Hematopoietic stem cells (HSCs) are characterized by two distinct abilities, that is, self-renewal ability and multipotency. To keep the homeostasis of hematopoiesis and protect the exhaustion of HSCs throughout the life, most of HSCs are kept quiescent and only a limited number of HSCs enter cell cycle to supply mature blood cells. Cell cycle state of HSCs is crucially regulated by external factors such as cytokines, Notch ligands, and Wnt signals in the bone marrow (BM) microenvironment, so called hematopoietic niche. In addition, the intrinsic factors expressed in HSCs such as c-Myc, c-Myb, GATA-2, HOX family proteins, and Bmi-1 also control their growth through the gene transcription. Cell cycle regulation in HSCs is not so unique but rather common to other cell types. However, the specific function of each cell cycle regulatory molecule in HSCs has been clarified during the last few years. Especially, p21WAF1 and p18INK4C keep the quiescence of HSCs and p27CIP1 keeps that of progenitor cells, respectively, thereby governing their pool sizes and/or preventing their exhaustion. On the other hand, inactivation or deletion of p16INK4A and p15INK4B genes is supposed to contribute to malignant transformation of hematopoietic cells. These results imply that appropriate cell cycle control at the stage of stem/progenitor cells in the BM is required for maintaining normal hematopoiesis.
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