CD95 antigen mutations in hematopoietic malignancies

The CD95 receptor, also known as Fas/Apo-1, is a member of the Tumor Necros is Factor receptor (TNF-R) family of death receptors. Apoptosis mediated by CD95 plays a central role in maintaining homeostasis of the immune system. Dysregulation of the CD95 apoptotic pathway has been proposed as a mechani sm of oncogenesis by providing a survival advantage to potentially malignan t cells. This extended lifespan could allow the accumulation of further mut ations leading to malignant transformation. Several mechanisms of resistanc e to CD95 mediated apoptosis have been identified, including reduced surfac e expression of the receptor, overexpression of anti-apoptotic molecules, a nd loss of function mutations. This review will focus on the potential role of the CD95-CD95 Ligand system in the pathogenesis of hematological malign ancies, with particular emphasis on recent work from our laboratory examini ng the expression of CD95 in B cell lymphomas. We demonstrate that CD95 mut ations occur at low frequency in NHL turnors, however, surface expression o f the CD95 protein varies with the subtype of lymphoma. Loss of surface CD9 5 is more likely to occur in lymphomas of aggressive histology, and is unre lated to the detection of CD95 mutations.