RNA TUMOR VIRUS-HEMATOPOIETIC CELL INTERACTION

在Abelson病毒（Ab-MLV）中发现的v-abl癌基因的表达， BCR/ABL癌基因，由易位产生， Philadelphia染色体，与多种血液学 这些疾病中的每一种都涉及不同的 并且在某些情况下，靶细胞定义不明确。 此外，小 已知癌基因的表达影响正常的 这些细胞的分化过程。 在某些情况下， 在其他疾病中，如慢性髓细胞性白血病， 白血病（CML），造血干细胞受到复杂的影响， 但分化持续很长一段时间。 理解 分化程序受Ab-MLV影响的方式， BCR/ABL将提供控制机制的见解 转型 我们将通过确定因素来处理这个问题 控制Ab-MLV与不同类型的淋巴细胞相互作用 前体，并确定转型如何影响其 分化 在其他实验中，我们利用我们最近的 开发了小鼠CML模型，以确定不同的 abl癌基因的表达形式对肿瘤细胞分化和转化的影响 造血干细胞 通过Ab-MLV或BCR/ABL的转化是一个多步骤过程， 需要abl癌基因的存在和未知的 细胞基因 尽管这种由Abl介导的肿瘤发生的特征 几乎所有的肿瘤系统都有， 这些细胞基因。 在我们工作的第二个方面， 研究两个似乎参与AbMLV介导的 肿瘤进展。 首先，我们将根据最近的结果， 许多淋巴转化体表达突变形式的p53， 蛋白质在体外建立后不久。 动力学与 这些突变在文化中占主导地位， 将监测突变对生长和致瘤性的影响。 第二，我们将研究10号染色体缺失， 在许多Abelson病毒转化的淋巴样细胞中发现。 映射删除和定义最小端点的实验将 补充关于删除影响的生物学研究 对生长和肿瘤的影响。

Expression of the v-abl oncogene found in Abelson virus (Ab-MLV) and the BCR/ABL oncogenes, generated by the translocation that creates the Philadelphia chromosome, are associated with a variety of hematologic neoplasms in mice and man. Each of these diseases involves different and, in some cases, poorly defined target cells. In addition, little is known about the way expression of the oncogenes affects the normal differentiation program of these cells. In some cases differentiation appears to be arrested while in others, such as chronic myelogenous leukemia (CML), hematopoietic stem cells are affected in complex ways but differentiation continues for long periods of time. Understanding the way in which differentiation programs are affected by Ab-MLV and BCR/ABL will provide insights into the mechanisms controlling transformation. We will approach this issue by identifying the factors that control the interaction of Ab-MLV with different types of lymphoid precursors and determine how transformation affects their differentiation. In other experiments, we exploit our recently developed murine CML model to determine the effect of the different forms of abl oncogenes on differentiation and transformation of hematopoietic stem cells. Transformation by Ab-MLV or BCR/ABL is a multi-step process that requires the presence of the abl oncogene and changes in unknown cellular genes. Although this feature of the abl-mediated oncogenesis is shared with virtually all tumor systems, very little is known about these cellular genes. In a second aspect of our work we will investigate two sequences that appear to be involved in AbMLV-mediated tumor progression. First, we will build on our recent results showing that many lymphoid transformants express mutant forms of the p53 protein soon after they are established in vitro. The kinetics with which these mutations become dominant in the cultures and the effect of the mutations on growth and tumorigenicity will be monitored. Second, we will study the chromosome 10 deletion that we have identified in many Abelson virus-transformed lymphoid cells. Experiments to map the deletion and define the minimal endpoints will complement the biological studies concerning the effect of the deletion on growth and tumorigenesis.