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用于鉴定参与小鼠脾边缘区淋巴瘤起始和进展的基因的高通量逆转录病毒标签法

High-throughput retroviral tagging for identification of genes involved in initiation and progression of mouse splenic marginal zone lymphomas.

作者信息

Shin Min Sun, Fredrickson Torgny N, Hartley Janet W, Suzuki Takeshi, Akagi Keiko, Morse Herbert C

机构信息

Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, Rockville, Maryland 20852, USA.

出版信息

Cancer Res. 2004 Jul 1;64(13):4419-27. doi: 10.1158/0008-5472.CAN-03-3885.

Abstract

Human B-cell lymphomas are frequently associated with specific genetic changes caused by chromosomal translocations that activate proto-oncogenes. For lymphomas of mice expressing murine leukemia virus, mutagenic proviral insertions are thought to play a similar role. Here we report studies designed to determine whether specific retroviral integration sites might be associated with a specific subset of mouse B-cell lymphomas and if the genes associated with these sites are regularly altered in expression. We studied splenic marginal zone lymphomas (MZL) of NFS.V(+) mice that are unusual in exhibiting frequent progression from low to high grade, potentially allowing assignment of cancer genes to processes of initiation and progression. We used inverse PCR to clone and analyze 212 retroviral integration sites from 43 MZL at different stages of progression. Sixty-two marked common integration sites and included 31 that had been marked previously. Among the new common integration sites, seven were unique to MZL. Using microarrays and real-time quantitative PCR analysis, we defined differential patterns of gene expression in association with disease progression for Gfi1, Sox4, Brca2, Snf1lk, Nfkb1, Pou2af1, Prdm1, Stat6, and Blnk. Heightened expression of Gfi1 distinguishes MZL from other lymphoma types. The combined use of proviral tagging and analyses of gene expression thus provides a powerful approach to understanding of genes that collaborate in tumorigenesis.

摘要

人类B细胞淋巴瘤常常与由染色体易位导致的特定基因变化相关,这些变化激活了原癌基因。对于表达鼠白血病病毒的小鼠淋巴瘤,诱变的前病毒插入被认为起着类似的作用。在此,我们报告了旨在确定特定逆转录病毒整合位点是否可能与小鼠B细胞淋巴瘤的特定亚群相关,以及与这些位点相关的基因在表达上是否经常发生改变的研究。我们研究了NFS.V(+)小鼠的脾边缘区淋巴瘤(MZL),这种淋巴瘤不同寻常之处在于它经常从低级别进展到高级别,这可能使我们能够将癌症基因与起始和进展过程联系起来。我们使用反向PCR从43个处于不同进展阶段的MZL中克隆并分析了212个逆转录病毒整合位点。62个标记的常见整合位点,其中包括31个先前已标记的位点。在新的常见整合位点中,有7个是MZL特有的。使用微阵列和实时定量PCR分析,我们确定了与Gfi1、Sox4、Brca2、Snf1lk、Nfkb1、Pou2af1、Prdm1、Stat6和Blnk疾病进展相关的基因表达差异模式。Gfi1表达的升高将MZL与其他淋巴瘤类型区分开来。因此,前病毒标签和基因表达分析的联合使用为理解在肿瘤发生中协同作用的基因提供了一种强大的方法。

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