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New insights from Fanconi anemiaStudy of rare genetic diseases often leads to significant advances in the understanding of cancer biology in general. Such is the case for Fanconi anemia (FA), a rare cancer susceptibility syndrome with an incidence of only 1 in 300 000 live births. Two papers in this issue provide new mechanistic insights to the function of the Fanconi anemia pathway and its possible role in the pathogenesis of sporadic leukemia in the general (non-FA) population.FA patients have congenital abnormalities, progressive bone marrow failure, and a predisposition to acute myeloid leukemia (AML), among other cancers. Seven FANC genes (corresponding to subtypes A, C, D1, D2, E, F, and G) have been cloned, and the encoded FANC proteins interact in a novel cellular pathway. The FANCD1 gene is identical to BRCA2, the well-known breast cancer susceptibility gene, thus linking the FA pathway to the BRCA2 homologous recombination DNA repair machinery. Disruption of the FA pathway leads to the common clinical and cellular phenotype observed in FA patients. Gordon and Buchwald (page 136) describe new molecular interactions among FANC proteins in the FA pathway. Using 2-hybrid and 3-hybrid strategies, the authors define specific interactions between the G and A subunits, the G and F subunits, the E and C subunits, and the E and D2 subunits. Since FA patient—derived mutations disrupt these interactions, the subunit contacts appear to be critical for the integrity of the FA pathway and for the mechanisms underlying DNA repair and chromosome stability. These protein-protein contacts also provide useful biochemical information for investigators exploring the crystal structure of the FA protein complex. Lensch and colleagues (page 7) examine the possible role of FA pathway disruption in the pathogenesis of sporadic AML in the general population. These investigators identify an AML cell line with phenotypic features reminiscent of primary FA cells: namely, chromosome instability, crosslinking sensitivity, and an inability to activate (mono-ubiquitinate) the downstream Fanconi anemia protein, FANCD2. Interestingly, this AML cell line was functionally complemented with the FANCA cDNA, but not with other FANC cDNA's. These results suggest that an acquired (somatic) defect in the FA pathway may have contributed to chromosome instability and drug sensitivity during AML progression. While no mutations were found in the FANCA gene of these AML cells, these data suggest a more subtle defect in FANCA expression or function. The authors propose that the AML blasts, but not the lymphoblasts derived from the same patient, may be deficient in cofactors that promote the nuclear localization or FANCG binding of FANCA. Regardless of the mechanism, the work suggests that acquired disruption of the FA/BRCA pathway will be observed in at least a fraction of AML patients, thus allowing predictions of drug responsiveness. Taken together, these 2 papers underscore the importance of FA research in elucidating the fundamental mechanism of chemotherapy sensitivity and cancer progression in the general population.
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| Copyright © 2003 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
