Fanconi anemia (FA) is a congenital form of aplastic anemia and is transmitted through an autosomal recessive mode. Inactivation of any of the 7 FA genes leads to progressive bone marrow (BM) failure, congenital abnormalities, and a predisposition to malignancy. Since a defect in any of the FA genes leads to a similar clinical phenotype, FA proteins appear to act together physically and functionally in a common pathway. However, the question remains: What role does each FA protein or the FA complex play in hematopoiesis?
Studies using the FA group C mouse model have shown that Fancc–/– hematopoietic stem cells have impaired function shown by reduced repopulating ability and are found at lower numbers in Fancc–/– BM. These results and the fact that BM aplasia in patients with FA is progressive suggest that the FA gene products are required for the maintenance of normal numbers of stem cells and/or for normal stem cell development.
In this issue, Li and colleagues (page 2081) have defined a new phenotype associated with Fancc–/– stem cells. Using 2 simple assays, these authors have evaluated the cycling state of the hematopoietic stem/progenitor cell fraction from Fancc–/– They show that the stem/progenitor-enriched fraction is less quiescent than wild-type (WT) controls showing more bromodeoxyuridine (BrdU) incorporation and fewer cells in G0. They go on to show that the altered cell cycle kinetics in Fancc–/– cells are, at least in part, cell autonomous and do not result from unscheduled DNA synthesis or increased damage and repair. In addition, the increased cycling activity found in Fancc–/– hematopoietic cells does not seem to be a compensatory response related to their proapoptotic phenotype but may indeed contribute to the increased apoptotic response of these cells to cytokines. On the other hand, the defect in cytokine signaling in Fancc–/– hematopoietic cells may contribute to the increased cycling activity. In any case, Li and colleagues clearly demonstrate that an accelerated cycling rate in Fancc–/– cells, whether a direct or indirect consequence of absence of the Fancc gene, is a contributing factor to stem cell exhaustion in FA leading to BM failure.