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.
Middendorp
Sabine
S
Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Xiao
Yanling
Y
Song
Ji-Ying
JY
Peperzak
Victor
V
Krijger
Peter H L
PH
Jacobs
Heinz
H
Borst
Jannie
J
D053330:4-1BB Ligand; D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D050976:Basic-Leucine Zipper Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D003564:Cytidine Deaminase / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D036383:Ephrin-A2 / Q000096:biosynthesis / Q000235:genetics; D020022:Genetic Predisposition to Disease; D018858:Germinal Center / Q000378:metabolism*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D051560:Proto-Oncogene Proteins c-bcl-6; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D053330:4-1BB Ligand; D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C102109:Bach2 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; C488088:Bcl10 protein, mouse; C490010:Bcl6 protein, mouse; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D036383:Ephrin-A2; D051560:Proto-Oncogene Proteins c-bcl-6; C505975:Tnfsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D025521:Tumor Suppressor Proteins; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase