Cell cycle control genes and hematopoietic cell differentiation

To maintain the fidelity and integrity of blood formation, the cell cycle is under strict regulation during hematopoietic cell differentiation. This review summarizes recent studies, including our own, on the expression of cell cycle control genes in hematopoietic stem cells and its changes during differentiation. In our study, mRNA expression of cyclin-dependent kinases (cdks) and cyclins, except cdk4, was found to be generally suppressed in CD34+ cells isolated from the bone marrow of healthy volunteers. Among four major cdk inhibitors, p16 was expressed higher in CD34+ cells than in CD34 bone marrow mononuclear cells, whereas the amounts of p21 and p27 transcripts increased in the CD34 population. The behavior of cell cycle control genes during hematopoietic differentiation was classified into four patterns: (i) universal up-regulation (cdc2, cdk2, cyclin A, cyclin B, p21); (ii) up-regulation in specific lineages (cyclin D1, cyclin D3, and p5); (iii) no induction or stable expression (cdk4, cyclin D2, cyclin E, and p27); and (iv) universal down-regulation (p16). Lineage-specific changes include a sustained elevation of cdc2 and cyclin A during erythroid differentiation, cyclin D1 and p15 induction in myeloid lineage cells, and selective up-regulation of cyclin D3 during megakaryocyte development. These results suggest that the expression of cell cycle control genes is distinctively regulated in a lineage-dependent manner, reflecting the cell cycle characteristics of each lineage. Additional data from other laboratories are summarized and their significance is discussed in comparison with our findings.