We proposed to study the mechanism of activation of c-myc at a molecular level in human lymphoma tissue and in mouse model of the translocation. The goal is to reach a better understanding of the mechanisms of malignant transformation. 1. Completion of the characterization of the regulatory elements in the murine and human immunoglobulin heavy chain (IgH) enhancers that deregulate c-myc transcription. We will continue to identify the regulatory elements that are required for activation of c-myc, including increased transcription and P2 to P1 promoter shift. 2. Identification of the regions of the c-myc promoter that are required for the interaction with the IgH enhancers for maximun transcriptional activity and the promoter shift. Study of the mechanisms involved. 3. Determination of the mechanisms of transcriptional silencing of the normal c-myc allele in Burkitt's lymphoma. 4. Construction of a mouse model of the c-myc-IgH translocation. We will target the active sites of the IgH enhancers to the murine c-myc gene to recreate the Burkitt's translocation. 5.Development of strategies to interfere with c-myc transcription that is driven by the IgH enhancers. We have shown that several NF-kB sites are critical for deregulated c-myc expression, and we will first target the function of NF-kB.
