Tumor necrosis factor-alpha and CD95 ligation suppress erythropoiesis in Fanconi anemia C gene knockout mice

J Cell Physiol. 1999 Apr;179(1):79-86. doi: 10.1002/(SICI)1097-4652(199904)179:1<79::AID-JCP10>3.0.CO;2-O.


Fanconi anemia (FA) is a genetic syndrome predisposing to hematopoietic failure. Little is known about the pathophysiology of FA, except that tumor necrosis factor-alpha (TNF-alpha) is overexpressed in patients. FA group C (Fac) gene knockout mice have been developed in order to model the human disease, but the mice do not spontaneously exhibit aplasia. To investigate secondary influences on hematopoiesis in the Fac-null mice, we studied the sensitivity of hematopoietic progenitor cells (HPC) to death receptor triggering by TNF-alpha and Fas receptor (CD95) ligation. Previously we had found that overexpression of a human FAC transgene protects hematopoietic progenitors from Fas-mediated apoptosis (Wang et al., 1998, Cancer Res 58:3538-3541). In the present experiments with Fac-null mice, growth of erythroid burst-forming units (BFU-E) was significantly inhibited by TNF-alpha and CD95 ligation. Flow cytometric analysis revealed that CD95 was induced more readily in the Fac-null CD34+ cell fraction. Apoptosis induced by TNF-alpha alone or with CD95 ligation also occurred more frequently in null mouse HPC. We then bred null mice against transgenic mice overexpressing TNF-alpha (at serum levels in the range of 100 pg/ml). Resultant Fac-null mice that overexpressed TNF-alpha not only yielded decreased numbers of BFU-E but also expressed higher levels of CD95 in the CD34+ fraction. We conclude that mutation in the Fac protein induces heightened sensitivity to TNF-alpha and Fas receptor ligation, results that may explain the mechanism of anemia in FA-C patients.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Bone Marrow / physiopathology
  • Cell Cycle Proteins*
  • Cell Lineage
  • Crosses, Genetic
  • DNA Damage
  • DNA-Binding Proteins*
  • Disease Models, Animal
  • Erythroid Precursor Cells / drug effects
  • Erythropoiesis / drug effects*
  • Fanconi Anemia / genetics
  • Fanconi Anemia / metabolism*
  • Fanconi Anemia Complementation Group C Protein
  • Fanconi Anemia Complementation Group Proteins
  • Female
  • Genetic Predisposition to Disease
  • Granulocytes
  • Hematopoietic Stem Cells / drug effects
  • In Situ Nick-End Labeling
  • Macrophages
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Nuclear Proteins*
  • Proteins / genetics
  • Proteins / physiology*
  • Receptors, Tumor Necrosis Factor / physiology
  • Recombinant Fusion Proteins / physiology
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Tumor Necrosis Factor-alpha / physiology
  • fas Receptor / physiology*


  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Fancc protein, mouse
  • Fanconi Anemia Complementation Group C Protein
  • Fanconi Anemia Complementation Group Proteins
  • Nuclear Proteins
  • Proteins
  • Receptors, Tumor Necrosis Factor
  • Recombinant Fusion Proteins
  • Tumor Necrosis Factor-alpha
  • fas Receptor