Survival and cell cycle control in early hematopoiesis: role of bcl-2, and the cyclin dependent kinase inhibitors P27 and P21.

Homeostasis of the hematopoietic system is maintained by proliferation and differentiation of a small number of long-term surviving, self-renewing stem cells, which give rise to the fully mature elements. The fine interplay between differentiation, proliferation and death by apoptosis determines the equilibrium of this system. Thus, genes involved in the control of these processes are very important in the regulation and development of hematopoietic cells especially in the initial stages. The interactions among cyclins, their specific cyclin-dependent kinases (CDKs) and, a number of cyclin-dependent kinase inhibitors (CDKIs) such as p27 and p21, exert a direct control on the cell cycle but can also produce other independent effects on hematopoietic differentiation. Proteins of the Bcl-2 family are also crucial in regulating the balance between entry into apoptosis and survival capacity and their roles change in the course of differentiation. In addition, a number of autocrine and paracrine soluble factors (such as TGF-beta1) modulate the behavior and differentiation potential of hematopoietic elements. Studies on a few in vitro systems of early hematopoietic differentiation have stressed the importance of Bcl-2 and of the CDKIs p27 and p21 at this stage, have confirmed cell-cycle independent effects and have demonstrated how the modulation and the effects in response to different stimuli is mostly dependent on the differentiation stage of the target cells.