[Science, 2000,287(5459):1804-1808]

Relative quiescence is a defining characteristic ofhematopoietic stem cells, while their progeny have dramatic proliferative ability andinexorably move toward termnial defferentiation.The quiescence of stem cells has beenconjectured to be of critical biologic importance in protecting the stem cell compartment,which we directly assessed using mice engineered to be deficient in the G1 checkpointregulator, cyclin-dependent kinase inhibitor, p21 cip1/waf1 (p21). In the absence of p21,hematopoietic stem cell proliferation and absolute number were increased under normalhomeostatic conditions.Exposing the animals to cell cycle-specific myelotoxic injuryresulted in premature death due to hematopoietic cell depletion. Further, self-renewal ofprimitive cells was impaired in serially transplanted bone marrow from p21-/- mice,leadingto hematopoietic failure. Therefore, p21 is the molecular switch governing the entry ofstem cells into the cell cycle, and in its absence, increased cell cycling leads to stemcell exhaustion. Under conditions of stress, restricted cell cycling is crucial to preventpremature stem cell depletion and hematopoietic death. (Cheng T(程 涛))