Bone Marrow Failure Secondary to Cytokinesis Failure
Technical Report,30 Sep 2012,29 Sep 2015
Dana-Farber Cancer Institute Boston United States
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Fanconi anemia FA is a human genetic disease characterized by a progressive bone marrow failure and heightened susceptibility to cancer. The main objective of our project was to understand the mechanisms of bone marrow failure in FA. The specific objective was to determine the role of cytokinesis failure of hematopoietic stem cells in the pathogenesis of bone marrow failure in FA. During the award period, we have assessed the role of FA pathway in mitosis and confirmed that murine FA-deficient hematopoietic stem cells exhibit p53-mediated growth defects, cytokinesis failure and apoptosis. In order to study the role of bone marrow microenvironment in bone marrow failure in FA, we have also evaluated primary FA-deficient bone marrow stromal cells for mitotic defects. Interestingly, these cells also exhibit cytokinesis defects. Collectively, our results suggest that bone marrow failure in FA may be caused, in part, by p53-mediated cellular defects and underscore the importance of therapeutically targeting p53 in FA.