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.

这项研究的总体目标是研究特定的激活 患病和正常细胞中的基因，以了解哪些基因可能 在恶性肿瘤的发展中发挥重要作用 疾病和正常分化。我们集中在表达式上 的“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 表示在不同的淋巴细胞或髓样细胞的永生线条 差异阶段。 MYC癌基因的放松调节表达 已经清楚地证明对诱导浆细胞至关重要 肿瘤，但是如何使用RCPT（6; 15）易位的“变体”浆细胞瘤 涉及PVT-1基因，即200-300 kb 3'c-myc，也放松管制 C-MYC表达仍然未知。我们已经克隆了几个cDNA的鼠标 PVT-1首次允许鉴定mRNA 来自正常小鼠组织和肿瘤中的基因。 “变体”浆细胞瘤 具有升高的PVT-1转录本水平，由于 染色体易位。 已经发现V-ABL癌基因与过表达的C-Myc合作 逆转录病毒（ABL-MYC），该逆转录病毒比诱导浆细胞瘤更快 先前报告的，也是第一次，在100％的成年小鼠中，即使 缺乏Pristane启动。这种诱导的速度具有 允许通过ABL-MYC生产抗原靶向抗原的骨髓瘤蛋白 免疫小鼠中浆细胞瘤的诱导。一个重要的家庭 正在研究蛋白激酶，蛋白激酶C（PKC）的可能性 在肿瘤发生中的作用。我们已经证明了这个基因家族的成员 在血压细胞的肿瘤中差异表达，那里 至少是一种在髓样肿瘤中表达的未描述的PKC形式。 或者，MYB原型癌基因的剪接成绩单已 在人类和小鼠的正常和肿瘤细胞中观察到。一个重要的 该物种之间的区别是人类C-Myb的替代形式 导致截短的蛋白质同工型，而不是预期的细长蛋白质。 在老鼠中。