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首页> 外文期刊>Nature >Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms
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Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms

机译：突变的C-CBL肿瘤抑制物在骨髓肿瘤中的功能获得

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摘要

Acquired uniparental disomy (aUPD) is a common feature of cancer genomes, leading to loss of heterozygosity. aUPD is associated not only with loss-of-function mutations of tumour suppressor genes1, but also with gain-of-function mutations of proto-oncogenes2. Here we show unique gain-of-function mutations of the C-CBL (also known as CBL) tumour suppressor that are tightly associated with aUPD of the 11q arm in myeloid neoplasms showing myeloproli-ferative features. The C-CBL proto-oncogene, a cellular homologue of v-Cbl, encodes an E3 ubiquitin ligase and negatively regulates signal transduction of tyrosine kinases. Homozygous C-CBL mutations were found in most 11q-aUPD-positive myeloid malignancies. Although the C-CBL mutations were oncogenic in NIH3T3 cells, c-Cbl was shown to functionally and genetically act as a tumour suppressor. C-CBL mutants did not have E3 ubiquitin ligase activity, but inhibited that of wild-type C-CBL and CBL-B (also known as CBLB), leading to prolonged activation of tyrosine kinases after cytokine stimulation. c-Cbl~(-/-) haematopoietic stem/progenitor cells (HSPCs) showed enhanced sensitivity to a variety of cyto-kines compared to c-Cbl~(+/+) HSPCs, and transduction of C-CBL mutants into c-Cbl~(-/-) HSPCs further augmented their sensitivities to a broader spectrum of cytokines, including stem-cell factor (SCF, also known as KITLG), thrombopoietin (TPO, also known as THPO), IL3 and FLT3 ligand (FLT3LG), indicating the presence of a gain-of-function that could not be attributed to a simple loss-of-function. The gain-of-function effects of C-CBL mutants on cytokine sensitivity of HSPCs largely disappeared in a c-Cbl~(+/+) background or by co-transduction of wild-type C-CBL, which suggests the pathogenic importance of loss of wild-type C-CBL alleles found in most cases of C-CBL-mutated myeloid neoplasms. Our findings provide a new insight into a role of gain-of-function mutations of a tumour suppressor associated with aUPD in the pathogenesis of some myeloid cancer subsets.
机译：获得性单亲二体性（aUPD）是癌症基因组的共同特征，导致杂合性丧失。 aUPD不仅与肿瘤抑制基因的功能丧失突变有关，而且与原癌基因2的功能获得突变有关。在这里，我们显示了C-CBL（也称为CBL）肿瘤抑制因子的独特功能获得性突变，该突变与显示骨髓增生性特征的骨髓瘤中11q臂的aUPD紧密相关。 C-CBL原癌基因是v-Cbl的细胞同源物，编码E3泛素连接酶，并负向调节酪氨酸激酶的信号转导。在大多数11q-aUPD阳性骨髓恶性肿瘤中发现纯合C-CBL突变。尽管C-CBL突变在NIH3T3细胞中是致癌的，但c-Cbl被证明在功能和基因上起着抑癌作用。 C-CBL突变体不具有E3泛素连接酶活性，但抑制野生型C-CBL和CBL-B（也称为CBLB）的活性，导致细胞因子刺激后酪氨酸激酶的活化时间延长。与c-Cbl〜（+ / +）HSPC相比，c-Cbl〜（-/-）造血干/祖细胞（HSPC）对各种细胞因子的敏感性增强，并且C-CBL突变体转导至c- Cbl〜（-/-）HSPC对更广泛的细胞因子，包括干细胞因子（SCF，也称为KITLG），血小板生成素（TPO，也称为THPO），IL3和FLT3配体（FLT3LG）的敏感性进一步增强。 ，表示存在无法归因于简单功能损失的功能获得。 C-CBL突变体对HSPC的细胞因子敏感性的功能获得效应在c-Cbl〜（+ / +）背景下或通过野生型C-CBL的共转导而基本消失，这提示C-CBL突变体的致病重要性。在大多数C-CBL突变的骨髓瘤病例中发现的野生型C-CBL等位基因缺失。我们的发现为与aUPD相关的抑癌基因的功能获得性突变在某些骨髓癌亚群的发病机理中的作用提供了新的见解。

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  • 来源
    《Nature》 |2009年第7257期|904-908|共5页
  • 作者

    Masashi Sanada; Takahiro Suzuki; Lee-Yung Shin; Makoto Otsu; Motohiro Kato; Satoshi Yamazaki; Azusa Tamura; Hiroaki Honda; Mamiko Sakata-Yanagimoto; Keiki Kumano; Hideaki Oda; Tetsuya Yamagata; Junko Takita; Noriko Gotoh; Kumi Nakazaki; Norihiko Kawamata; Masafumi Onodera; Masaharu Nobuyoshi; Yasuhide Hayashi; Hiroshi Harada; Mineo Kurokawa; Shigeru Chiba; Hiraku Mori; Keiya Ozawa; Mitsuhiro Omine; Hisamaru Hirai; Hiromitsu Nakauchi; H. Phillip Koeffler; Seishi Ogawa;

  • 作者单位

    Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi-shi, Saitama 332-0012, Japan;

    Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan;

    Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, 199 Tung Hwa North Road, Taipei 105, Taiwan;

    Division of Stem Cell Therapy, Center for Stem Cell and Regenerative Medicine, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan;

    Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan;

    Exploratory Research for Advanced Technology, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi-shi, Saitama 332-0012, Japan;

    Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan;

    Department of Developmental Biology, Research Institute of Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan;

    Department of Clinical and Experimental Hematology, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tukuba-shi, Ibaraki, 305-8571, Japan;

    Cell Therapy and Transplantation Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan;

    Department of Pathology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan;

    Department of Hematology, Dokkyo University School of Medicine, 800 Kitabayashi, Mibu, Tochigi 321-0293, Japan;

    Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan Cell Therapy and Transplantation Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan;

    Division of Systems Biomedical Technology, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan;

    Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan Hemato!ogy and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan;

    Hematoiogy/Oncology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048, USA;

    Department of Genetics, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan;

    Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan;

    Gunma Children's Medical Center, 779 Shimohakoda, Hokkitsu-machi, Shibukawa-shi, Gunma 377-8577, Japan;

    Division of Hematology, Internal Medicine, Showa University Fujigaoka Hospital, 1-30 Fujigaoka, Aoba-ku, Yokohama, Kanagawa 227-8501, Japan;

    Cell Therapy and Transplantation Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan Hemato!ogy and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan;

    Department of Clinical and Experimental Hematology, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tukuba-shi, Ibaraki, 305-8571, Japan;

    Division of Hematology, Internal Medicine, Showa University Fujigaoka Hospital, 1-30 Fujigaoka, Aoba-ku, Yokohama, Kanagawa 227-8501, Japan;

    Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi 329-0498, Japan;

    Division of Hematology, Internal Medicine, Showa University Fujigaoka Hospital, 1-30 Fujigaoka, Aoba-ku, Yokohama, Kanagawa 227-8501, Japan;

    Cell Therapy and Transplantation Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan Hemato!ogy and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan;

    Exploratory Research for Advanced Technology, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi-shi, Saitama 332-0012, Japan Division of Stem Cell Therapy, Center for Stem Cell and Regenerative Medicine, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan;

    Hematoiogy/Oncology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048, USA;

    Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi-shi, Saitama 332-0012, Japan;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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