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首页> 外文期刊>Nature >Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia
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Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia

机译：组蛋白3赖氨酸27脱甲基酶在急性淋巴细胞白血病中的对比作用

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摘要

T-cell acute lymphoblastic leukaemia (T-ALL) is a haematplogical 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 bymodulating 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.
机译：T细胞急性淋巴细胞白血病（T-ALL）是一种血液恶性肿瘤，总体预后不佳，包括高达25％的复发率，主要是因为缺乏非细胞毒性靶向治疗选择。靶向关键表观遗传因子功能的药物已在造血系统疾病的背景下得到批准，最近已鉴定出可影响多种白血病中染色质调节剂的突变。然而，“表观遗传”药物目前尚未用于T-ALL治疗最近，我们描述了多梳阻抑复合物2（PRC2）在T-ALL中具有肿瘤抑制作用。在这里，我们描述了组蛋白3赖氨酸27（H3K27）去甲基化酶JMJD3和UTX在T-ALL中的作用。我们显示JMJD3对于T-ALL的启动和维持至关重要，因为它通过调节H3K27甲基化来控制重要的致癌基因靶标。相比之下，我们发现UTX可以起到抑癌作用，并且在T-ALL中经常被基因灭活。此外，我们证明了小分子抑制剂GSKJ4（参考文献5）通过靶向JMJD3活性而影响T-ALL的生长。这些发现表明，具有相同酶功能的两种蛋白质在同一疾病中可能具有相反的作用，从而为利用新型表观遗传抑制剂治疗造血系统恶性肿瘤铺平了道路。

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  • 来源
    《Nature》 |2014年第7523期|513-517|共5页
  • 作者

    Panagiotis Ntziachristos; 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; Iannis Aifantis;

  • 作者单位

    Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA,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;

    Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA,Center for Health Informatics and Bioinformatics, NYU School of Medicine, New York, New York 10016, USA;

    Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA,Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA,Editas Medicine, Cambridge,Massachusetts 02142, USA;

    Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA,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;

    Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA,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;

    Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA,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;

    Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA;

    Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA,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;

    Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA,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;

    Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA,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;

    Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA;

    Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA,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;

    Montefiore Medical Center North, Bronx, New York, New York 10467, USA;

    Memorial Sloan Kettering Cancer Center, New York, New York 10065,USA;

    Technion,Israel Institute of Technology,Haifa 31096, Israel,Shaare Zedek Medical Center, Jerusalem9103102, 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;

    Laboratory of Host Defense, WPI Immunology Frontier Research Center (WPIIFReC), Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan,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;

    Epinova DPU,Immuno-Inflammation Therapy Area, GlaxoSmithKline R&D, Medicines Research Centre, GunnelsWood Road, Stevenage SG1 2NY.UK;

    Laboratory of Host Defense, WPI Immunology Frontier Research Center (WPIIFReC), Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan,Department of Host Defense, Research Institute for Microbial Diseases (RIMD), Osaka University, 3-1Yamada-oka, Suita, Osaka 565-0871, Japan;

    Institute for Cancer Genetics, Columbia University Medical Center, New York, New York 10032, USA,Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium;

    Institute for Cancer Genetics, Columbia University Medical Center, New York, New York 10032, USA,Department of Pathology, Columbia University Medical Center, New York, New York 10032, USA,Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA;

    Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA,Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;

    Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA;

    Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York 10016, USA,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;

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