Cyclin D3 and Msh6 in germinal center function and lymphomagenesis

Abstract

B cells generate a diverse antibody response in the context of a proliferative program in the germinal centers (GC) of secondary lymphoid organs. Although these GC B cells have mechanisms to tolerate the genotoxic stress, compelling evidence suggests that events related to DNA damage are nevertheless a major cause of B cell lymphomas. In my thesis research I studied how this proliferation is regulated, and why lymphomas arise in these cells in the absence of mismatch repair, which is an important guardian of genomic stability but also a source of antibody diversity.;Mice deficient in Cyclin D3 are impaired in their ability to form GCs, as assessed by immunohistochemistry and flow cytometry. Affinity maturation is concomitantly reduced in these animals. These phenotypes can be partially explained by a block in the G1/S phase of GC B cells in vivo. This is the first demonstration that Cyclin D3 plays a unique role during the GC response in that it is required for its optimal structure and function.;Mice lacking the MMR protein MSH6 develop B cell lymphomas, which I characterized as mature B cells with heterogeneous immunohistochemical features of GC B cells. A cell line derived from one of these lymphomas was extensively characterized. It forms transplantable tumors and is inducible for expression of AID and thus offers a novel model for studying mismatch repair in GC function. Loss of AID had no effect on the survival of MSH6-deficient animals, suggesting that MSH6 protects B cells from neoplastic transformation through an AID-independent mechanism. While spectral-karyotype analysis of the lymphomas did not show translocations, genome-wide instability was demonstrated in these lymphomas by microsatellite instability assays and by array comparative genomic hybridization. These results suggest that MSH6 protects mature B cells from lymphomagenesis by preserving genomic stability.;These studies offer new information about the unique programs executed by GC B cells with respect to cell-cycle regulation and tolerating the genotoxic stress that accompanies antibody diversification. In addition, they directly inform our understanding of the pathogenesis of B cell lymphoma.