B and T lineage cells fulfill extremely important roles in antigen specific immunity and have served as tools in the development of novel therapeutics such as monoclonal antibodies and cancer killing LAK and TIL cells. Also, neoplastic transformation of these cells results in a large proportion of human leukemias and lymphomas. We have been studying molecular mechanisms governing lymphoid cell differentiation and neoplasia using several approaches. (1) We have been studying the process of neoplastic transformation in a mouse model system that mimics human preB and preT ALL (acute lymphocytic leukemia). These transgenic mice overexpress the myc oncogene under transcriptional regulation of several lymphoid lineage specific enhancers. Tumorigenesis can be targeted to the B or T cell lineage using enhancers specific for immunoglobulin genes or the T cell receptor genes. We use tumors representing different stages of differentiation to further understand the process of lymphoid cell development and to compare and contrast the oncogenic events leading to tumors in different cell lineages. We study the role of oncogenes in lymphoid cell transformation using an RT-PCR assay capable of quantifying expression of 20 candidate oncogenes. We have found that p53 gene mRNA is mutated or not expressed in 30% of the B lineage tumors and that lack of p53 expression sometimes correlates with DNA rearrangements of the p53 gene. (2)We have used Ebeta-myc mice to determine the influence of the myc gene on T cell development in the thymus by examining effects on positive selection, negative selection, and co-receptor determination. Myc gene overexpression seems to leave negative selection intact, to disrupt positive selection, and to favor differentiation into the CD4 lineage. (3)We have used tumors and normal cells to examine regulation of immunoglobulin heavy chain genes in mouse B preB cells. B cell tumors expressing the surrogate immunoglobulin complex (consisting of heavy chain plus surrogate light chains lambda-5 and VpreB) had down-regulated RAG gene expression nullifying their ability to catalyze V(D)J recombination. These cells may represent an important stage in which preB cells undergo allelic exclusion at the immunoglobulin heavy chain locus. We are now testing this idea using normal mouse preB cells in attempts to demonstrate that these surrogate light chains can signal down-regulation of the RAG genes. These cells express the surrogate light chains and RAG genes but have not yet completely rearranged the immunoglobulin heavy chain gene. Transfectants expressing the immunoglobulin heavy chain transiently down-regulate RAG gene expression.
