The origin of CD95-gene mutations in B-cell lymphoma.
CD95 (Apo-1/Fas) is crucial for the negative selection of B cells within the germinal center (GC). Impairment of CD95-mediated apoptosis results in defective affinity maturation and the persistence of autoreactive B-cell clones. CD95 was defined recently as a tumor-suppressor gene and is silenced in many tumor entities. In contrast to other malignancies, in GC-derived B-cell lymphomas, inactivation of the CD95 gene is often a result of deleterious mutations. Such mutations occur also at a low frequency in normal GC, but not naive, B cells. We propose that CD95 mutations in B-cell lymphomas originate from the GC reaction and are introduced most probably as targeting errors of the somatic hypermutation machinery, which bears--besides its physiological role--an inherent risk of malignant transformation and the persistence of autoreactive B-cell specificities.
Müschen
Markus
M
Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Universität zu Köln, Germany. markus.mueschen@uni-koeln.de
Rajewsky
Klaus
K
Krönke
Martin
M
Küppers
Ralf
R
D019070:Cell Lineage; D016147:Genes, Tumor Suppressor; D018858:Germinal Center / Q000276:immunology; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000276:immunology; D019014:fas Receptor / Q000235:genetics*
D019014:fas Receptor