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Tumor necrosis factor-α and CD95 ligation suppress erythropoiesis in fanconi anemia C gene knockout mice

✍ Scribed by Tetsuya Otsuki; Shoichi Nagakura; Jianxiang Wang; Michael Bloom; Markus Grompe; Johnson M. Liu

Publisher
John Wiley and Sons
Year
1999
Tongue
English
Weight
266 KB
Volume
179
Category
Article
ISSN
0021-9541

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✦ Synopsis

Fanconi anemia (FA) is a genetic syndrome predisposing to hematopoietic failure. Little is known about the pathophysiology of FA, except that tumor necrosis factor-␣ (TNF-␣) 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-␣ 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-␣ and CD95 ligation. Flow cytometric analysis revealed that CD95 was induced more readily in the Fac-null CD34ϩ cell fraction. Apoptosis induced by TNF-␣ alone or with CD95 ligation also occurred more frequently in null mouse HPC. We then bred null mice against transgenic mice overexpressing TNF-␣ (at serum levels in the range of 100 pg/ml). Resultant Fac-null mice that overexpressed TNF-␣ not only yielded decreased numbers of BFU-E but also expressed higher levels of CD95 in the CD34ϩ fraction. We conclude that mutation in the Fac protein induces heightened sensitivity to TNF-␣ and Fas receptor ligation, results that may explain the mechanism of anemia in FA-C patients.

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