Fanon anemia (FA) is a complex genetic disorder characterized by a progressive bone marrow aplasia, chromosomal instability, and the acquisition of malignancies, particularly myeloid leukemia. Eight complementation types (FA-A to FA-H), inferring the existence of eight genes, have been identified in FA patients. The cDNAs of the FA-A, FA-C, and FA-G genes, (FANCA), (FANCC) and (FANCG), respectively, have been identified raising the potential of using gene transfer technology to introduce the functional cDNA into autologous stem cells. Currently the only cure for the uniformly fatal hematopoietic disease in FA patients is HLA identical allogeneic bone marrow umbilical cord blood cell transplantation, a therapy available to only about 30% of patients. Previously, a major limitation in studying the pathogenesis of this hematopoietic disease was the inability to evaluate cellular phenotypes resulting from gene inactivation as well as hematopoietic function following insertion of the correct cDNA into the cell in an in vivo system. The recent development of a murine model containing a disruption of the murine homologue of FANCC (Fanc) now allows studies of these questions. The laboratory has utilized this model and determined that hematopoietic progenitors from mice that are homozygous for a disruption of FancC are hypersensitive to mitomycin c in myeloid progenitor assays similar to the mitomycin c hypersensitivity observed in progenitors cultured from bone marrow cells of FA-C patients. In addition, the investigator has shown that FanC -/- progenitors are predisposed to apoptosis in response to inhibitory cytokines. Recently, the investigator demonstrated that loss of FancC results in a decrease of the long term repopulating ability of freshly isolated bone marrow hematopoietic stem cells. The goal of the studies proposed here are to utilize this murine model to evaluate hematopoietic stem and progenitor cell function in FancC -/- hematopoietic cells, to determine whether introduction of recombinant FancC can restore normal hematopoietic progenitor and stem cell function and to determine whether normal FancC +/+ cells or genetically corrected repopulating stem cells can engraft into FancC -/- mice in the absence of myeloablation.
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