1. TET2 as a tumor suppressor and therapeutic target in T-cell acute lymphoblastic leukemia.
- Author
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Bensberg M, Rundquist O, Selimović A, Lagerwall C, Benson M, Gustafsson M, Vogt H, Lentini A, and Nestor CE
- Subjects
- Antimetabolites, Antineoplastic pharmacology, Antioxidants pharmacology, Apoptosis, Biomarkers, Tumor genetics, Cell Proliferation, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Dioxygenases genetics, Dioxygenases metabolism, Drug Therapy, Combination, Humans, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma metabolism, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma pathology, Promoter Regions, Genetic, RNA-Seq, Tumor Cells, Cultured, Ascorbic Acid pharmacology, Azacitidine pharmacology, Biomarkers, Tumor metabolism, DNA Methylation, DNA-Binding Proteins antagonists & inhibitors, Dioxygenases antagonists & inhibitors, Gene Expression Regulation, Neoplastic, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
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., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)
- Published
- 2021
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