The goal of this research proposal is to discover modular control structures (genetic modules), within pathways that coordinate the germinal center (GC) reaction in B cells, and to elucidate their disregulation in GC-derived tumors. The GC reaction of antigen-activated B-lymphocytes is the key biological process for the selection of B cells producing antibodies with high affinity for antigens. As such, the GC represents a key structure for the development of physiologic antibody-mediated immune responses. Furthermore, GC B-cells are involved in the pathogenesis of B cell related cancers, which include a heterogeneous group of malignancies, representing together the 5th most common class of tumors in humans. We have assembled a large collection (>300) of gene expression profile data from different B cell populations including: 1) normal cells representing the main stages of GC development; 2) panels of tumors representing the main subtypes of GC-derived malignancies; and 3) B cell lines experimentally manipulated in vitro to reflect single-gene alterations found in human tumors. Using this data set in combination with new reverse-engineering and gene clustering algorithms, we will discover the genetic modules that orchestrate the GC reaction, especially those with different expression patterns in normal vs. tumor B cells. In particular, we propose to investigate the subnetworks that involve two proto-oncogenes: BCL6 (a gene playing an important role in the coordination of the genetic programs leading to the GC reaction) and c-MYC (a gene co-expressed with BCL6 only in tumors). ? ? ?
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