ORGANIZATION AND CONTROL OF GENETIC MATERIAL IN PLASMACYTOMAS

浆细胞瘤中遗传物质的组织和控制

• 批准号: 3813388
• 负责人: J F MUSHINSKI
• 金额: --
• 依托单位: DIVISION OF CANCER BIOLOGY AND DIAGNOSIS
• 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/3813388
• 关键词: B lymphocyte; Retroviridae; Retroviridae disease; T cell receptor; T lymphocyte; autoimmune disorder; cell differentiation; chemical carcinogenesis; chromosome translocation; complementary DNA; gene expression; genetic manipulation; genetic transcription; immunoglobulin genes; lymphocyte; lymphocytic leukemia; molecular cloning; molecular oncology; multiple myeloma; neoplasm /cancer genetics; neoplasm /cancer immunology; oncogenes; oncoproteins; petroleum oil; plasma cell neoplasm; protein kinase; protein kinase C; protooncogene; provirus; transposon /insertion element; viral carcinogenesis

The overall goal of this research is to study the activation of particular genes in diseased and normal cells in order to understand which genes may play important roles in the development of malignancies, autoimmune diseases and normal differentiation. We have concentrated on the expression of "oncogenes," especially abl, bcl-2, myc, myb, Pvt-1, raf, ras and rel, as well as immunoglobulin and T-cell receptor genes in tumors that represent immortalized lines of lymphocytes or myeloid cells at different stages of differentiation. The deregulated expression of the myc oncogene has been clearly shown to be essential to the induction of plasma cell tumors, but how "variant" plasmacytomas with rcpt(6;15) translocations involving the Pvt-1 gene, which is 200-300 kb 3' of c-myc, also deregulate c-myc expression remains unknown. We have cloned several cDNAs for mouse Pvt-1, which has, for the first time, permitted the identification of mRNA from this gene in normal mouse tissues and tumors. "Variant" plasmacytomas have elevated levels of Pvt-1 transcripts which are also truncated due to the chromosomal translocation. The v-abl oncogene has been found to cooperate with over-expressed c-myc in a retrovirus (ABL-MYC) which induces plasmacytomas more rapidly than previously reported and, for the first time, in 100% of adult mice, even in the absence of pristane priming. The rapidity of this induction has permitted the production of antigen-targeted myeloma proteins by ABL-MYC induction of plasmacytomas in immunized mice. An important family of protein kinases, Protein Kinase C (PKC), is being studied for its possible role in tumorigenesis. We have shown that the members of this gene family are differentially expressed in tumors of hemopoietic cell and that there is at least one undescribed form of PKC expressed in myeloid tumors. Alternatively spliced transcripts of the myb proto-oncogene have been observed in normal and tumor cells in man as well as mouse. An important difference between the species is that the alternate forms of human c-myb result in truncated protein isoforms instead of the elongated ones expected in mice.

本研究的总体目标是研究特定的激活 患病细胞和正常细胞中的基因，以了解哪些基因可能 在恶性肿瘤、自身免疫性疾病的发生发展中起重要作用 疾病和正常分化。我们把注意力集中在表达上 “癌基因”，特别是 abl、bcl-2、myc、myb、Pvt-1、raf、ras 和 rel， 以及肿瘤中的免疫球蛋白和 T 细胞受体基因 代表不同时点的淋巴细胞或骨髓细胞的永生系 分化阶段。 myc癌基因的表达失调 已被清楚地证明对于浆细胞的诱导至关重要 肿瘤，但具有 rcpt(6;15) 易位的“变异”浆细胞瘤是如何发生的 涉及 Pvt-1 基因，即 c-myc 的 200-300 kb 3'，也解除管制 c-myc 表达仍然未知。我们已经克隆了几种小鼠的 cDNA Pvt-1，首次允许鉴定 mRNA 来自正常小鼠组织和肿瘤中的该基因。 “变异”浆细胞瘤 Pvt-1 转录本的水平升高，并且由于以下原因也被截断 染色体易位。 已发现 v-abl 癌基因与过度表达的 c-myc 协同作用 一种逆转录病毒（ABL-MYC），其诱导浆细胞瘤的速度比 之前报道过，并且首次在 100% 的成年小鼠中，甚至在 缺乏降植烷底漆。这种感应的速度 允许通过 ABL-MYC 生产抗原靶向骨髓瘤蛋白 在免疫小鼠中诱导浆细胞瘤。一个重要的家庭 蛋白激酶，蛋白激酶 C (PKC)，正在研究其可能的作用 在肿瘤发生中的作用。我们已经证明这个基因家族的成员 在造血细胞肿瘤中存在差异表达，并且存在 是在骨髓肿瘤中表达的至少一种未描述的 PKC 形式。 myb 原癌基因的选择性剪接转录本已被 在人和小鼠的正常细胞和肿瘤细胞中观察到。一个重要的 物种之间的区别在于人类 c-myb 的替代形式 导致截短的蛋白质亚型而不是预期的延长的蛋白质亚型 在小鼠中。