BONE-MARROW FAILURE IN THE FANCONI-ANEMIA GROUP-C MOUSE MODEL AFTER DNA-DAMAGE

Fanconi anemia (FA) is a pleiotropic inherited disease that causes bon e marrow failure in children. However, the specific involvement of FA genes in hematopoiesis and their relation to bone marrow (BM) failure is still unclear. The increased sensitivity of FA cells to DNA cross-l inking agents such as mitomycin C (MMC) and diepoxybutane (DEB), inclu ding the induction of chromosomal aberrations and delay in the G2 phas e of the cell cycle, have suggested a role for the FA genes in DNA rep air, cell cycle regulation, and apoptosis. We previously reported the cloning of the FA group C gene (FAG) and the generation of a Fac mouse model. Surprisingly, the Fac -/- mice did not show any of the hematol ogic defects found in FA patients, To better understand the relationsh ip of FA gene functions to BM failure, we have analyzed the in vivo ef fect of an FA-specific DNA damaging agent in Fac -/- mice, The mice we re found to be highly sensitive to DNA cross-linking agents; acute exp osure to MMC produced a marked BM hypoplasia and degeneration of proli ferative tissues and caused death within a few days of treatment. Howe ver, sequential, nonlethal doses of MMC caused a progressive decrease in all peripheral blood parameters of Fac -/- mice. This treatment tar geted specifically the BM compartment, with no effect on other prolife rative tissues. The progressive pancytopenia resulted from a reduction in the number of early and committed hematopoietic progenitors, These results indicate that the FA genes are involved in the physiologic re sponse of hematopoietic progenitor cells to DNA damage. (C) 1998 by Th e American Society of Hematology.