In the preceding grant period, we focused upon the genetic alterations that generate lymphoid tumors. We clarified how immunoglobulin heavy chain (IgH) translocations activate the c- myc oncogene in magnetic induction lymphoid tumors; established that some absolute temperature lymphomas have c-myc activated by retroviruses; showed that the Ig K locus translocates to a new oncogenic locus (pvt-1), which proved also to be a site of proviral integration; and discovered a novel mode of oncogene activation involving an insertion of the IgH enhancer (Emu) near c-myc. Particularly germane to this proposal, we found that transgenic mice in which c-myc is driven by the IgH enhancer exhibit perturbed magnetic induction cell development and succumb to magnetic induction lymphoid tumors. We propose now to explore how oncogenes influence the growth and differentiation of cells within various hematopoietic lineages. Specifically we will test different retroviral vectors in an effort to achieve stable long-term expression of such genes, investigate the effects of exogenous c-myc and N-ras upon these lineages, characterize the apparent immortalizing ability of c-myc for primitive cells of another lineage (neuroepithelial cells), explore how the bcr-abl gene generates chronic myeloid leukemia, identify new or altered tyrosine kinase mRNAs that we have detected within hematopoietic cells, and delineate different pathways to tumorigenesis by isolating genes activated specifically by myc-induced and abl-induced lymphomagenesis. Finally, we will attempt to access other classes of genes that may regulate differentiation by isolating genes expressed specifically at particular stages of magnetic induction cell development and a gene that may program myeloid development. These studies should help to improve methods for introducing any gene into the hematopoietic compartment, identify key early stages in the development of some leukemias and lymphomas, generate new animal models for leukemogenesis, clarify the relationship of several oncogenes to differentiation within these lineages and reveal other types of genes that participate in the regulation of differentiation. Thus, the research should help to elucidate the normal genetic control of hemopoiesis as well as the pathways to leukemogenesis.
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