Clonal variability in CD95 expression is the major determinant in Fas-mediated, but not chemotherapy-mediated apoptosis in the RPMI 8226 multiple myeloma cell line

K. H. Shain, T. H. Landowski, I. Buyuksal, A. B. Cantor, W. S. Dalton

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

CD95 (Fas/APO-1) is a member of the TNFR superfamily that induces apoptosis following cross-linking with its cognate ligand, CD95L (FasL/APO-1L) or agonist antibody. The human myeloma cell line, RPMI 8226, has limited sensitivity to CD95-mediated apoptosis, with a maximum of 65% of the population responding. To determine the source of the limited sensitivity to CD95-mediated apoptosis, we isolated multiple clones from the RPMI-8226 cell line by limiting dilution. Analysis of these clones demonstrated that sensitivity to CD95-mediated cell death directly correlated with CD95 expression. Clones with high levels of CD95 expression had greater than 90% cell death, whereas cells with low levels of expression had less than 10% cell death. In contrast, no correlative differences were identified for other members of the DISC complex, or for members of the anti-apoptotic Bcl-2 family. We further examined the sensitivity of the 8226 clones to various cytotoxic agents. Although modest clonal variability was demonstrated in response to the chemotherapeutic drugs, doxorubicin, etoposide (VP-16), and vincristine, there was no correlation between CD95 function and sensitivity to chemotherapeutic drugs. These results indicate that in this cell line, receptor expression is rate limiting in CD95-mediated apoptosis, whereas CD95 expression was not a determinant in drug-induced programmed cell death.

Original languageEnglish (US)
Pages (from-to)830-840
Number of pages11
JournalLeukemia
Volume14
Issue number5
DOIs
StatePublished - Jan 1 2000

Keywords

  • Apoptosis
  • CD59/Fas/APO-1
  • Chemotherapy
  • Clonal variability
  • Drug resistance
  • Multiple myeloma

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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