BCL6 IN GERMINAL CENTER FORMATION AND LYMPHOMAGENESIS

Dana-Farber Cancer Institute, Boston MA

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Abstract

DESCRIPTION:(provided by Applicant) The general objective of this project is to understand the biological function of the BCL-6 proto-oncogene and its role in lymphomagenesis. BCL-6 is specifically required for the formation of GC and is expressed in all NHL subtypes deriving from GC (greater than 90 percent NHL). In 40 percent of diffuse large cell lymphoma (DLCL), the BCL-6 gene is directly involved in chromosomal translocations that deregulate its expression. As a transcriptional repressor, BCL-6 presumably functions by regulating the expression of genes containing its DNA binding site. Initial results indicate that BCL-6 silences the expression of a subset of genes induced by IL-4, CD-4O and antigen-induced B cell receptor (BCR) signaling. We plan to comprehensively identify BCL-6-regulated genes and construct an animal model of BCL-6-induced lymphomagenesis. Specifically, we will: i) identify the genes targeted by BCL-6 by oligonucleotide-based (Affymetrix) gene expression profiling of cells stimulated by IL-4, BCR, and CD-40 signaling in the presence or absence of BCL-6; ii) determine whether normal GC cells and various NHL subtypes receive IL-4/CD-4O/BCR signals and whether they are repressed by BCL-6 through the analysis of signal-specific gene expression "signatures"; iii) study the consequences of deregulated BCL-6 expression on B cell development and lymphomagenesis in vivo by constructing transgenic mice with constitutive or inducible expression of BCL-6 in B cells.