Functional aspects of apoptosis in hematopoiesis and consequences of failure.

Apoptosis is an internally directed, physiological method of cell destruction. Cellular components are dismantled within the confines of an intact cell membrane, and rapid ingestion by phagocytic cells prevents local inflammation. A variety of genes have now been identified as positive or negative regulators of apoptosis. Transfection experiments and studies of gene cooperation in viral transformation suggest that full cellular transformation requires not only the deregulation of proliferation, but also the inhibition of concomitant apoptosis programs. The regulation of apoptosis is fundamental to hematopoietic homeostasis. Stem cell renewal is continuously counterbalanced by apoptosis in functionally inactive or terminally differentiated cells. Extensive cell death in developing lymphocyte populations ensures that only cells recognizing non-self antigens are released into the periphery, and the finite lifespan of terminally differentiated cells enables the extensive cell turnover demanded by functional aspects of the hematopoietic system. The requirement of each hematopoietic sub-population for a specific sub-set of survival factors, provides a flexible mechanism for dictating the cellular composition of the mature population and for controlling population size. Surplus cell production and apoptosis are therefore normal features of hematopoiesis. The consequences of deregulated apoptosis are severe. Excessive apoptosis in lymphocyte populations plays a major role in the pathogenesis of acquired immunodeficiency syndrome (AIDS), whereas ineffective apoptosis has been associated with the development of inflammation, autoimmunity and hematological malignancies. The identification of various genetic abnormalities which influence apoptosis in leukaemic cells (e.g., mutant p53, Bcr-Abl and over-expression of Bcl-2), suggests that the acquisition of an anti-apoptotic lesions is an important event in the multi-step evolution of hematological malignancies. In addition, the nature of some leukaemias particularly the chronic leukemias, in which the leukemic cells are nonproliferative and long lived, suggests that anti-apoptotic lesions are early events in the pathogenesis of these diseases. It is likely that the utilization of mechanisms to evade apoptosis would facilitate disease progression in all leukemias and contribute to the development of multi-drug resistance. A better understanding of apoptosis mechanisms in hematopoietic cells, and their exploitation by leukemic cells should be useful in the development of improved cytotoxic regimes.