Fanconi anemia type C-deficient hematopoietic cells are resistant to TRAIL (TNF-related apoptosis-inducing ligand)-induced cleavage of pro-caspase-8

Uwe Platzbecker, Peter Kurre, Philippe Guardiola, Jessica L. Ward, Jerald P. Radich, Hans Peter Kiem, H. Joachim Deeg

Research output: Contribution to journalArticle

7 Scopus citations


The pathophysiology of bone marrow failure in Fanconi anemia (FA) patients is thought to involve excessive apoptosis involving signaling triggered by fas ligation and tumor necrosis factor (TNF)-α, or interferon (IFN)-γ exposure. We investigated whether a new member of the TNF family, TRAIL (TNF-related apoptosis-inducing ligand), would similarly trigger preferential apoptotic cell death in FA phenotype cells.Hematopoietic cells from FANCC -/- transgenic mice and human FA-C lymphoblasts (HSC536N) as well as their phenotypically corrected counterparts (FANCC +/+, HSC536/FA-Cneo) were compared for their response to apoptosis induction by TRAIL and fas ligation in the presence or absence of IFN-γ. Cells were also studied for the protein and gene expression of TRAIL-receptors, caspase-8 and its inhibitory protein, FLIP.TRAIL exposure by itself or in combination with IFN-γ did not lead to preferential apoptosis induction in human and murine FA-C phenotype hematopoietic cells. This resistance was unrelated to the expression of TRAIL receptors or FLIP isoforms, but correlated with absent cleavage of pro-caspase-8. Results were validated by those from gene expression profiling of relevant genes in the two lymphoblast cell lines.TRAIL, in contrast to fas ligation, does not induce preferential apoptosis in FA-C phenotype cells despite shared downstream signaling described in non-FA models. These data provide further insight into the complexity of FA-C-regulated apoptotic signaling.

Original languageEnglish (US)
Pages (from-to)815-821
Number of pages7
JournalExperimental hematology
Issue number9
StatePublished - Sep 1 2004


ASJC Scopus subject areas

  • Molecular Biology
  • Hematology
  • Genetics
  • Cell Biology
  • Cancer Research

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