The c-myc proto-oncogene, whose expression is linked to cell growth and differentiation, is expressed aberrantly in many neoplastic states, including lymphomas, leukemias and small cell lung carcinomas. Molecular analyses of the regulation of expression of the c-myc gene in normal and neoplastic cells have uncovered novel mechanisms for the transcriptional regulation of eukaryotic gene expression. One level of control of c-myc expression is modulation in the quantity and ratio of transcription initiating from the c-myc P1 and P2 promoters. In addition, a second and novel mode of transcription regulation, a block to transcription elongation, is also regulated in normal cells. This mechanism, which is promoter-specific and regulatable, controls the amount of initiated transcription that elongates past a block at the 3' end of exon 1 to produce full length c-myc transcripts. Transcription initiated at the P1 promoter reads through the exon 1 block, whereas transcription from the P2 promoter can be modulated to read through or block. In normal cells, P2 is the predominant promoter. In Burkitt's lymphoma (BL) cells, characterized by translocations that juxtapose c-myc and immunoglobulin (Ig) sequences, the non-translocated c-myc gene is unexpressed. However, in those translocations in which the first exon of c-myc is intact, there is a shift of transcription initiation predominantly to the P1 promoter of the translocated c-myc gene, and the elongation block is abrogated, resulting in high or constitutive levels of steady-state c-myc RNA. In BL cells, the shift to P1 transcription may be due to the presence of trans-acting factors that suppress P2 activity and/or increase P1 utilization, or due to cis effects on promoter utilization and strength imposed by the proximity of the c-myc promoters to Ig regulatory sequences as a consequence of the translocation. The goals of this proposal are to determine the molecular basis of the abrogation of the c-myc elongation block and constitutive expression of c-myc in BL. In addition, we will attempt to identify elements within the Ig locus that are postulated to maintain the translocated c-myc gene in an active state in cells in which the normal c- myc allele is no longer active. We will also test the hypothesis that preferential use of the P1 promoter and consequent read-through transcription of the intact c-myc gene are essential steps in the neoplastic transformation of B cells.
