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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Gene Deregulation And Spatial Genome Reorganization Near Breakpoints Prior To Formation Of Translocations In Anaplastic Large Cell Lymphoma
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Gene Deregulation And Spatial Genome Reorganization Near Breakpoints Prior To Formation Of Translocations In Anaplastic Large Cell Lymphoma

机译：间变性大细胞淋巴瘤易位前的基因失调和空间基因组重组接近断点。

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摘要

Although the identification and characterization of translocations have rapidly increased, little is known about the mechanisms of how translocations occur in vivo. We used anaplastic large cell lymphoma (ALCL) with and without the characteristic t(2;5)(p23;q35) transloca-tion to study the mechanisms of formation of translocations and of ALCL transformation. We report deregulation of several genes located near the ALCL translocation breakpoint, regardless of whether the tumor contains the t(2;5). The affected genes include the onco-genic transcription factor Fra2 (located on 2p23), the HLH protein Id2 (2p25), and the oncogenic tyrosine kinase CSF1-receptor (5q33.1). Their up-regulation promotes cell survival and repression of T cell-specific gene expression programs that are characteristic for ALCL. The deregulated genes are in spatial proximity within the nuclear space of t(2;5)-negative ALCL cells, facilitating their translocation on induction of double-strand breaks. These data suggest that deregulation of breakpoint-proximal genes occurs before the formation of translocations, and that aberrant transcriptional activity of genomic regions is linked to their propensity to undergo chromosomal translocations. Also, our data demonstrate that deregulation of breakpoint-proximal genes has a key role in ALCL.rncancer genetics; signal transduction; nuclear architecture; lymphomatoid papulosis
机译：尽管易位的鉴定和表征已迅速增加，但是关于在体内如何发生易位的机制知之甚少。我们使用具有和不具有特征性t（2; 5）（p23; q35）易位的间变性大细胞淋巴瘤（ALCL）来研究易位形成和ALCL转化的机制。我们报告解除调节位于ALCL易位转折点附近的几个基因，无论肿瘤是否包含t（2; 5）。受影响的基因包括致癌转录因子Fra2（位于2p23），HLH蛋白Id2（2p25）和致癌酪氨酸激酶CSF1受体（5q33.1）。它们的上调促进了细胞存活和对ALCL特有的T细胞特异性基因表达程序的抑制。失调的基因在t（2; 5）阴性ALCL细胞的核空间内空间接近，从而在诱导双链断裂时促进其易位。这些数据表明，断点附近基因的失调发生在易位形成之前，并且基因组区域的异常转录活性与其发生染色体易位的倾向有关。同样，我们的数据表明，断点附近基因的失控在ALCL中具有关键作用。信号转导;核建筑淋巴瘤样丘疹

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    Stephan Mathas; Stephan Kreher; Karen J. Meaburn; Korinna Joehrens; Bjoern Lamprecht; Chalid Assaf; Wolfram Sterry; Marshall E. Kadin; Masanori Daibata; Stefan Joos; Michael Hummel; Harald Stein; Martin Janz; Ioannis Anaqnostopoulos; Evelin Schrock; Tom Misteli; Bemd Doerken;

  • 作者单位

    Max-Delbrueck-Center for Molecular Medicine, Robert-Rossle-Strasse 10, 13125 Berlin, Germany Hematology, Oncology, and Tumorimmunology, Charite, Medical University Berlin, Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany;

    Max-Delbrueck-Center for Molecular Medicine, Robert-Rossle-Strasse 10, 13125 Berlin, Germany Hematology, Oncology, and Tumorimmunology, Charite, Medical University Berlin, Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany;

    Cell Biology of Genomes, National Cancer Institute, National Institutes of Health, 41 Library Drive, Bethesda, MD 20892;

    Institute of Pathology, Charite, Medical University Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany;

    Max-Delbrueck-Center for Molecular Medicine, Robert-Rossle-Strasse 10, 13125 Berlin, Germany Hematology, Oncology, and Tumorimmunology, Charite, Medical University Berlin, Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany;

    Department of Dermatology, Allergy, and Venerology, Skin Cancer Center Charite, Medical University Berlin, Chariteplatz 1, 10117 Berlin, Germany;

    Department of Dermatology, Allergy, and Venerology, Skin Cancer Center Charite, Medical University Berlin, Chariteplatz 1, 10117 Berlin, Germany;

    Department of Pathology, Harvard Medical School, Boston, MA 02115 Department of Dermatology, Boston University, and Roger Williams Medical Center, 50 Maude Street, Providence, RI 02908;

    Department of Hematology, Kochi Medical School, Kohasu, Okoh-cho, Nankuko-city, Kochi 783-8505, Japan;

    German Cancer Research Center, B060, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany;

    Institute of Pathology, Charite, Medical University Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany;

    Institute of Pathology, Charite, Medical University Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany;

    Max-Delbrueck-Center for Molecular Medicine, Robert-Rossle-Strasse 10, 13125 Berlin, Germany Hematology, Oncology, and Tumorimmunology, Charite, Medical University Berlin, Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany;

    Institute of Pathology, Charite, Medical University Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany;

    Institute for Clinical Genetics, Dresden University of Technology, Fetscherstrasse 74, 01307 Dresden, Germany;

    Cell Biology of Genomes, National Cancer Institute, National Institutes of Health, 41 Library Drive, Bethesda, MD 20892;

    Max-Delbrueck-Center for Molecular Medicine, Robert-Rossle-Strasse 10, 13125 Berlin, Germany Hematology, Oncology, and Tumorimmunology, Charite, Medical University Berlin, Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany;

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