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Nature. 2014 Oct 23;514(7523):513-7. doi: 10.1038/nature13605. Epub 2014 Aug 17.

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

Author information

1
1] Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA [2] NYU Cancer Institute and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, New York 10016, USA [3].
2
1] Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA [2] Center for Health Informatics and Bioinformatics, NYU School of Medicine, New York, New York 10016, USA [3].
3
1] Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3].
4
1] Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA [2] NYU Cancer Institute and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, New York 10016, USA.
5
Institute for Cancer Genetics, Columbia University Medical Center, New York, New York 10032, USA.
6
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
7
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
8
Montefiore Medical Center North, Bronx, New York, New York 10467, USA.
9
Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
10
1] Technion, Israel Institute of Technology, Haifa 31096, Israel [2] Shaare Zedek Medical Center, Jerusalem 9103102, Israel.
11
Functional Genomics of Cancer Unit, Division of Molecular Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, 20132 Milan, Italy.
12
1] Laboratory of Host Defense, WPI Immunology Frontier Research Center (WPI IFReC), Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan [2] Department of Host Defense, Research Institute for Microbial Diseases (RIMD), Osaka University, 3-1Yamada-oka, Suita, Osaka 565-0871, Japan.
13
Epinova DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline R&D, Medicines Research Centre, GunnelsWood Road, Stevenage SG1 2NY, UK.
14
1] Institute for Cancer Genetics, Columbia University Medical Center, New York, New York 10032, USA [2] Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
15
1] Institute for Cancer Genetics, Columbia University Medical Center, New York, New York 10032, USA [2] Department of Pathology, Columbia University Medical Center, New York, New York 10032, USA [3] Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA.
16
1] Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

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.

PMID:
25132549
PMCID:
PMC4209203
DOI:
10.1038/nature13605
[Indexed for MEDLINE]
Free PMC Article

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