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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >PRDM1 is a tumor suppressor gene in natural killer cell malignancies
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PRDM1 is a tumor suppressor gene in natural killer cell malignancies

机译：PRDM1是天然杀伤细胞恶性肿瘤的抑癌基因

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摘要

Natural killer cell lymphoma (NKCL) constitutes a rare and aggressive form of non-Hodgkin lymphoma, and there is little insight into its pathogenesis. Here we show that PRDM1 is a tumor suppressor gene in NKCLs that is inactivated by a combination of monoallelic deletion and promoter CpG island hypermethylation. We observed monoallelic deletion of PRDM1 loci in 8 of 18 (44%) NKCL cases. The other allele showed significant promoter methyl-ation in 12 of 17 (71%) cases. In support of its role as a tumor suppressor gene, the reconstitution of PRDM1 in PRDM1-null NK cell lines led to G2/M cell cycle arrest, increased apoptosis, and a strong negative selection pressure with progressive elimination of PRDM1-expressing cells, which was enhanced when IL-2 concentration is limiting. We observed a progressive increase in PRDM1 expression-in particular, PRDMIa-in normal NK cells in response to IL-2 and in normal NK cells activated with an engineered NK cell target, K562-CI9-mb21, suggesting its role in NK cell homeostasis. In support of this role, knockdown of PRDM1 by shRNA in normal NK cells resulted in the positive selection of these cells. We identified MYC and 4-1BBL as targets of PRDM1 in NK cells. Disruption of homeostatic control by PRDM1 may be an important pathoge-netic mechanism for NKCL.
机译：天然杀伤细胞淋巴瘤（NKCL）构成非霍奇金淋巴瘤的罕见且侵袭性形式，对其发病机理知之甚少。在这里，我们显示PRDM1是NKCL中的一种抑癌基因，该基因通过单等位基因缺失和启动子CpG岛超甲基化的结合而失活。我们观察到18个（44％）NKCL病例中的8个中PRDM1基因座的单等位基因缺失。其他等位基因在17例中的12例（71％）中显示出明显的启动子甲基化。为了支持其作为抑癌基因的作用，PRDM1空NK细胞系中PRDM1的重组导致G2 / M细胞周期停滞，细胞凋亡增加以及强烈的负选择压力，并逐渐消除了表达PRDM1的细胞。当IL-2浓度受到限制时，蛋白被增强。我们观察到正常NK细胞对IL-2的反应以及被工程NK细胞靶K562-CI9-mb21激活的正常NK细胞中PRDM1表达，尤其是PRDMIa的表达逐渐增加，表明其在NK细胞稳态中的作用。为了支持该作用，shRNA在正常NK细胞中敲低PRDM1导致这些细胞的阳性选择。我们确定MYC和4-1BBL作为NK细胞PRDM1的目标。 PRDM1破坏稳态控制可能是NKCL的重要发病机制。

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  • 作者

    Can Kuecuek; Javeed lqbal; Xiaozhou Hu; Phillip Gaulard; Laurence De Leval; Gopesh Srivastava; Wing Yan Au; Timothy W. McKeithan; Wing C. Chan;

  • 作者单位

    Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198;

    Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198;

    Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198;

    Departement de Pathologie, Groupe Henri-Mondor Albert-Chenevier, Institut National de la Sante et de la Recherche Medicale U955, University Paris Est, Creteil 94000, France;

    Institute of Patholoy, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland;

    Departments of Pathology and Medicine, University of Hong Kong, Queen Mary Hospital,Hong Kong, China;

    Departments of Pathology and Medicine, University of Hong Kong, Queen Mary Hospital,Hong Kong, China;

    Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198;

    Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    NK-cell activation and homeostasis; neoplastic transformation; biotage pyrosequencing; CCA/67; CCNG2;

    机译：NK细胞活化和体内平衡;肿瘤转化;生物年龄焦磷酸测序;CCA / 67;CCNG2;

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