TET2 as a tumor suppressor and therapeutic target in T-cell acute lymphoblastic leukemia

Bensberg, MaikeLinköpings universitet,Avdelningen för barns och kvinnors hälsa,Medicinska fakulteten (author)

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.

Rundquist, OlofLinköpings universitet,Bioinformatik,Tekniska fakulteten(Swepub:liu)oloru74 (author)
Selimovic, AidaLinköpings universitet,Avdelningen för barns och kvinnors hälsa,Medicinska fakulteten(Swepub:liu)aidse07 (author)
Lagerwall, CathrineLinköpings universitet,Avdelningen för kirurgi, ortopedi och onkologi,Medicinska fakulteten,Region Östergötland, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus(Swepub:liu)catha65 (author)
Benson, MikaelKarolinska Institutet,Linköpings universitet,Avdelningen för barns och kvinnors hälsa,Medicinska fakulteten,Region Östergötland, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus(Swepub:liu)mikbe05 (author)
Gustafsson, MikaLinköpings universitet,Bioinformatik,Tekniska fakulteten(Swepub:liu)mikgu75 (author)
Vogt, HartmutLinköpings universitet,Avdelningen för barns och kvinnors hälsa,Medicinska fakulteten,Region Östergötland, H.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus(Swepub:liu)harki85 (author)
Lentini, AntonioKarolinska Inst, Sweden (author)
Nestor, ColmLinköpings universitet,Avdelningen för barns och kvinnors hälsa,Medicinska fakulteten(Swepub:liu)colne37 (author)
Linköpings universitetAvdelningen för barns och kvinnors hälsa (creator_code:org_t)

In:Proceedings of the National Academy of Sciences of the United States of America: National Academy of Sciences118:340027-84241091-6490

By the author/editor: Bensberg, Maike; Rundquist, Olof; Selimovic, Aida; Lagerwall, Cathr ...; Benson, Mikael; Gustafsson, Mika; show more...; Vogt, Hartmut; Lentini, Antonio; Nestor, Colm; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Cell and Molecul ...

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.