CONSTITUTIVE AND INDUCED EXPRESSION OF HEMATOPOIETIC GROWTH-FACTOR GENES BY FIBROBLASTS FROM CHILDREN WITH FANCONI-ANEMIA

The pathophysiological abnormalities leading to marrow failure and leu kemogenesis in children with Fanconi anemia (FA) are not understood. W e tested the hypothesis that the Fanconi anemia mutation results in in sufficient production of hematopoietic growth factors by stromal cells by quantifying constitutive and induced production of interleukin-6 ( IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), gran ulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulati ng factor (M-CSF), and steel factor (SF) by untransformed fibroblasts from eight patients with FA from five different families. While no abn ormalities were noted in SF or M-CSF production, we noted substantial variability in IL-6, GM-CSF, and G-CSF responses of cells obtained fro m different FA patients. Responses ranged from blunting to augmentatio n when compared to normal controls. Because there was variation betwee n fibroblast strains from affected members of two multiplex sibships, however, it is clear that neither augmentation nor blunting is a direc t effect of the FA mutations. In addition, because there was discordan ce between the G-CSF responses and the GM-CSF and IL-6 responses, the abnormalities noted in IL-1 responsiveness must lie distal to IL-1 rec eptor function and to stimulus-response coupling pathways shared betwe en the three cytokines.