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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Epigenetic changes during disease progression in a murine model of human chronic lymphocytic leukemia
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Epigenetic changes during disease progression in a murine model of human chronic lymphocytic leukemia

机译：人类慢性淋巴细胞性白血病小鼠模型在疾病进展过程中的表观遗传变化

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摘要

Epigenetic alterations, including gain or loss of DNA methylation, are a hallmark of nearly every malignancy. Changes in DNA methylation can impact expression of cancer-related genes including apoptosis regulators and tumor suppressors. Because such epigenetic changes are reversible, they are being aggressively investigated as potential therapeutic targets. Here we use the Eμ-TCL1 transgenic mouse model of chronic lymphocytic leukemia (CLL) to determine the timing and patterns of aberrant DNA methylation, and to investigate the mechanisms that lead to aberrant DNA methylation. We show that CLL cells from E^-TCL1 mice at various stages recapitulate epigenetic alterations seen in human CLL. Aberrant methylation of promoter sequences is observed as early as 3 months of age in these animals, well before disease onset. Abnormally methylated promoter regions include binding sites for the transcription factor FOXD3. We show that loss of Foxd3 expression due to an NF-κB p50/p50:HDAC1 repressor complex occurs in TCL1-positive B cells before methylation. Therefore, specific transcriptional repression is an early event leading to epigenetic silencing of target genes in murine and human CLL. These results provide strong rationale for the development of strategies to target NF-kB components in CLL and potentially other B-cell malignancies.
机译：表观遗传学改变，包括DNA甲基化的获得或丧失，是几乎所有恶性肿瘤的标志。 DNA甲基化的变化会影响与癌症相关的基因的表达，包括细胞凋亡调节因子和肿瘤抑制因子。由于这种表观遗传变化是可逆的，因此正在积极地研究它们作为潜在的治疗靶标。在这里，我们使用慢性淋巴细胞性白血病（CLL）的Eμ-TCL1转基因小鼠模型来确定异常DNA甲基化的时间和模式，并研究导致异常DNA甲基化的机制。我们显示，来自E1-TCL1小鼠在不同阶段的CLL细胞概括了在人类CLL中所见的表观遗传学改变。在这些动物中，早在疾病发作之前的3个月大就观察到启动子序列的异常甲基化。异常甲基化的启动子区域包括转录因子FOXD3的结合位点。我们显示由于NF-κBp50 / p50：HDAC1阻遏物复合物而导致的Foxd3表达的丧失在甲基化之前发生在TCL1阳性B细胞中。因此，特异性转录抑制是导致鼠和人CLL中靶基因表观遗传沉默的早期事件。这些结果为针对CLL和潜在的其他B细胞恶性肿瘤中的NF-kB成分开发策略提供了有力的依据。

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  • 作者

    Shih-Shih Chen; Aparna Raval; Amy J. Johnsons; Erin Hertlein; Te-Hui Liu; Victor X. Jin; Mara H. Sherman; Shu-Jun Liu; David W. Dawson; Katie E. Williams; Mark Lanasa; Sandya Liyanarachchi; Thomas S. Lin; Guido Marcucci; Yuri Pekarsky; Ramana Davuluri; Carlo M. Croce; Denis C. Guttridge; Michael A. Teitell; John C. Byrd; Christoph Plass;

  • 作者单位

    Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, the Comprehensive Cancer Center, Department of Medicine, Ohio State University, Columbus, OH 43210 Department of Molecular Genetics, Department of Medicine, Ohio State University, Columbus, OH 43210 Division of Hematology-Oncology, Department of Medicine, Ohio State University, Columbus, OH 43210;

    Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, the Comprehensive Cancer Center, Department of Medicine, Ohio State University, Columbus, OH 43210 Department of Oncology, CCSR 2250, Stanford University, Stanford, CA 94305;

    Division of Hematology-Oncology, Department of Medicine, Ohio State University, Columbus, OH 43210;

    Division of Hematology-Oncology, Department of Medicine, Ohio State University, Columbus, OH 43210;

    Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, the Comprehensive Cancer Center, Department of Medicine, Ohio State University, Columbus, OH 43210 Department of Infectious Disease, The Children's Hospital of Philadelphia, Philadelphia, PA 19104;

    Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, the Comprehensive Cancer Center, Department of Medicine, Ohio State University, Columbus, OH 43210;

    Molecular Biology Institute, Department of Pathology and Laboratory Medicine, Broad Stem Cell Research Center, and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095;

    Division of Hematology-Oncology, Department of Medicine, Ohio State University, Columbus, OH 43210;

    Department of Infectious Disease, The Children's Hospital of Philadelphia, Philadelphia, PA 19104;

    Department of Molecular Genetics, Department of Medicine, Ohio State University, Columbus, OH 43210;

    Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, NC 27710;

    Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, the Comprehensive Cancer Center, Department of Medicine, Ohio State University, Columbus, OH 43210;

    Department of Molecular Genetics, Department of Medicine, Ohio State University, Columbus, OH 43210;

    Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, the Comprehensive Cancer Center, Department of Medicine, Ohio State University, Columbus, OH 43210 Department of Molecular Genetics, Department of Medicine, Ohio State University, Columbus, OH 43210;

    Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, the Comprehensive Cancer Center, Department of Medicine, Ohio State University, Columbus, OH 43210;

    Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, the Comprehensive Cancer Center, Department of Medicine, Ohio State University, Columbus, OH 43210;

    Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, the Comprehensive Cancer Center, Department of Medicine, Ohio State University, Columbus, OH 43210;

    Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, the Comprehensive Cancer Center, Department of Medicine, Ohio State University, Columbus, OH 43210;

    Molecular Biology Institute, Department of Pathology and Laboratory Medicine, Broad Stem Cell Research Center, and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095;

    Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, the Comprehensive Cancer Center, Department of Medicine, Ohio State University, Columbus, OH 43210 Division of Hematology-Oncology, Department of Medicine, Ohio State University, Columbus, OH 43210;

    Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, the Comprehensive Cancer Center, Department of Medicine, Ohio State University, Columbus, OH 43210 Division of Epigenomics and Cancer Risk, German Cancer Research Center, 69120 Heidelberg, Germany;

  • 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
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  • 关键词

    CLL; DNA methylation; epigenetics; FOXD3;

    机译：CLL;DNA甲基化;表观遗传学FOXD3;

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