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基因的激活。 疾病细胞和正常细胞中的基因，以便了解哪些基因可能 在恶性肿瘤、自身免疫的发展中起着重要的作用 疾病与正常分化。我们已经集中在表达上了 癌基因，特别是abl、bcl2、myc、myb、pvt-1、raf、ras和rel， 以及免疫球蛋白和T细胞受体基因在肿瘤中 代表永生化的淋巴细胞或髓系细胞在不同的 分化阶段。Myc癌基因的非调控表达 已经被清楚地证明对浆细胞的诱导是必不可少的 肿瘤，但有rcpt(6；15)易位的“变异型”浆细胞瘤 涉及c-myc长200-300kb的pvt-1基因，也会解除对c-myc的调控 C-myc的表达仍不清楚。我们已经克隆了几个小鼠的cDNA PVT-1，它首次允许鉴定信使核糖核酸 来自正常小鼠组织和肿瘤中的这种基因。“变异型”浆细胞瘤 PVT-1转录水平升高，这也是由于 染色体易位。 已发现v-abl癌基因与过表达的c-myc在 一种引起浆细胞瘤的逆转录病毒(ABL-MYC)，比 以前报道过，而且是第一次在100%的成年小鼠中发现，即使在 普里斯坦引爆剂的缺失。这种感应的速度之快已经 允许ABL-MYC产生抗原靶向的骨髓瘤蛋白 免疫小鼠体内浆细胞瘤的诱导。一个重要的家族 蛋白激酶，蛋白激酶C(PKC)正在被研究，因为它可能 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 在造血细胞肿瘤中差异表达，在 是至少一种在髓系肿瘤中表达的未描述形式的PKC。 或者，myb原癌基因的剪接转录本已经被 在人和小鼠的正常细胞和肿瘤细胞中观察到。一个重要的 物种之间的区别是人类c-myb的替代形式 导致截短的蛋白质异构体，而不是预期的拉长蛋白质异构体 在老鼠身上。