Back to Search
Start Over
TET2 as a tumor suppressor and therapeutic target in T-cell acute lymphoblastic leukemia.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Aug 24; Vol. 118 (34). - Publication Year :
- 2021
-
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.<br />Competing Interests: The authors declare no competing interest.<br /> (Copyright © 2021 the Author(s). Published by PNAS.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 118
- Issue :
- 34
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 34413196
- Full Text :
- https://doi.org/10.1073/pnas.2110758118