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Aberrant activation of stress-response pathways leads to TNF-α oversecretion in Fanconi anemia

Delphine Briot, Gaëtane Macé-Aimé, Frédéric Subra and Filippo Rosselli

Abstract

Fanconi anemia (FA), an inherited syndrome that associates bone marrow failure, cancer predisposition, and genetic instability, is characterized by an overproduction of the myelosuppressive cytokine TNF-α through unknown mechanisms. We demonstrate here that FANC pathway loss-of-function results in the aberrant activation of 2 major stress-signaling pathways: NF-κB and MAPKs. These responses are independent on TNF-α expression. On the contrary, inhibition of the MAPK pathways normalizes TNF-α oversecretion in FA. Moreover, our data show that the overexpression of the matrix metalloproteinase MMP-7 is the key event directly responsible for the high rate of TNF-α shedding and release from the cytoplasmic membrane in FA. TNF-α overproduction is, indeed, normalized by MMP-7 inhibition. Finally, MAPK inhibition impacts on MMP-7 overexpression. Evidence is provided of the existence of a linear pathway in which FANC mutations activate MAPK signaling that induces MMP-7 overexpression leading, in fine, to TNF-α oversecretion. TNF-α may, in turn, sustain or amplify both MAPKs and NF-κB activation. Aberrant expression or activity of NF-κB and/or MAPKs has been already involved in bone marrow failure and leukemia, and their inhibition offered clinical benefit for patients. In conclusion, our data provide a strong rationale for new clinical trials on FA patients.

  • Submitted July 2, 2007.
  • Accepted November 14, 2007.
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