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

Blood. 2009 Sep 10;114(11):2280-9. doi: 10.1182/blood-2009-03-208215. Epub 2009 Jul 16.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-1BB Ligand*
  • Adaptor Proteins, Signal Transducing / biosynthesis
  • Adaptor Proteins, Signal Transducing / genetics
  • Animals
  • B-Cell CLL-Lymphoma 10 Protein
  • Basic-Leucine Zipper Transcription Factors / biosynthesis
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cytidine Deaminase / biosynthesis
  • Cytidine Deaminase / genetics
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / genetics
  • Ephrin-A2 / biosynthesis
  • Ephrin-A2 / genetics
  • Genetic Predisposition to Disease
  • Germinal Center / metabolism*
  • Humans
  • Lymphoma, B-Cell / genetics
  • Lymphoma, B-Cell / metabolism*
  • Mice
  • Mice, Knockout
  • Proto-Oncogene Proteins c-bcl-6
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / genetics
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / metabolism
  • Tumor Suppressor Proteins*

Substances

  • 4-1BB Ligand
  • Adaptor Proteins, Signal Transducing
  • B-Cell CLL-Lymphoma 10 Protein
  • Bach2 protein, mouse
  • Basic-Leucine Zipper Transcription Factors
  • Bcl10 protein, mouse
  • Bcl6 protein, mouse
  • Biomarkers, Tumor
  • DNA-Binding Proteins
  • Ephrin-A2
  • Proto-Oncogene Proteins c-bcl-6
  • Tnfsf9 protein, mouse
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Tumor Suppressor Proteins
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase