Identification of Chromosomal Aberrations in Hematologic

血液学中染色体畸变的鉴定

• 批准号: 7331447
• 负责人: Thomas E. Ried
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7331447
• 关键词: Identification; Chromosomal; Aberrations; Hematologic

Murine models of human carcinogenesis are widely used to delineate genetic mechanisms that determine tumor initiation and progression and improved methods for genetic manipulation open new avenues to study biological pathways of tumorigenesis. We have therefore devoted considerable effort to the development of molecular cytogenetic tools for the analyses of chromosomal aberrations in mouse models of human cancer. Karyotype analysis of chemically induced plasmacytomas in mice, and in lymphomas from ATM or Ku80 deficient animals. These analyses helped to define genetic pathways involved in the maintenance of chromosomal integrity and elucidated mechanisms that contribute to chromosomal translocations, e.g., break induced replication. As part of the intramural mouse models of mammary cancer consortium (MMMC), we have analyzed a plethora of mammary gland adenocarcinomas (MMTC-c-myc, MMTV-her2neu, her2neu-ednogeneous promoter, C3SV40Tag, PyV-mT). These analyses have provided evidence for the conservation of mechanisms leading to chromosomal aberrations and to the maintenance of cancer specific patterns of chromosomal aneuploidies across species boundaries. Our development of molecular cytogenetic methods for the analysis of murine genomes allows us to further contribute to the validation of mouse models of human cancers. The analysis of the PyV-mT mouse model also resulted in the molecular cloning of a septin 9 as a novel oncogene involved in human breast cancers and mouse models thereof.In addition to the use of genetically engineered mice as model systems of human cancer, we have also developed cell lines from several different epithelial organs from normal mice, including cervix, mammary gland, and colon. After having overcome senescence, these cells become immortalized, transformed, and eventually can form tumors in nude mice. The careful molecular characterization of these steps using chromosomal analysis by SKY, high-resolution mapping of genomic imbalances using arrayCGH, determination of transcriptional alterations by expression profiling, and cell biological tests for the integrity of centrosomes and telomeres now allow establishing a precise and comprehensive sequence of events. These analyses suggest that the process of spontaneous transformation of murine epithelial cells mimics in many aspects changes during human tumorigenesis. We have therefore developed valuable tools to not only study multiple aspects of the sequential changes during carcinogenesis, but to also functionally characterize novel signaling pathways. The modification of these pathways will eventually point to relevant targets for therapeutic intervention in human cancer.

人类癌变的小鼠模型被广泛用于描述决定肿瘤发生和发展的遗传机制，改进的遗传操作方法为研究肿瘤发生的生物学途径开辟了新的途径。因此，我们投入了相当大的努力来开发分子细胞遗传学工具，用于分析人类癌症小鼠模型中的染色体畸变。化学诱导小鼠浆细胞瘤及ATM或Ku80缺陷动物淋巴瘤的核型分析。这些分析有助于确定参与维持染色体完整性的遗传途径，并阐明导致染色体易位的机制，例如断裂诱导复制。作为乳腺癌联盟（MMMC）小鼠体内模型的一部分，我们分析了过多的乳腺腺癌（MMTC-c-myc, MMTV-her2neu， her2neu- edno异构启动子，C3SV40Tag, PyV-mT）。这些分析为导致染色体畸变和维持跨物种染色体非整倍体的癌症特定模式的机制的保护提供了证据。我们开发的用于小鼠基因组分析的分子细胞遗传学方法使我们能够进一步为人类癌症小鼠模型的验证做出贡献。PyV-mT小鼠模型的分析还导致了septin 9作为一种新的致癌基因参与人类乳腺癌及其小鼠模型的分子克隆。除了使用基因工程小鼠作为人类癌症的模型系统外，我们还从正常小鼠的几种不同上皮器官中开发了细胞系，包括子宫颈，乳腺和结肠。在克服衰老后，这些细胞变得不朽，转化，最终可以在裸鼠体内形成肿瘤。使用SKY染色体分析对这些步骤进行细致的分子表征，使用arrayCGH对基因组失衡进行高分辨率定位，通过表达谱测定转录改变，以及对中心体和端粒完整性进行细胞生物学测试，现在可以建立一个精确而全面的事件序列。这些分析表明，小鼠上皮细胞的自发转化过程在许多方面模仿了人类肿瘤发生过程中的变化。因此，我们开发了有价值的工具，不仅可以研究癌变过程中顺序变化的多个方面，还可以从功能上表征新的信号通路。这些途径的修改将最终指向人类癌症治疗干预的相关靶点。

项目成果

The Septin 9 (MSF) gene is amplified and overexpressed in mouse mammary gland adenocarcinomas and human breast cancer cell lines.

• 发表时间: 2003-05
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: C. Montagna;M. Lyu;K. Hunter;L. Lukes;W. Lowther;Tricia Reppert;B. Hissong;Z. Weaver;T. Ried

Molecular and cytological features of the mouse B-cell lymphoma line iMycEmu-1.

• DOI: 10.1186/1476-4598-4-40
• 发表时间: 2005-11-09
• 期刊: Molecular cancer
• 影响因子: 37.3
• 作者: Han SS;Shaffer AL;Peng L;Chung ST;Lim JH;Maeng S;Kim JS;McNeil N;Ried T;Staudt LM;Janz S
• 通讯作者: Janz S