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

Sabine Middendorp, Yanling Xiao, Ji-Ying Song, Victor Peperzak, Peter H. L. Krijger, Heinz Jacobs, Jannie Borst*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    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 languageEnglish
    Pages (from-to)2280-2289
    Number of pages10
    JournalBlood
    Volume114
    Issue number11
    DOIs
    Publication statusPublished - 10 Sept 2009

    Keywords

    • FOLLICULAR DENDRITIC CELLS
    • IMMUNE-RESPONSES
    • 4-1BB LIGAND
    • T-CELLS
    • IN-VIVO
    • SPI-B
    • EXPRESSION
    • GENE
    • MOUSE
    • BCL6

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