HEMATOPOIESIS Functional correction of FA-C cells with FANCC suppresses the expression of interferon g–inducible genes

Because hematopoietic cells derived from Fanconi anemia (FA) patients of the C-complementation group (FA-C) are hyper-sensitive to the inhibitory effects of inter-feron g (IFNg), the products of certain IFNg-inducible genes known to influence hematopoietic cell survival were quanti-fied. High constitutive expression of the IFNg-inducible genes, IFN-stimulated gene factor 3 gamma subunit (ISGF3g), IFN regulatory factor-1 (IRF-1), and the cyclin-dependent kinase inhibitor p21WAF1 was found in FANCC mutant B lympho-blasts, low-density bone marrow cells, and murine embryonic fibroblasts. Para-doxically, these cells do not activate sig-nal transducer and activator of transcrip-tion (STAT) 1 properly. In an attempt to clarify mechanisms by which FA-C cells overexpress IFNg-inducible genes in the face of defective STAT1 phosphorylation, it was reasoned that decreased levels of activated STAT1 might result in reduced expression of a hematopoietic IFNg-re-sponsive protein that normally modu-lates expression of other IFNg-respon-sive genes. Levels of the IFNg-inducible factor IFN consensus sequence binding protein (ICSBP), a negative trans-acting regulator of some IFNg-inducible genes, were quantified. ICSBP levels were re-duced in FA-C B lymphoblasts and MEFs. However, enforced expression of ICSBP failed to down-regulate IRF-1, ISGF3g, and p21WAF1. Thus, the FANCC protein functions to modulate expression of a family of genes that in normal cells are inducible only by specific environmental cues for apoptosis or mitogenic inhibi-tion, but it does so independently of the classic IFN-STAT1 pathway and is not the direct result of reduced ICSBP expression. (Blood. 2001;97:3017-3024) © 2001 by The American Society of Hematolog