Abstract
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. (Blood. 2009; 114: 2280-2289)
Original language | English |
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Pages (from-to) | 2280-2289 |
Number of pages | 10 |
Journal | Blood |
Volume | 114 |
Issue number | 11 |
DOIs | |
Publication status | Published - 10 Sept 2009 |
Keywords
- FOLLICULAR DENDRITIC CELLS
- IMMUNE-RESPONSES
- 4-1BB LIGAND
- T-CELLS
- IN-VIVO
- SPI-B
- EXPRESSION
- GENE
- MOUSE
- BCL6