MULTIPLE INHIBITORY CYTOKINES INDUCE DEREGULATED PROGENITOR GROWTH AND APOPTOSIS IN HEMATOPOIETIC-CELLS FROM FAC(- -) MICE/

We used a murine model containing a disruption of the murine homologue (Fac) of Fanconi Anemia group C (FAC) to evaluate the role of Fac in the pathogenesis of bone marrow (BM) failure. Methylcellulose cultures of BM cells from Fac(-/-) and Fac(+/+) mice were established to exami ne the growth of multipotent and lineage-restricted progenitors contai ning inhibitory cytokines, including interferon-gamma (IFN-gamma), tum or necrosis factor-alpha (TNF-alpha), and macrophage inflammatory prot ein-1 alpha (MIP-1 alpha). Clonogenic growth of Fac(-/-) progenitors w as reduced by 50% at 50- to 100-fold lower concentrations of all inhib itory cytokines evaluated. We hypothesized that the aberrant responsiv eness to inhibitory cytokines in clonogenic cells may he a result of d eregulated apoptosis. To test this hypothesis, we performed the TUNEL assay on purified populations of primary BM cells enriched for hematop oietic progenitors or differentiated myeloid cells. After stimulation with TNF-alpha, accentuated apoptosis was observed in both populations of Fac(-/-) cells. In addition, deregulated apoptosis was also noted in the most immature phenotypic population of hematopoietic cells afte r stimulation with MIP-1 alpha. Together these data suggest a role of Fac in affecting the signaling of multiple cytokine pathways and suppo rt cytokine-mediated apoptosis as a major mechanism responsible for BM failure observed in FA patients. (C) 1998 by The American Society of Hematology.