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

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-alpha through unknown mechanisms. We demonstrate here that FANC pathway loss-of-function results in the aberrant activation of 2 major stress-signaling pathways: NF-kappaB and MAPKs. These responses are independent on TNF-alpha expression. On the contrary, inhibition of the MAPK pathways normalizes TNF-alpha 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-alpha shedding and release from the cytoplasmic membrane in FA. TNF-alpha 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-alpha oversecretion. TNF-alpha may, in turn, sustain or amplify both MAPKs and NF-kappaB activation. Aberrant expression or activity of NF-kappaB 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.