Dolors Colomer German Ott Emili Montserrat

The tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is a cytokine involved in the modulation of cell survival in different cell models. Similarly to other tumor necrosis factor (TNF) family members, TRAIL mediates apoptosis by binding to two receptors, DR4 and DR5, with a common structural organization characterized by an extracellular cysteinerich domain required for ligand binding and an intracellular death domain essential for the apoptotic signal transduction. Like the homologous FAS, TRAIL receptors seem to participate in the regulation of different lymphoid cell populations, in particular by preventing the expansion of autoreactive lymphocytes and the development of autoimmune disorders. Inactivation of the coding for these receptors may interfere with the normal mechanisms of cell survival facilitating the accumulation of abnormal lymphoid cell clones and eventually the development of lymphoid neoplasms. Apoptosisrelated TNF receptors have been found to be inactivated in several human neoplasms and cancer cell lines. Germ-line mutations of FAS cause an autoimmune lymphoproliferative syndrome and an increased risk of lymphoid malignancies. In addition, somatic mutations of FAS have been detected in human tumors, including lymphoid neoplasms. Similarly, mutations of the DR4 and DR5 TRAIL receptors have been found in different types of solid tumors and occasional cases of non-Hodgkin ́s lymphoma (NHL). Most of these mutations occur in the functional death and ligand binding domains and changes in other regions of the receptors are extremely rare. In addition to somatic mutations, several polymorphisms of regulatory regions or functional domains of FAS and TRAIL receptors have been frequently assoFrom the Hematopathology Section, Laboratory of Pathology (VF, SB, IS, DC, EC), Genomics Unit (PJ), and Hematology Department, Hospital Clínic, Institut d’Investigacions Biomediques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain (EM), Epidemiology and Cancer Register Service, Institut Català d ́Oncologia (EG, SdS); Institute of Pathology, University of Würzburg, Würzburg, Germany (GO).