RNA TUMOR VIRUS-HEMATOPOIETIC CELL INTERACTION

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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.