Inactivation of the Fanconi Anemia Group C Gene Augments Interferon-γ–Induced Apoptotic Responses in Hematopoietic Cells

• Published in: Blood Vol. 90; no. 3; pp. 974 - 985
• Main Authors: Rathbun, R. Keaney, Faulkner, Gregory R., Ostroski, Marika H., Christianson, Tracy A., Hughes, Grant, Jones, Gary, Cahn, Robert, Maziarz, Richard, Royle, Gordon, Keeble, Winifred, Heinrich, Michael C., Grompe, Markus, Tower, Paula A., Bagby, Grover C.
• Format: Journal Article
• Language: English
• Published: 01.08.1997
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V90.3.974.974_974_985

Hematopoietic progenitor cells (HPC) from mice nullizygous at the Fanconi anemia (FA) group C locus (FAC −/−) are hypersensitive to the mitotic inhibitory effects of interferon (IFN-γ). We tested the hypothesis that HPC from the bone marrow of Fanconi group C children are similarly hypersensitive and that the fas pathway is involved in affecting programmed cell death in response to low doses of IFN-γ. In normal human and murine HPC, IFN-γ primed the fas pathway and induced both fas and interferon response factor-1 (IRF-1) gene expression. These IFN-γ-induced apoptotic responses in HPC from the marrow of a child with FA of the C group (FA-C) and in FAC −/− mice occurred at significantly lower IFN doses (by an order of magnitude) than did the apoptotic responses of normal HPC. Treatment of FA-C CD34+ cells with low doses of recombinant IFN-γ, inhibited growth of colony forming unit granulocyte-macrophage and burst-forming unit erythroid, while treatment with blocking antibodies to fas augmented clonal growth and abrogated the clonal inhibitory effect of IFN-γ. Transfer of the normal FAC gene into FA-C B-cell lines prevented mitomycin C–induced apoptosis, but did not suppress fas expression or inhibit the primed fas pathway. However, the kinetics of Stat1-phosphate decay in IFN-γ–treated cells was prolonged in mutant cells and was normalized by transduction of the normal FAC gene. Therefore, the normal FAC protein serves, in part, to modulate IFN-γ signals. HPC bearing inactivating mutations of FAC fail to normally modulate IFN-γ signals and, as a result, undergo apoptosis executed through the fas pathway.