ROLE OF THE BCL 6 PROTO ONCOGENE IN B CELL LYMPHOMAS

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DESCRIPTION: (Adapted from the investigator's abstract) Aggressive non Hodgkin's B-cell lymphomas often carry chromosomal translocations in the proto-oncogene BCL-6 locus. Translocations deregulate BCL-6 expression via promoter substitution, leading to constitutive high levels of the wild type BCL-6 protein in lymphoma B cells. In normal B cells, the BCL-6 protein is expressed only at the germinal center stage. BCL-6 is a zinc finger-containing transcription repressor. Knock out studies in mice have suggested important regulatory functions for BCL-6 in the immune system. Still, very little is known about how its expression is normally regulated in B as well as in non-B cells. In addition, the mechanism by which abnormal BCL-6 expression contributes to lymphomagenesis is still unclear. The first specific aim will attempt to characterize a negative autoregulatory mechanism governing BCL-6 transcription. Experiments are designed to first firmly establish its existence in B cells with a wild type BCL-6 gene. Its integrity in tumor B cells with genetically altered BCL-6 gene will then studied. In the second aim, we will test our hypothesis that continued expression of the BCL-6 protein is essential for maintaining the tumorigenicity of lymphoma cell lines. We will attempt to downregulate the activity of BCL-6 protein by expression of either the antisense or dominant negative BCL-6 mutants (knock down approach). Corresponding changes in the cellular phenotype of lymphoma cells will be studied. As our preliminary data suggests a role of BCL-6 in preventing apoptosis, identifying a link between BCL-6 and apoptosis regulators will be a priority. In the third aim, effort will be made to search for BCL-6 genes genes based upon this knock down approach. A combination of cDNA RDA and the cDNA microarray techniques will be used. The last specific aim is to establish the causative role of BCL-6 in lymphomagenesis in vivo by generating conditional BCL-6 transgenic mice using the cre-lox system. Phenotypes to be analyzed include germinal center enter function, B cell proliferation and tumorigenesis.