Submitted July 2, 2007
Accepted November 14, 2007
Aberrant activation of stress-response pathways leads to TNF-
oversecretion in Fanconi anemia
Delphine Briot, Gaetane Mace-Aime, Frederic Subra, and Filippo Rosselli*
CNRS FRE2939-Univ Paris-Sud, Institut Gustave Roussy, Villejuif, France
CNRS UMR8113-LBPA, ENS Cachan, Cachan, France
* Corresponding author; email: rosselli{at}igr.fr.
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-
through unknown mechanisms. We demonstrate here that FANC pathway loss-of-function results in the aberrant activation of two major stress-signaling pathways: NF-
B and MAPKs. These responses are independent on TNF- expression. On the contrary, inhibition of the MAPK pathways normalizes TNF- 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- shedding and release from the cytoplasmic membrane in FA. TNF- overproduction is, indeed, normalized by MMP-7 inhibition. Finally, MAPKs inhibition impacts on MMP-7 overexpression. Evidences are 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- oversecretion. TNF- may, in turn, sustain or amplify both MAPKs and NF-B activation. Aberrant expression or activity of NF-B and/or MAPKs have been already involved in bone marrow failure and leukemia and their inhibition showed be positive for outcome. In conclusion, our data provide a strong rationale for new clinical trials on FA patients.
