In order for steady-state levels of the various hematopoietic cells to be maintained, cell division and differentiation in each of the lineages is balanced by a process called programmed cell death. Cells undergoing programmed cell death often exhibit distinctive morphologic changes, collectively referred to as apoptosis. These changes include a pronounced decrease in cell volume, modification of the cytoskeleton-resulting in

pronounced membrane blebbing, a condensation of the chromatin, and degradation of the DNA into oligonucle

osomal fragments. Following these morphologic changes, an apoptotic cell sheds tiny membrane-bound apoptotic

bodies containing intact organelles. Macrophages quickly phagocytosis apoptotic bodies, ensuring that their intra

cellular contents, including proteolytic and other lytic enzymes, cationic proteins, and oxidizing molecules are not released into the surrounding tissue. In this way app

tosis occur without inducing a localized inflammatory response. Apoptosis differs markedly from necrosis, the changes associated with cell death arising from injury. In necrosis the injured cell swells and bursts, releasing its intracellular contents, which are cytotoxic to other cells in the tissue; as a result, an inflammatory response develops.

Each of the cells produced by hematopoiesis has a characteristic life span and then dies by programmed cell death. In the adult human, for example, there are about 5 X 1010 neutrophils in the circulation. These cells have

a life span of only 1 day and then die by programmed cell death. This death, coupled with constant neutrophil production, maintains steady-state levels of these cells. If programmed cell death fails to occur, a leukemic state may develop. Programmed cell death also plays a role in maintaining proper levels of hematopoietic progenitor cells.

For example, when colony-stimulating factors are removed, progenitor cells undergo programmed cell death.

The expression of several genes has been associatedwith the regulation of apoptosis in hematopoietic cell lineages. Some of these gene products induce apoptosis, whereas other gene products inhibit apoptosis.

The bcl-2 (B-cell lymphoma 2) gene, for example, encodes a protein product that inhibits apoptosis.

Bcl-2 levels have been found to play an important role in regulating the normal life span of various hematopoietic cell lineages, including lymphocytes.

Activated lymphocytes have been found to express lower levels of Bcl-2 and therefore are more susceptible to apoptotic death than native lymphocytes or memory cells.