TY - JOUR
T1 - Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia
AU - Ntziachristos, Panagiotis
AU - Tsirigos, Aristotelis
AU - Welstead, G. Grant
AU - Trimarchi, Thomas
AU - Bakogianni, Sofia
AU - Xu, Luyao
AU - Loizou, Evangelia
AU - Holmfeldt, Linda
AU - Strikoudis, Alexandros
AU - King, Bryan
AU - Mullenders, Jasper
AU - Becksfort, Jared
AU - Nedjic, Jelena
AU - Paietta, Elisabeth
AU - Tallman, Martin S.
AU - Rowe, Jacob M.
AU - Tonon, Giovanni
AU - Satoh, Takashi
AU - Kruidenier, Laurens
AU - Prinjha, Rab
AU - Akira, Shizuo
AU - Van Vlierberghe, Pieter
AU - Ferrando, Adolfo A.
AU - Jaenisch, Rudolf
AU - Mullighan, Charles G.
AU - Aifantis, Iannis
N1 - Publisher Copyright:
© 2014 Macmillan Publishers Limited. All rights reserved.
PY - 2014/10/23
Y1 - 2014/10/23
N2 - 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 disorders1, and mutations that affect chromatin modulators in a variety of leukaemias have recently been identified2,3; however, 'epigenetic' drugs arenot currently used forT-ALLtreatment.Recently,wedescribedthat the polycomb repressive complex 2 (PRC2) has a tumour-suppressor role in T-ALL4. 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 thatUTXfunctions as a tumour suppressor and is frequently genetically inactivated in T-ALL.Moreover, wedemonstrated that the smallmolecule 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.
AB - 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 disorders1, and mutations that affect chromatin modulators in a variety of leukaemias have recently been identified2,3; however, 'epigenetic' drugs arenot currently used forT-ALLtreatment.Recently,wedescribedthat the polycomb repressive complex 2 (PRC2) has a tumour-suppressor role in T-ALL4. 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 thatUTXfunctions as a tumour suppressor and is frequently genetically inactivated in T-ALL.Moreover, wedemonstrated that the smallmolecule 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.
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U2 - 10.1038/nature13605
DO - 10.1038/nature13605
M3 - Article
C2 - 25132549
AN - SCOPUS:84907526739
SN - 0028-0836
VL - 514
SP - 513
EP - 517
JO - Nature
JF - Nature
IS - 7523
ER -