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Bamezai, S.* ; Demir, D.* ; Pulikkottil, A.J.* ; Ciccarone, F.* ; Fischbein, E.* ; Sinha, A.* ; Borga, C.* ; Te Kronnie, G.* ; Meyer, L.H.* ; Mohr, F.* ; Götze, M.* ; Caiafa, P.* ; Debatin, K.M.* ; Döhner, K.* ; Döhner, H.* ; González-Menéndez, I.* ; Quintanilla-Fend, L.* ; Herold, T. ; Jeremias, I. ; Feuring-Buske, M.* ; Buske, C.* ; Rawat, V.P.S.*

TET1 promotes growth of T-cell acute lymphoblastic leukemia and can be antagonized via PARP inhibition.

Leukemia 35, 389–403 (2020)
Postprint DOI PMC
Open Access Green
Free by publisher: Publ. Version/Full Text online available 05/2025
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer characterized by skewed epigenetic patterns, raising the possibility of therapeutically targeting epigenetic factors in this disease. Here we report that among different cancer types, epigenetic factor TET1 is highly expressed in T-ALL and is crucial for human T-ALL cell growth in vivo. Knockout of TET1 in mice and knockdown in human T cell did not perturb normal T-cell proliferation, indicating that TET1 expression is dispensable for normal T-cell growth. The promotion of leukemic growth by TET1 was dependent on its catalytic property to maintain global 5-hydroxymethylcytosine (5hmC) marks, thereby regulate cell cycle, DNA repair genes, and T-ALL associated oncogenes. Furthermore, overexpression of the Tet1-catalytic domain was sufficient to augment global 5hmC levels and leukemic growth of T-ALL cells in vivo. We demonstrate that PARP enzymes, which are highly expressed in T-ALL patients, participate in establishing H3K4me3 marks at the TET1 promoter and that PARP1 interacts with the TET1 protein. Importantly, the growth related role of TET1 in T-ALL could be antagonized by the clinically approved PARP inhibitor Olaparib, which abrogated TET1 expression, induced loss of 5hmC marks, and antagonized leukemic growth of T-ALL cells, opening a therapeutic avenue for this disease.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Acute Myeloid-leukemia; Dna-damage; Genomic Landscape; Tumor-suppressor; Self-renewal; Stem-cells; 5-hydroxymethylcytosine; Hypomethylation; Proteins; Mll
ISSN (print) / ISBN 0887-6924
e-ISSN 1476-5551
Journal Leukemia
Quellenangaben Volume: 35, Issue: , Pages: 389–403 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place Macmillan Building, 4 Crinan St, London N1 9xw, England
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)