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CHAPTER 15 It is now well established that defects in the normal mechanisms that
control programmed cell death (PCD) occur commonly in human dis-
APOPTOSIS MECHANISMS: eases. Cell numbers in the body are governed not only by cell division,
which determines the rate of cell production, but also by cell death,
RELEVANCE TO THE which dictates the rate of cell loss. In the course of a typical day, an aver-
age adult human produces, and in parallel eradicates, approximately
50 to 70 billion cells, representing approximately 1 million cells per sec-
HEMATOPOIETIC SYSTEM ond. Normally, these two processes of cell division and cell death are
tightly coupled so that no net increase in cell numbers occurs, or so that
such increases represent only temporary responses to environmental
stimuli. However, alternations in the expression or function of the
John C. Reed genes that control PCD can upset this delicate balance, contributing to
or causing disease.
In most cases, PCD occurs by apoptosis. Apoptosis is defined by
SUMMARY its morphologic features. As viewed with the assistance of the light-
(or, preferably, electron-) microscope, the characteristics of the apop-
Apoptosis was originally coined to describe the morphologic features of a totic cell include chromatin condensation and nuclear fragmentation
form of cell death characterized by cell shrinkage, membrane blebbing, and (pyknosis), plasma membrane blebbing, and cell shrinkage. Eventually,
nuclear condensation. This type of cell death occurs in a wide variety of physi- the cell breaks into small membrane-surrounded fragments (apoptotic
ologic contexts, and thus is sometimes referred to as programmed cell death. bodies), which are cleared by phagocytosis, without inciting an inflam-
Apoptosis occurs in all animal species as a means to balance cell proliferation matory response. The release of apoptotic bodies is what inspired the
term “apoptosis” from the Greek, meaning “to fall away from” and con-
with cell loss. The physiologic benefits of apoptosis include eliminating cells juring notions of the falling of leaves in the autumn from deciduous
that are unneeded, defective, or infected, and maintenance of tissue homeo- trees. 1
stasis by continuously renewing adult tissues so as to maintain appropriate In recent years, the molecular machinery responsible for apop-
organ mass. In the hematopoietic system, production of leukocytes is deli- tosis has been elucidated, revealing a family of intracellular proteases,
cately balanced against cell death, until a need arises for rapidly generating caspases (cysteine aspartyl proteases), which are responsible directly
immune and inflammatory cells for combating pathogens. The life span of or indirectly for most of the morphologic and biochemical changes
2,3
hematopoietic cells is regulated by numerous cytokines and lymphokines, as that characterize the phenomenon of apoptosis. Diverse regulators
well as by signals derived from microanatomical niches through cell adhesion of the caspases have also been discovered, including activators and
molecules and other regulators. Defects in the regulation of hematopoietic cell inhibitors of these cell death proteases. Inputs from signal transduc-
life span contribute to myriad diseases, including disorders characterized by tion pathways into the core of the cell death machinery have also been
inappropriate cell accumulation, such as leukemia, lymphoma, and autoim- identified, demonstrating ways of linking environmental stimuli to
cell death responses or cell survival maintenance. Knowledge of the
munity, and diseases where pathologic loss of cells occurs, such as immunode- molecular mechanisms of apoptosis is providing insights into the
ficiency and various blood dyscrasias. pathogenesis of many diseases, revealing strategies for possible novel
treatments.

CASPASES—PROTEASES THAT CAUSE
APOPTOSIS

Intracellular proteases called caspases are responsible for most of the
Acronyms and Abbreviations: ALL, acute lymphocytic leukemia; ALPS, auto- morphologic changes that we recognize as “apoptosis,” as well as many
immune lymphoproliferative syndrome; Asp, aspartic acid; B-CLL, B-cell chronic of the biochemical changes often associated with this route of cell
lymphocytic leukemia; BH, Bcl-2 homology domain; CARDs, caspase recruitment demise. Specifically, activation of a family of intracellular cysteine pro-
domains; caspases, cysteine aspartyl proteases; CLLs, chronic lymphocytic leuke- teases that cleave their substrates at aspartic acid residues, known as
mias; CHOP, C/EBP homologous protein; CML, chronic myelogenous leukemias; “caspases” for cysteine aspartyl-specific proteases. These proteases are
4
CTL, cytolytic T lymphocyte; Cyt-c, cytochrome c; DD, death domain; DEDs, death present as inactive zymogens in essentially all animal cells, but can be
effector domains; DISC, death-inducing signaling complex; DLBCL, diffuse large triggered to assume active states, generally involving their proteolytic
B-cell lymphoma; DR, death receptor; EBV, Epstein-Barr virus; ER, endoplasmic processing at conserved aspartic acid (Asp) residues. During activation,
reticulum; FasL, Fas ligand; FKHD, forkhead transcription factors; IAP, inhibitor of the zymogen proproteins are cleaved to generate the large (~20 kDa)
apoptosis; IBD, inflammatory bowel disease; IgH, immunoglobulin heavy chain; and small (~10 kDa) subunits of the active enzymes, typically liberating
IKKs, I-κB kinases; IL, interleukin; KSV, Kaposi sarcoma virus; MALT, mucosa- an N-terminal prodomain from the processed polypeptide chain. The
associated lymphoid tissue; miRNAs, microRNAs; MLKL, mixed-lineage kinase active enzymes consist of heterotetramers composed of two large and
domain-like; MMs, multiple myelomas; MOMP, mitochondrial outer membrane two small subunits, generally with two active sites per molecule. 2,3
permeabilization; MPT, mitochondrial permeability transition; NHLs, non- The observation that caspases cleave their substrates at Asp res-
Hodgkin lymphomas; NK, natural killer; PARP, poly-ADP ribosyl polymerase; PCD, idues and are also activated by proteolytic processing at Asp residues
programmed cell death; PI3K, phosphatidylinositol 3’-kinase; pro/pre–B-cells, makes evident that these proteases collaborate in proteolytic cascades,
B-lymphocyte progenitors; ROS, reactive oxygen species; TNF, tumor necrosis fac- where caspases activate themselves and each other. Humans contain 11
tor; TNFR1, TNF receptor-1; UBCs, ubiquitin conjugating enzymes. caspases. They can be subgrouped according to either their amino-acid
sequence similarities or their protease specificities.

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