Fanconi anemia (FA) is a genetic syndrome manifested by bone marrow failure, physical anomalies, and cancer susceptibility. The hallmark of the FA cell is hypersensitivity to bifunctional alkylating agents such as mitomycin C (MMC), a feature enabling diagnostic testing for FA as well as classification of the different FA complementation groups (and gene mutations). Marked by both genotypic and phenotypic heterogeneity, FA can be divided into at least five such groups: A, B, C, D, E. The defective gene responsible for the C group (FAC) was identified in 1992. In studies aimed at studying the function of FAC, we used the yeast two-hybrid method to identify a novel interaction between FAC and glucose-regulated protein (GRP94). GRP94, also known as endoplasmin or gp96, is an abundant member of the 90 kD molecular chaperone family, present in the endoplasmic reticulum (ER) where it plays a role in protein transit. GRP94 is induced in response to stress and protects against various forms of cellular stress. The interaction of FAC with GRP94 may recruit cellular proteins to repair DNA or may modify cellular apoptosis. We have shown that wild-type FAC can suppress cell apoptosis induced by growth factor deprivation. Recently, we also documented in a transgenic mouse model that overexpression of human FAC protects trangenic hematopoietic progenitors from Fas-mediated apoptosis. Furthermore, complementation of mutant hematopoietic cells by transfer of the normal FAC gene markedly enhances colony formation. These studies suggest that bone marrow failure in FA may be related to an exaggerated susceptibility to apoptosis and that complementation with the normal FAC gene may be a useful therapeutic strategy. Currently, a trial of hematopoietic progenitor cell transduction is being conducted at the Clinical Center of the National Institutes of Health for FA-C patients lacking a compatible BMT donor. This pilot study seeks to determine the feasibility of FAC gene transduction of hematopoietic progenitor and stem cells from patients with FAC mutations. The mutations of patients on study include the three major categories of FAC mutations: exon 1, exon 14, and intron 4. The study thus far has confirmed that transfer of the FAC gene to multipotential progenitor cells is possible. Function of the wild-type FAC gene is suggested by the marked increase in progenitor numbers and MMC-resistant colonies with successive cycles of gene transduction in the three patients studied.
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