INACTIVATION OF THE FANCONI-ANEMIA GROUP-C GENE AUGMENTS INTERFERON-GAMMA-INDUCED APOPTOTIC RESPONSES IN HEMATOPOIETIC-CELLS

Hematopoietic progenitor cells (HPC) from mice nullizygous at the Fanc oni anemia (FA) group C locus (FAC -/-) are hypersensitive to the mito tic inhibitory effects of interferon (IFN-gamma). We tested the hypoth esis that HPC from the bone marrow of Fanconi group C children are sim ilarly hypersensitive and that the fas pathway is involved in affectin g programmed cell death in response to low doses of IFN-gamma. In norm al human and murine HPC, IFN-gamma primed the fas pathway and induced both fas and interferon response factor-1 (IRF-1) gene expression. The se IFN-gamma-induced apoptotic responses in HPC from the marrow of a c hild with FA of the C group (FA-C) and in FAC -/- mice occurred at sig nificantly lower IFN doses (by an order of magnitude) than did the apo ptotic responses of normal HPC. Treatment of FA-C CD34(+) cells with l ow doses of recombinant IFN-gamma, inhibited growth of colony forming unit granulocyte-macrophage and burst-forming unit erythroid, while tr eatment with blocking antibodies to fas augmented clonal growth and ab rogated the clonal inhibitory effect of IFN-gamma. Transfer of the nor mal FAC gene into FA-C B-cell lines prevented mitomycin C-induced apop tosis, but did not suppress fas expression or inhibit the primed fas p athway. However, the kinetics of Stat1-phosphate decay in IFN-gamma-tr eated cells was prolonged in mutant cells and was normalized by transd uction of the normal FAC gene. Therefore, the normal FAC protein serve s, in part, to modulate IFN-gamma signals. HPC bearing inactivating mu tations of FAC fail to normally modulate IFN-gamma signals and, as a r esult, undergo apoptosis executed through the fas pathway. This is a U S government work. There are no restrictions on its use.