Carreau M, Gan O I, Liu L, Doedens M, McKerlie C, Dick J E, Buchwald M
Department of Genetics, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
Blood. 1998 Apr 15;91(8):2737-44.
Fanconi anemia (FA) is a pleiotropic inherited disease that causes bone 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-linking agents such as mitomycin C (MMC) and diepoxybutane (DEB), including the induction of chromosomal aberrations and delay in the G2 phase of the cell cycle, have suggested a role for the FA genes in DNA repair, cell cycle regulation, and apoptosis. We previously reported the cloning of the FA group C gene (FAC) and the generation of a Fac mouse model. Surprisingly, the Fac -/- mice did not show any of the hematologic defects found in FA patients. To better understand the relationship of FA gene functions to BM failure, we have analyzed the in vivo effect of an FA-specific DNA damaging agent in Fac -/- mice. The mice were found to be highly sensitive to DNA cross-linking agents; acute exposure to MMC produced a marked BM hypoplasia and degeneration of proliferative tissues and caused death within a few days of treatment. However, sequential, nonlethal doses of MMC caused a progressive decrease in all peripheral blood parameters of Fac -/- mice. This treatment targeted specifically the BM compartment, with no effect on other proliferative 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 response of hematopoietic progenitor cells to DNA damage.
范可尼贫血（FA）是一种多效性遗传病，可导致儿童骨髓衰竭。然而，FA基因在造血过程中的具体作用及其与骨髓（BM）衰竭的关系仍不清楚。FA细胞对丝裂霉素C（MMC）和二环氧丁烷（DEB）等DNA交联剂的敏感性增加，包括染色体畸变的诱导和细胞周期G2期的延迟，提示FA基因在DNA修复、细胞周期调控和细胞凋亡中发挥作用。我们之前报道了FA组C基因（FAC）的克隆以及Fac小鼠模型的构建。令人惊讶的是，Fac-/-小鼠并未表现出FA患者中发现的任何血液学缺陷。为了更好地理解FA基因功能与BM衰竭的关系，我们分析了FA特异性DNA损伤剂在Fac-/-小鼠中的体内作用。发现这些小鼠对DNA交联剂高度敏感；急性暴露于MMC会导致明显的BM发育不全和增殖组织退化，并在治疗后几天内导致死亡。然而，连续给予非致死剂量的MMC会导致Fac-/-小鼠所有外周血参数逐渐下降。这种治疗特异性地针对BM区室，对其他增殖组织没有影响。进行性全血细胞减少是由于早期和定向造血祖细胞数量减少所致。这些结果表明，FA基因参与造血祖细胞对DNA损伤的生理反应。
