Increased sensitivity of Fancc-deficient hematopoietic cells to nitric oxide and evidence that this species mediates growth inhibition by cytokines

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Abstract
Fanconi anemia complementation group C (Fancc)–deficient murine bone marrow progenitors demonstrate increased sensitivity to growth inhibition by interferon γ (IFNγ), tumor necrosis factor α (TNFα), and macrophage inflammatory protein 1α (MIP-1α). This property has been proposed as a possible pathogenic factor in the marrow failure seen in Fanconi anemia. Supporting our hypothesis that nitric oxide (NO) production might be a common effector in this sensitivity, we found that cytokine-mediated growth inhibition ofFancc −/− bone marrow cells was prevented by inhibiting NO synthase activity. Interestingly,Fancc −/− hematopoietic cells also exhibited increased growth inhibition on exposure to 2 distinct NO-generating agents, S-nitroso-N-acetyl-D, L-penicillamine (SNAP) and diethylenetriamine nitric oxide adduct (DETA/NO). In keeping with the sensitivity of Fancc −/− cells to IFNγ, inducible nitric oxide synthase (iNOS) levels and nitrite release were both increased following stimulation ofFancc −/− macrophages with this cytokine, either alone or in combination with bacterial lipopolysaccharide. Suggesting a plausible mechanism for the increased expression of iNOS, IFNγ-stimulated Fancc −/− macrophages generated higher levels of phospho-Stat1, a positive regulator ofinos (nos2) gene expression. These observations, while confined to C57BL/6 Fancc −/−hematopoietic cells, raise the possibility that nitric oxide has a role in the pathogenesis of Fanconi anemia.