MOLECULAR BIOLOGY OF GENETIC BONE MARROW FAILURE SYNDROMES

Heart, Lung, And Blood Institute

Investigators

Abstract

Fanconi anemia (FA) is a rare genetic disorder that leads to aplastic anemia and predisposes to cancer (particularly myeloid leukemia). To date, four FA genes, FANCA, FANCC, FANCF, and FANCG, have been identified, although the biochemical function of each encoded protein is unknown. We have sought to understand the pathophysiology of FA using transgenic and knock-out mouse models. We discovered that overexpression of FANCC protects hematopoietic cells from apoptosis induced by ligation of the Fas death receptor, a member of the tumor necrosis factor (TNF) receptor superfamily. Conversely, hematopoietic cells from Fancc gene knock-out mice are hypersensitive to TNF-alpha and Fas-mediated cell death. These findings point to a link between FA gene products and an important apoptosis pathway mediated by death receptors. In order to understand the mechanism for this, we searched for potential protein interactions between FA gene products and both cloned and unknown proteins. We discovered that the FANCA protein interacts with I kappa B kinase-2 (IKK-2). IKK-2 is a cytokine-activated I kappa B kinase and member of a multiprotein complex, the IKK signalsome, that is essential for nuclear factor-kappa B (NF-kappa B) activation. In turn, NF-kappa B is involved in preventing TNF-alpha-induced cell death. FA gene products appear to be novel targets of the IKK signalsome, distinct from the activation pathway for NF-kappa B. Finally, based upon our prior findings that the FA proteins may influence the viability of hematopoietic cells, we developed gene transfer strategies aimed at correcting the hematopoietic defect and testing the hypothesis that gene-corrected cells have a survival advantage.