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

A. L. Snow, Linda J Chen, R. R. Nepomuceno, S. M. Krams, C. O. Esquivel, O. M. Martinez

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Post-transplant lymphoproliferative disorder is characterized by the outgrowth of EBV-infected B cell lymphomas in immuno-suppressed transplant recipients. Using a panel of EBV-infected spontaneous lymphoblastoid cell lines (SLCL) derived from post-transplant lymphoproliferative disorder patients, we assessed the sensitivity of such lymphomas to Fas-mediated cell death. Treatment 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 addition, all SLCL are sensitive to staurosporine-induced cell death, indicating that there is no global defect in apoptosis. Although all SLCL express comparable levels of Fas signaling molecules including Fas-associated death domain protein, caspase 8, and caspase 3, Fas-resistant SLCL exhibit a block in Fas-signaling before caspase 3 activation. In two SLCL, this block results 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 formation and caspase 8 activation. Whereas multiple mechanisms exist by which tumor cells can evade Fas-mediated apoptosis, these studies suggest that the proximal Fas-signaling pathway is impeded in Fas-resistant post-transplant lymphoproliferative disorder-associated EBV+ B cell lymphomas.

Original languageEnglish
Pages (from-to)5404-5411
Number of pages8
JournalJournal of Immunology
Volume167
Issue number9
StatePublished - Nov 1 2001
Externally publishedYes

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B-Cell Lymphoma
Human Herpesvirus 4
Apoptosis
Cell Line
Lymphoproliferative Disorders
Caspase 8
Death Domain Receptor Signaling Adaptor Proteins
Caspase 3
Transplants
Cell Death
Fas-Associated Death Domain Protein
Fas Ligand Protein
Staurosporine
Lymphoma
Mutation
Neoplasms

ASJC Scopus subject areas

  • Immunology

Cite this

Snow, A. L., Chen, L. J., Nepomuceno, R. R., Krams, S. M., Esquivel, C. O., & Martinez, O. M. (2001). Resistance to Fas-mediated apoptosis in EBV-infected B cell lymphomas is due to defects in the proximal Fas signaling pathway. Journal of Immunology, 167(9), 5404-5411.

Resistance to Fas-mediated apoptosis in EBV-infected B cell lymphomas is due to defects in the proximal Fas signaling pathway. / Snow, A. L.; Chen, Linda J; Nepomuceno, R. R.; Krams, S. M.; Esquivel, C. O.; Martinez, O. M.

In: Journal of Immunology, Vol. 167, No. 9, 01.11.2001, p. 5404-5411.

Research output: Contribution to journalArticle

Snow, AL, Chen, LJ, Nepomuceno, RR, Krams, SM, Esquivel, CO & Martinez, OM 2001, 'Resistance to Fas-mediated apoptosis in EBV-infected B cell lymphomas is due to defects in the proximal Fas signaling pathway', Journal of Immunology, vol. 167, no. 9, pp. 5404-5411.
Snow, A. L. ; Chen, Linda J ; Nepomuceno, R. R. ; Krams, S. M. ; Esquivel, C. O. ; Martinez, O. M. / Resistance to Fas-mediated apoptosis in EBV-infected B cell lymphomas is due to defects in the proximal Fas signaling pathway. In: Journal of Immunology. 2001 ; Vol. 167, No. 9. pp. 5404-5411.
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