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TET2 as a tumor sup...
TET2 as a tumor suppressor and therapeutic target in T-cell acute lymphoblastic leukemia
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- Bensberg, Maike (author)
- Linköpings universitet,Avdelningen för barns och kvinnors hälsa,Medicinska fakulteten
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- Rundquist, Olof (author)
- Linköpings universitet,Bioinformatik,Tekniska fakulteten
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- Selimovic, Aida (author)
- Linköpings universitet,Avdelningen för barns och kvinnors hälsa,Medicinska fakulteten
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- Lagerwall, Cathrine (author)
- Linköpings universitet,Avdelningen för kirurgi, ortopedi och onkologi,Medicinska fakulteten,Region Östergötland, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus
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- Benson, Mikael (author)
- Karolinska Institutet,Linköpings universitet,Avdelningen för barns och kvinnors hälsa,Medicinska fakulteten,Region Östergötland, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus
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- Gustafsson, Mika (author)
- Linköpings universitet,Bioinformatik,Tekniska fakulteten
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- Vogt, Hartmut (author)
- Linköpings universitet,Avdelningen för barns och kvinnors hälsa,Medicinska fakulteten,Region Östergötland, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus
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- Lentini, Antonio (author)
- Karolinska Inst, Sweden
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- Nestor, Colm (author)
- Linköpings universitet,Avdelningen för barns och kvinnors hälsa,Medicinska fakulteten
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(creator_code:org_t)
- 2021-08-19
- 2021
- English.
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In: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 118:34
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Abstract
Subject headings
Close
- Pediatric T-cell acute lymphoblastic leukemia (T-ALL) is an aggres-sive malignancy resulting from overproduction of immature T-cells in the thymus and is typified by widespread alterations in DNA methyl-ation. As survival rates for relapsed T-ALL remain dismal (10 to 25%), development of targeted therapies to prevent relapse is key to improv-ing 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, respec-tively. Furthermore, we show that TET2 silencing is often associated with hypermethylation of the TET2 promoter in primary T-ALL. Impor-tantly, 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 ret-roviruses (HERVs), which was further enhanced by the addition of phys-iological 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Keyword
- TET2; T-ALL; 5-azacytidine; HERV; vitamin C
Publication and Content Type
- ref (subject category)
- art (subject category)
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