Publikationsdatum:
2014-08-19
Beschreibung:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209203/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209203/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ntziachristos, Panagiotis -- Tsirigos, Aristotelis -- Welstead, G Grant -- Trimarchi, Thomas -- Bakogianni, Sofia -- Xu, Luyao -- Loizou, Evangelia -- Holmfeldt, Linda -- Strikoudis, Alexandros -- King, Bryan -- Mullenders, Jasper -- Becksfort, Jared -- Nedjic, Jelena -- Paietta, Elisabeth -- Tallman, Martin S -- Rowe, Jacob M -- Tonon, Giovanni -- Satoh, Takashi -- Kruidenier, Laurens -- Prinjha, Rab -- Akira, Shizuo -- Van Vlierberghe, Pieter -- Ferrando, Adolfo A -- Jaenisch, Rudolf -- Mullighan, Charles G -- Aifantis, Iannis -- 1R01CA105129/CA/NCI NIH HHS/ -- 1R01CA133379/CA/NCI NIH HHS/ -- 1R01CA149655/CA/NCI NIH HHS/ -- 5 T32 CA009161-37/CA/NCI NIH HHS/ -- 5P30CA16087-31/CA/NCI NIH HHS/ -- 5R01CA169784/CA/NCI NIH HHS/ -- 5R01CA173636/CA/NCI NIH HHS/ -- K99 CA188293/CA/NCI NIH HHS/ -- K99CA188293/CA/NCI NIH HHS/ -- P30 CA014051/CA/NCI NIH HHS/ -- P30 CA016087/CA/NCI NIH HHS/ -- P30 CA016087-30/CA/NCI NIH HHS/ -- P30 CA021765/CA/NCI NIH HHS/ -- R01 CA105129/CA/NCI NIH HHS/ -- R01 CA133379/CA/NCI NIH HHS/ -- R01 CA149655/CA/NCI NIH HHS/ -- R01 CA173636/CA/NCI NIH HHS/ -- R01CA120196/CA/NCI NIH HHS/ -- R37 HD045022/HD/NICHD NIH HHS/ -- R37-HD04502/HD/NICHD NIH HHS/ -- U10 CA180820/CA/NCI NIH HHS/ -- U10 CA180827/CA/NCI NIH HHS/ -- U10 CA21115/CA/NCI NIH HHS/ -- U24 CA114737/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Oct 23;514(7523):513-7. doi: 10.1038/nature13605. Epub 2014 Aug 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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]. ; 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]. ; 1] Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3]. ; 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. ; Institute for Cancer Genetics, Columbia University Medical Center, New York, New York 10032, USA. ; Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Montefiore Medical Center North, Bronx, New York, New York 10467, USA. ; Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; 1] Technion, Israel Institute of Technology, Haifa 31096, Israel [2] Shaare Zedek Medical Center, Jerusalem 9103102, Israel. ; 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. ; 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. ; Epinova DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline R&D, Medicines Research Centre, GunnelsWood Road, Stevenage SG1 2NY, UK. ; 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. ; 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. ; 1] Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25132549" target="_blank"〉PubMed〈/a〉
Schlagwort(e):
Animals
;
Benzazepines/pharmacology
;
Epigenesis, Genetic/drug effects
;
Histone Demethylases/genetics/*metabolism
;
Histones/chemistry/metabolism
;
Jumonji Domain-Containing Histone Demethylases/antagonists &
;
inhibitors/*metabolism
;
Lysine/metabolism
;
Methylation/drug effects
;
Mice
;
Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug
;
therapy/*enzymology/genetics/pathology
;
Pyrimidines/pharmacology
;
Tumor Suppressor Proteins/genetics/metabolism
Print ISSN:
0028-0836
Digitale ISSN:
1476-4687
Thema:
Biologie
,
Chemie und Pharmazie
,
Medizin
,
Allgemeine Naturwissenschaft
,
Physik
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