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- Title
Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia.
- Authors
Ntziachristos, Panagiotis; Rowe, Jacob M.; Tonon, Giovanni; Satoh, Takashi; Akira, Shizuo; Kruidenier, Laurens; Prinjha, Rab; Van Vlierberghe, Pieter; Ferrando, Adolfo A.; Jaenisch, Rudolf; Tsirigos, Aristotelis; Welstead, G. Grant; Trimarchi, Thomas; Bakogianni, Sofia; Loizou, Evangelia; Strikoudis, Alexandros; King, Bryan; Mullenders, Jasper; Nedjic, Jelena; Aifantis, Iannis
- Abstract
T-cell acute lymphoblastic leukaemia (T-ALL) is a haematological malignancy with a dismal overall prognosis, including a relapse rate of up to 25%, mainly because of the lack of non-cytotoxic targeted therapy options. Drugs that target the function of key epigenetic factors have been approved in the context of haematopoietic disorders, and mutations that affect chromatin modulators in a variety of leukaemias have recently been identified; however, 'epigenetic' drugs are not currently used for T-ALL treatment. Recently, we described that the polycomb repressive complex 2 (PRC2) has a tumour-suppressor role in T-ALL. Here we delineated the role of the histone 3 lysine 27 (H3K27) demethylases JMJD3 and UTX in T-ALL. We show that JMJD3 is essential for the initiation and maintenance of T-ALL, as it controls important oncogenic gene targets by modulating H3K27 methylation. By contrast, we found that UTX functions as a tumour suppressor and is frequently genetically inactivated in T-ALL. Moreover, we demonstrated that the small molecule inhibitor GSKJ4 (ref. 5) affects T-ALL growth, by targeting JMJD3 activity. These findings show that two proteins with a similar enzymatic function can have opposing roles in the context of the same disease, paving the way for treating haematopoietic malignancies with a new category of epigenetic inhibitors.
- Subjects
HISTONE demethylases; LYMPHOBLASTIC leukemia; ONCOGENES; METHYLATION; TUMOR suppressor genes; T cells
- Publication
Nature, 2014, Vol 514, Issue 7523, p513
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature13605