Apoptosis was originally coined to describe the morphologic features of a form of cell death characterized by cell shrinkage, membrane blebbing, and nuclear condensation. This type of cell death occurs in a wide variety of physiologic contexts, and thus is sometimes referred to as programmed cell death. Apoptosis occurs in all animal species as a means to balance cell proliferation with cell loss. The physiologic benefits of apoptosis include eliminating cells that are unneeded, defective, or infected, and maintenance of tissue homeostasis by continuously renewing adult tissues so as to maintain appropriate organ mass. In the hematopoietic system, production of leukocytes is delicately balanced against cell death, until a need arises for rapidly generating immune and inflammatory cells for combating pathogens. The life span of hematopoietic cells is regulated by numerous cytokines and lymphokines, as well as by signals derived from microanatomical niches through cell adhesion molecules and other regulators. Defects in the regulation of hematopoietic cell life span contribute to myriad diseases, including disorders characterized by inappropriate cell accumulation, such as leukemia, lymphoma, and autoimmunity, and diseases where pathologic loss of cells occurs, such as immunodeficiency and various blood dyscrasias.
Acronyms and Abbreviations
ALL, acute lymphocytic leukemia; ALPS, autoimmune lymphoproliferative syndrome; Asp, aspartic acid; B-CLL, B-cell chronic lymphocytic leukemia; BH, Bcl-2 homology domain; CARDs, caspase recruitment domains; caspases, cysteine aspartyl proteases; CLLs, chronic lymphocytic leukemias; CHOP, C/EBP homologous protein; CML, chronic myelogenous leukemias; CTL, cytolytic T lymphocyte; Cyt-c, cytochrome c; DD, death domain; DEDs, death effector domains; DISC, death-inducing signaling complex; DLBCL, diffuse large B-cell lymphoma; DR, death receptor; EBV, Epstein-Barr virus; ER, endoplasmic reticulum; FasL, Fas ligand; FKHD, forkhead transcription factors; IAP, inhibitor of apoptosis; IBD, inflammatory bowel disease; IgH, immunoglobulin heavy chain; IKKs, I-κB kinases; IL, interleukin; KSV, Kaposi sarcoma virus; MALT, mucosa-associated lymphoid tissue; miRNAs, microRNAs; MLKL, mixed-lineage kinase domain-like; MMs, multiple myelomas; MOMP, mitochondrial outer membrane permeabilization; MPT, mitochondrial permeability transition; NHLs, non-Hodgkin lymphomas; NK, natural killer; PARP, poly-ADP ribosyl polymerase; PCD, programmed cell death; PI3K, phosphatidylinositol 3’-kinase; pro/pre–B-cells, B-lymphocyte progenitors; ROS, reactive oxygen species; TNF, tumor necrosis factor; TNFR1, TNF receptor-1; UBCs, ubiquitin conjugating enzymes.
It is now well established that defects in the normal mechanisms that control programmed cell death (PCD) occur commonly in human diseases. Cell numbers in the body are governed not only by cell division, which determines the rate of cell production, but also by cell death, which dictates the rate of cell loss. In the course of a typical day, an average adult human produces, and in parallel eradicates, approximately 50 to 70 billion cells, representing approximately 1 million cells per second. Normally, these two processes of cell division and cell death are tightly coupled so that no net increase in cell numbers occurs, or so thatsuch increases represent only temporary responses to environmental stimuli. However, alternations in the expression or function of the genes that control PCD can upset this delicate ...