Resistance to Fas-mediated apoptosis in EBV-infected B cell lymphomas is due to defects in the proximal Fas signaling pathway

Post-transplant lymphoproliferative disorder is characterized by the outgro wth of EBV-infected B cell lymphomas in immuno-suppressed transplant recipi ents. Using a panel of EBV-infected spontaneous lymphoblastoid cell lines ( SLCL) derived from post-transplant lymphoproliferative disorder patients, w e assessed the sensitivity of such lymphomas to Fas-mediated cell death. Tr eatment with either an agonist anti-Fas mAb or Fas ligand-expressing cells identifies two subsets of SLCL based on their sensitivity or resistance to Fas-driven apoptosis. Fas resistance in these cells cannot be attributed to reduced Fas expression or to mutations In the Fas molecule itself. In addi tion, all SLCL are sensitive to staurosporine-induced cell death, indicatin g that there Is no global defect in apoptosis. Although all SLCL express co mparable levels of Fas signaling molecules Including Fas-associated death d omain protein, caspase 8, and caspase 3, Fas-resistant SLCL exhibit a block in Fas-signaling before caspase 3 activation. In two SLCL, this block resu lts in impaired assembly of the death-inducing signaling complex, resulting in reduced caspase 8 activation. In a third Fas-resistant SLCL, caspase 3 activation is hindered despite intact death-inducing signaling complex form ation and caspase 8 activation. Whereas multiple mechanisms exist by which tumor cells can evade Fas-mediated apoptosis, these studies suggest that th e proximal Fas-signaling pathway is impeded in Fas-resistant post-transplan t lymphoproliferative disorder-associated EBV+ B cell lymphomas.