell acute lymphoblastic leukemia".Proceedings of the National Academy of Sciences of the United States of America 118.34(2021).