Studies on the molecular mechanisms of chromosome instability and development of MDS/AML

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Fanconi anemia (FA) is an autosomal recessive disease characterized by bone marrow failure, which is predisposed to development of myelodysplastic syndrome and acute myeloid leukemia, chromosomal instability and hypersensitivity to DNA damaging agents such as mitomycin C.There are at least eight genetically distinct groups (A, B, C, D1, D2, E, F and G) in FA, and thus far six genes (FANCA, C, D2, E, F and G) have been cloned. Multiple FA proteins encoded by these genes have been shown to cooperate in a molecular pathway, which is critical in the maintenance of genomic stability in hematopoietic stem cells. Our purpose is to clarify molecular pathogenesis in Japanese FA patients, based on the new understanding of pathophysiology of FA.In order to study structure-function relationship of FANCA, we established multiple transformants stably expressing various mutant FANCA proteins in FANCA(-) cells and are analyzing several functions of these cells. Also, we detected some FANCA-interacting proteins using yeast two-hybrid and co-immunopecipitation and are studying functional significance of these interactions. We developed a diagnostic method to identify abnormalities of FA genes, using protein analyses and functional complementation of patient cells with retroviral transduction of wildtype FA genes. We detected some mutations characteristic to the Japanese population. Our data indicate that analyses of FANCD2 ubiquitination is a reliable diagnostic tool for FA.