Mice deficient for CD137 ligand are predisposed to develop germinal center-derived B-cell lymphoma
In the germinal center (GC), B cells proliferate dramatically and diversify their immunoglobulin genes, which increases the risk of malignant transformation. The GC B-cell reaction relies on crosstalk with follicular dendritic cells (FDCs), to which the costimulatory receptor CD137 on FDCs and its ligand on GC B cells potentially contribute. We report that mice deficient for CD137 ligand (CD137L) are predisposed to develop B-cell lymphoma, with an incidence of approximately 60% at 12 months of age. Lymphoma membrane markers were characteristic of GC B cells. Longitudinal histologic analysis identified the GC as site of oncogenic transformation and classified 85% of the malignancies found in approximately 200 mice as GC-derived B-cell lymphoma. To delineate the mechanism underlying lymphomagenesis, gene expression profiles of wild-type and CD137L-deficient GC B cells were compared. CD137L deficiency was associated with enhanced expression of a limited gene set that included Bcl-10 and the GC response regulators Bcl-6, Spi-B, Elf-1, Bach2, and activation-induced cytidine deaminase. Among these are proto-oncogenes that mediate GC B-cell lymphoma development in humans. We conclude that CD137L ordinarily regulates the GC B-cell response and thereby acts as a tumor suppressor.
|Persistent URL||dx.doi.org/10.1182/blood-2009-03-208215, hdl.handle.net/1765/25326|
Middendorp, S., Xiao, Y., Song, J.Y., Peperzak, V., Krijger, P.H.L., Jacobs, H., & Borst, J.G.G.. (2009). Mice deficient for CD137 ligand are predisposed to develop germinal center-derived B-cell lymphoma. Blood, 114(11), 2280–2289. doi:10.1182/blood-2009-03-208215