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.