Fanconi anemia (FA) is an autosomal recessive disorder characterized by congenital malformations, chromosomal instability, a progressive aplastic anemia, and an increased incidence of malignancy. Inhibitory cytokines such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) have been implicated in the development of acquired bone marrow failure syndromes, and TNF-α and macrophage inflammatory protein-1 alpha(MIP-1α) are elevated in the serum of FA patients. We used a murine model containing a disruption of the murine homologue (Fac) of Fanconi Anemia group C (FAC) to evaluate the role of inhibitory cytokines in the pathogenesis of bone marrow failure in FA. Methylcellulose cultures of bone marrow cells from Fac -/- and Fac+/+ mice were established to examine the growth of multipotent and lineage restricted progenitors containing inhibitory cytokines including IFN-γ, TNF-α, and MIP-1α. Clonogenic growth of Fac -/- progenitors was reduced by 50% at 50-100 fold lower concentrations of all inhibitory cytokines evaluated. We hypothesized that the aberrant responsiveness to inhibitory cytokines in clonogenic cells may be a result of deregulated apoptosis. To test this hypothesis, we performed the TUNEL assay on purified populations of primary bone marrow cells enriched for hematopoietic progenitors or differentiated myeloid cells in four independent experiments. Following stimulation with TNF-α, accentuated apoptosis was observed in both populations of Fac -/- cells evaluated. In addition, deregulated apoptosis was noted in the most immature phenotypic population of hematopoietic cells following stimulation with MIP-1α. Together these data suggest a role of Fac in affecting the signaling of multiple cytokine pathways and support cytokine-mediated apoptosis as a major mechanism responsible for bone marrow failure observed in FA patients.

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