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 Blood, 10 September 2009, Vol. 114, No. 11, pp. 2280-2289.
Prepublished online as a Blood First Edition Paper on July 16, 2009; DOI 10.1182/blood-2009-03-208215.

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LYMPHOID NEOPLASIA

Mice deficient for CD137 ligand are predisposed to develop germinal center–derived B-cell lymphoma

Sabine Middendorp1, Yanling Xiao1,*, Ji-Ying Song2,*, Victor Peperzak1,{dagger}, Peter H. L. Krijger1,{dagger}, Heinz Jacobs1, and Jannie Borst1

1 Division of Immunology and 2 Laboratory of Experimental Animal Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

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.


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