Abstract IA03: Role of MYC in germinal-center development and in lymphomagenesis

Abstract

Abstract Germinal centers (GCs) are transient structures that form in second¬ary lymphoid organs where B cells are selected on the basis of their ability to produce high-affinity antibodies. B cells in the GCs are also the cells of origin for most B cell lymphomas, including Burkitt Lymphoma carrying chromosomal translocations involving c-Myc. After antigenic challenge, B cells enter the dark zone (DZ) of germinal centers (GCs) to proliferate and hypermutate their immunoglobulin genes. Mutants with greater affinity for the antigen are positively selected in the light zone (LZ) to either differentiate into plasma and memory cells or reenter the DZ. We have shown that the GC reaction requires a biphasic regulation of expression of c-Myc that involves: 1) its transient induction during early GC commitment; 2) its repression by Bcl-6 in highly proliferating DZ B cells; 3) its re-induction in B cells selected for reentry into the DZ. Elimination of c-MYC expression during GC formation results in GC absence, while its inhibition in formed GCs leads to GC collapse. Thus c-Myc has essential roles in early induction of GCs and in their maintenance, by eliminating the LZ-to DZ recirculation. These results suggest an unusual, independent of cell proliferation role of c-Myc in GC development and has implications for the role of c-Myc in lymphomagenesis. By overriding the physiological control of c-Myc expression at critical checkpoints in the GC reaction (entry into the GC and reentry into the DZ), translocations involving immunoglobu¬lin loci and c-MYC may allow B cells to bypass affinity-based selection signals and impose a continuous reentry phenotype that, by perturb¬ing normal GC dynamics, may contribute to lymphomagenesis. Note: This abstract was not presented at the conference. Citation Format: Riccardo Dalla-Favera. Role of MYC in germinal-center development and in lymphomagenesis. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr IA03.