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Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia

Panagiotis Ntziachristos, Aristotelis Tsirigos, G Grant Welstead, Thomas Trimarchi, Sofia Bakogianni, Luyao Xu, Evangelia Loizou, Linda Holmfeldt, Alexandros Strikoudis, Bryan King, et al.
(2014) NATURE. 514(7523). p.513-517
Author
Organization
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(1), and mutations that affect chromatin modulators in a variety of leukaemias have recently been identified(2,3); 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(4). 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.
Keywords
ACUTE MYELOID-LEUKEMIA, INITIATING CELL-ACTIVITY, H3K27 DEMETHYLASE, EXPRESSION PROFILES, JMJD3 CONTRIBUTES, STEM-CELL, UTX, MUTATIONS, ACTIVATION, GENOME

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MLA
Ntziachristos, Panagiotis, et al. “Contrasting Roles of Histone 3 Lysine 27 Demethylases in Acute Lymphoblastic Leukaemia.” NATURE, vol. 514, no. 7523, 2014, pp. 513–17, doi:10.1038/nature13605.
APA
Ntziachristos, P., Tsirigos, A., Welstead, G. G., Trimarchi, T., Bakogianni, S., Xu, L., … Aifantis, I. (2014). Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia. NATURE, 514(7523), 513–517. https://doi.org/10.1038/nature13605
Chicago author-date
Ntziachristos, Panagiotis, Aristotelis Tsirigos, G Grant Welstead, Thomas Trimarchi, Sofia Bakogianni, Luyao Xu, Evangelia Loizou, et al. 2014. “Contrasting Roles of Histone 3 Lysine 27 Demethylases in Acute Lymphoblastic Leukaemia.” NATURE 514 (7523): 513–17. https://doi.org/10.1038/nature13605.
Chicago author-date (all authors)
Ntziachristos, Panagiotis, Aristotelis Tsirigos, G Grant Welstead, Thomas Trimarchi, Sofia Bakogianni, Luyao Xu, Evangelia Loizou, Linda Holmfeldt, Alexandros Strikoudis, Bryan King, Jasper Mullenders, Jared Becksfort, Jelena Nedjic, Elisabeth Paietta, Martin S Tallman, Jacob M Rowe, Giovanni Tonon, Takashi Satoh, Laurens Kruidenier, Rab Prinjha, Shizuo Akira, Pieter Van Vlierberghe, Adolfo A Ferrando, Rudolf Jaenisch, Charles G Mullighan, and Iannis Aifantis. 2014. “Contrasting Roles of Histone 3 Lysine 27 Demethylases in Acute Lymphoblastic Leukaemia.” NATURE 514 (7523): 513–517. doi:10.1038/nature13605.
Vancouver
1.
Ntziachristos P, Tsirigos A, Welstead GG, Trimarchi T, Bakogianni S, Xu L, et al. Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia. NATURE. 2014;514(7523):513–7.
IEEE
[1]
P. Ntziachristos et al., “Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia,” NATURE, vol. 514, no. 7523, pp. 513–517, 2014.
@article{7066203,
  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(1), and mutations that affect chromatin modulators in a variety of leukaemias have recently been identified(2,3); 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(4). 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.}},
  author       = {{Ntziachristos, Panagiotis and Tsirigos, Aristotelis and Welstead, G Grant and Trimarchi, Thomas and Bakogianni, Sofia and Xu, Luyao and Loizou, Evangelia and Holmfeldt, Linda and Strikoudis, Alexandros and King, Bryan and Mullenders, Jasper and Becksfort, Jared and Nedjic, Jelena and Paietta, Elisabeth and Tallman, Martin S and Rowe, Jacob M and Tonon, Giovanni and Satoh, Takashi and Kruidenier, Laurens and Prinjha, Rab and Akira, Shizuo and Van Vlierberghe, Pieter and Ferrando, Adolfo A and Jaenisch, Rudolf and Mullighan, Charles G and Aifantis, Iannis}},
  issn         = {{0028-0836}},
  journal      = {{NATURE}},
  keywords     = {{ACUTE MYELOID-LEUKEMIA,INITIATING CELL-ACTIVITY,H3K27 DEMETHYLASE,EXPRESSION PROFILES,JMJD3 CONTRIBUTES,STEM-CELL,UTX,MUTATIONS,ACTIVATION,GENOME}},
  language     = {{eng}},
  number       = {{7523}},
  pages        = {{513--517}},
  title        = {{Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia}},
  url          = {{http://doi.org/10.1038/nature13605}},
  volume       = {{514}},
  year         = {{2014}},
}
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