Trouble in the Fas Lane: Lessons Learned from an "Experiment of Nature"
DLM, CC, DHHS
AIM: To assess the risk of lymphoma in the autoimmune lymphoproliferative syndrome (ALPS) METHODS: Review of ALPS families for incidence of lymphoma and consider this in the context of in vitro Fas mediated lymphocyte apoptosis and TNFRSF6 mutations. Determine the relative risk of lymphoma compared to the general population RESULTS: The diagnosis of ALPS requires the presence of non-malignant lymphadenopathy along with an abnormality in Fas mediated lymphocyte apoptosis and an expansion of CD3+ T cells that express the alpha beta form of the TcR that fail to express either CD4 or CD8 (double negative [DN] T cells). The most commonly associated genetic defect in ALPS involves a heterozygous mutation in the gene encoding Fas (TNFRSF6) and in most cases the mutation involves the intracellular death domain. Within the extended pedigree of ALPS probands that carry germline mutations affecting the intracellular portion of the Fas protein (majority in the death domain), we found that there was a higher incidence of lymphoma. This was initially based on examination of more than 200 family members in 39 ALPS families and revealed an increased incidence of lymphomas, both Hodgkin’s disease (HD) and non-Hodgkin lymphoma (NHL). There was varied histology and the increase in relative risk for HD was 51 times and for NHL was 14 greater than expected (p < .001 for each). These findings are in concert with the data from the murine models of defective Fas mediated apoptosis (lpr and gld mice) where increased incidence of B cell tumors are found. This adds the additional common feature of an increased incidence of lymphoma associated with defective Fas mediated apoptosis in both the human disorder, ALPS, and the lpr/gld murine models. CONCLUSIONS: These data identify that Fas mediated lymphocyte apoptosis plays a role in preventing lymphoma development in humans.
Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in plenary session 903 (Cancer immunity).