Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia
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Author(s)
Ntziachristos, Panagiotis
Tsirigos, Aristotelis
Welstead, G. Grant
Trimarchi, Thomas
Bakogianni, Sofia
Xu, Luyao
Loizou, Evangelia
Holmfeldt, Linda
Strikoudis, Alexandros
King, Bryan
Date Issued
August 2014
Journal
Nature
Publisher
Nature Publishing Group
Citation
Ntziachristos, Panagiotis, Aristotelis Tsirigos, G. Grant Welstead, Thomas Trimarchi, Sofia Bakogianni, Luyao Xu, Evangelia Loizou, et al. “Contrasting Roles of Histone 3 Lysine 27 Demethylases in Acute Lymphoblastic Leukaemia.” Nature 514, no. 7523 (August 17, 2014): 513–517.
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Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
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DOI of Published Version
https://doi.org/10.1038/nature13605
