Fanconi anemia (FA) is an autosomal recessive disease manifesting regressive bone marrow failure, skeletal abnormalities, altered skin pigmentation, developmental defects, decreased fertility, chromosome instability and increased risk of acute myelogenous leukemia. Therefore FA presents bone marrow stem cell failure with risk of leukemia. It couples genome instability with clonal tumor development. This Program Project will use a multidisciplinary approach to understanding the molecular defects in FA and developing therapy for the disease. Clinical disciplines represented by the investigators include medicine, pediatrics, medical genetics, hematology and oncology. Scientific areas include molecular hematology, molecular genetics, mouse genetics, gene therapy, stem cell biology and DNA repair. The proposed Program will have three investigative units and three support core components: Project 1 will investigate functions of the FANC proteins as mechanisms for genome stability and tumor suppression. The work will test whether the FA pathway is directly involved in genome stability via chromatin remodeling and whether FANCD2 interacts in a complex with DNA processing proteins from other pathways. Project 2 will develop novel practical and useful therapies for FA. The work will utilize new methods of gene therapy based on site-specific recombination and develop rational small molecule therapy for pre-clinical testing. Existing mouse models of FA are key tools for this work. Project 3 will determine the function of FANC proteins in signaling in stem cells as a means to understanding the anemia of FA and the failure of STAT signal transduction in FA cells. Work will also address the loss of apoptotic cues for these cells in clonal development of leukemia. The Cytogeneties Core will serve a critical role since analysis of chromosome breakage will be the end point for many of the proposed studies. The Cell Repository Core will characterize FA cells lines as to complementation group and provide investigators with isogenic FA lines, corrected and uncorrected, for comparative trials in the above projects. The Administrative Core will be responsible for organization of all meetings and financial management.
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