The longterm objective of the research plan is to define neoplastic progression on a molecular level. An in vitro culture system where vmyc and vHaras act in synergy to elicit neoplastic transformation of murine B lymphoid cells will be used as a model system. The four specific aims are to determine: 1) if the fully transformed state observed in cells expressing both vHaras and vmyc is the result of an ordered sequence in their expression or an additive effect irrespective of temporal context. 2) the structure/function relationship of the myc oncogene to the cooperative transformation of B lymphoid cells. 3) if cells at particular stages of lymphopoiesis or comprising defined B cell subpopulations are preferred targets for neoplastic transformation. 4) if other oncogene activations are involved with either in vitro transformation or tumor progression. Retroviral vectors will be employed to introduce and express vHaras or various myc alleles into fresh bone marrow or cultured B lymphoid cells. Experimentally manipulated cells will be analyzed by a variety of nucleic acid hybridzation, serological and cell culture techniques as well as in vivo tumorigenicity. It is hoped that parallels can be drawn to human leukemogenesis.
