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Blood, 15 February 2008, Vol. 111, No. 4, pp. 1913-1923. Prepublished online as a Blood First Edition Paper on November 30, 2007; DOI 10.1182/blood-2007-07-099218. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-07-099218v1 111/4/1913    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Briot, D. Articles by Rosselli, F. Search for Related Content PubMed PubMed Citation Articles by Briot, D. Articles by Rosselli, F. Related Collections Hematopoiesis and Stem Cells Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS Aberrant activation of stress-response pathways leads to TNF- oversecretion in Fanconi anemia Delphine Briot1, Gaëtane Macé-Aimé1, Frédéric Subra2, and Filippo Rosselli1 1 Centre National de la Recherche Scientifique (CNRS) FRE2939, Université Paris-Sud, Institut Gustave Roussy, Villejuif, France; 2 CNRS UMR8113, Laboratoire de Biotechnologies et de Pharmacologie génétique Appliquée, Ecole Normale Supérieure, Cachan, France 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 2 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, 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- oversecretion. TNF- may, in turn, sustain or amplify both MAPKs and NF-B activation. Aberrant expression or activity of NF-B 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Dissecting "stress" in Fanconi anemia Inderjeet Dokal Blood 2008 111: 1756-1757. [Full Text] [PDF] This article has been cited by other articles: I. Dokal Fanconi anemia is a highly penetrant cancer susceptibility syndrome Haematologica, April 1, 2008; 93(4): 486 - 488. [Full Text] [PDF]

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