Research Project
9406180
PROJECT SUMMARY/ABSTRACT Approximately 80% of B-cell non-Hodgkin's lymphomas are derived from germinal center (GC) B-cells. Somatic hypermutation within GC B-cells is necessary for antibody affinity maturation, but somatic mutations can also drive epigenetic lesions that enhance survival, maintain the hyperproliferative state of GC B-cells, and promote lymphomagenesis. Given the susceptibility of GC B-cells to malignant transformation, it is not surprising that the natural process of selection within the GC is thought to help protect against the selection of malignant clones. Accordingly, a deeper understanding of factors that restrain the GC are needed. Siglec- 10/G (human/mouse ortholog) are members of the Siglec family of inhibitory receptors that recognize sialic acid-containing glycan ligands. Siglec-10/G dampen B-cell activation through the B-cell receptor. In mice, the role of Siglec-G in inhibiting the initial events of B-cell activation have been described, but it is unknown if Siglec-G plays a role at later stages, such as in the GC. Interestingly, an expanded GC compartment is observed in Siglec-G-/- mice, Siglec-G-/- mice develop B-cell lymphomas, and Siglec-10 expression is lost on GC-derived B-cell lymphomas. Taken together, we hypothesize that Siglec-G restrains the GC reaction under healthy conditions and that loss of Sigelc-10/G expression promotes the development of GC-derived B-cell lymphomas due to a poorly controlled GC reaction. Preliminary results support a role for Siglec-G in restraining GC B-cells, as B-cell responses in mixed bone marrow chimeras reveal that Siglec-G-/- GC B-cells gradually outcompete WT GC B-cells. Additional preliminary evidence demonstrates a unique phenotype (increased ICOS expression) in GC T-follicular helper (GC-Tfh) cells within Siglec-G-/- mice, supporting other lines of evidence for a role for Siglec-G in modulating B-T cell interactions. This project aims to investigate a causal relationship between loss of Siglec-G and the development of GC-derived B-cell lymphomas and assess a potential role for Siglec-G in regulating B-T cell interactions. Two independent approaches will be used to test causality between loss of Siglec-G-/-, a dysregulated GC, and the development of GC-derived B- cell lymphomas. In the first approach, Tfh cells will be ablated in Siglec-G-/- mice. In the second approach, Siglec-G expression will be maintained transgenically in an independent mouse model that develops GC- derived B-cell lymphomas and loose Siglec-G expression. To examine a role for Siglec-G as a negative regulator of B-T cell interactions, the ligand specificity of Siglec-G will be dissected in reference to glycans on naïve GC-Tfh CD4+ cells, and glycan ligands on CD4+ T-cells will be manipulated to examine what impact this has on B-T cell interactions. The overall objective of this project is to test the role of Siglec-G as a tumor suppressor in GC B-cells and examine one potential mechanism by which Siglec-G restrains the GC. This knowledge will lead to new insights into the etiology of GC-derived B-cell lymphomas, and potentially offer clues for new treatment strategies, which are especially needed for the incurable FL.
