Differential recruitment of caspase 8 to cFlip confers sensitivity or resistance to Fas-mediated apoptosis in a subset of familial lymphoma patients

Leuk Res. 2003 Sep;27(9):841-51. doi: 10.1016/s0145-2126(03)00018-3.

Abstract

Resistance to Fas-mediated apoptosis (FMA) has been implicated in the pathogenesis of hematologic malignancies. Recently, a collaborative study showed that germline Fas mutations represent a genetic risk factor for the development of Hodgkin's and non-Hodgkin lymphoma. Here, we report that transformed B cell lines from familial lymphoma patients show a range of sensitivity to Fas-mediated apoptosis with lymphocytes from two patients with a marked resistance to Fas-, but not p53-mediated cell death. Fas resistance in these cells was associated with reduced recruitment of the initiator caspase 8 compared to cFlip, an inhibitor of apoptosis, to the death-inducing signaling complex (DISC). A decreased ratio of caspase 8 to cFlip in total cell extracts as well as in the DISC was associated with a profound disturbance of the Fas signaling cascade. We propose here that the relative reduction in caspase 8 to cFlip in the Fas DISC confers a survival advantage to lymphocytes and predisposes to the development of malignancy in some familial lymphoma patients.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Apoptosis*
  • Blotting, Western
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Carrier Proteins / physiology*
  • Caspase 8
  • Caspase 9
  • Caspases / metabolism*
  • Cell Line
  • Death Domain Receptor Signaling Adaptor Proteins
  • Drug Resistance, Neoplasm*
  • Female
  • Gamma Rays / adverse effects
  • Humans
  • Intracellular Signaling Peptides and Proteins*
  • Lymphoma / genetics*
  • Lymphoma / metabolism*
  • Lymphoma / pathology
  • Male
  • Membrane Potentials / drug effects
  • Middle Aged
  • Mitochondria / drug effects
  • Polymerase Chain Reaction
  • Polymorphism, Single-Stranded Conformational
  • Precipitin Tests
  • Receptors, Tumor Necrosis Factor / metabolism
  • Signal Transduction
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / radiation effects
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / radiation effects
  • Tumor Suppressor Protein p53 / metabolism
  • fas Receptor / analysis
  • fas Receptor / physiology*

Substances

  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CFLAR protein, human
  • Carrier Proteins
  • Death Domain Receptor Signaling Adaptor Proteins
  • Intracellular Signaling Peptides and Proteins
  • Receptors, Tumor Necrosis Factor
  • Tumor Suppressor Protein p53
  • fas Receptor
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 8
  • Caspase 9
  • Caspases