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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 93 No. 11 (June 1), 1999:
pp. 3587-3600
REVIEW ARTICLE
Biochemical and Genetic Control of Apoptosis: Relevance to Normal
Hematopoiesis and Hematological Malignancies
By
R. Gitendra Wickremasinghe and
A. Victor Hoffbrand
From the Department of Hematology, Royal Free and University College
School of Medicine, London, UK.
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INTRODUCTION |
GENETIC CHANGES involving oncogenes and
tumor suppressor genes contribute to the deregulated expansion of
malignant cells. While some of these changes result in increased
proliferation, others contribute to an increase in cell numbers by
inhibiting apoptosis (programmed cell death).1 Because
cytotoxic drugs or irradiation result in cell killing by apoptosis, the
genetic changes underlying malignancy often reduce the ability of these agents to destroy malignant cells.1,2 The elucidation of the pathways involved in the regulation of apoptosis in normal and
malignant hematopoietic cells is therefore likely to contribute to the
development of improved therepeutic stategies in the treatment of
leukemia and lymphoma. This review first summarizes recent advances in
the understanding of the control of apoptosis. Examples of how this
control is altered in leukemic cells is then described.
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1. MORPHOLOGICAL AND BIOCHEMICAL FEATURES OF APOPTOSIS |
Apoptosis is a tightly regulated form of physiological cell death which
is dependent on the expression of cell-intrinsic suicide machinery.3 Prominent morphological changes include cell
shrinkage, condensation of the nuclear chromatin, fragmentation of the
nucleus, and cleavage of chromosomal DNA at internucleosomal sites,
resulting in the generation of a characteristic ladder pattern of DNA
fragments on electrophoresis. Blebbing of the cell surface results in
the release of membrane-bound apoptotic bodies.3
Phosphatidylserine, which is normally located on the inner face of the
plasma membrane, becomes exposed on the outer surface and provides a
recognition signal for engulfment by phagocytes.4,5 Thus,
apoptosis results in the rapid and efficient removal of superfluous or
damaged cells.
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2. GENETIC STUDIES IN CAENORHABDITIS ELEGANS PROVIDE A
FRAMEWORK FOR UNDERSTANDING PATHWAYS OF APOPTOSIS REGULATION |
Genetic studies in the nematode C elegans have resulted in the
identification of a set of genes involved in the regulation of
apoptosis.6 The ced-3 gene encodes a cysteine
protease, which is homologous to members of the caspase protease family that execute the apoptotic program in mammalian cells (see section 3.1). The ced-4 gene product is required for the activation of CED-3. This activation step is blocked by the CED-9 protein,
which is homologous to mammalian BCL-2. BCL-2 can substitute for CED-9 in blocking apoptosis in C elegans7,8 whereas
overexpression of CED-4 induces apoptosis in mammalian
cells,9 suggesting a high degree of conservation of the
mechanisms of apoptosis regulation. Therefore, the C elegans
model has been of value in the identification of the proteins that
control apoptosis in human cells (see sections 3 and 4).
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3. SIGNAL TRANSDUCTION PROCESSES IN THE REGULATION OF APOPTOSIS |
The induction of apoptosis may conveniently be divided into three
stages: (1) the interaction of the inducing signal with the cell, (2)
biochemical transduction of the death signal, and (3) the execution of
apoptosis. Because different extracellular signals and signal
transduction pathways converge on a final common pathway during the
execution phase, this terminal stage of apoptosis will be summarized first.
3.1. The caspase family of proteases mediates the terminal stages of
apoptotic cell death.
The terminal stages of apoptosis involve the activation of a related
family of proteases, the caspases.10,11 These enzymes possess an essential cysteine residue within their active sites and
cleave substrates adjacent to aspartate residues. The cDNAs encoding 10 caspases have been cloned.10
Caspases are expressed as inactive pro-enzymes. Cleavage of these
pro-caspases adjacent to aspartate residues results in the generation
of active subunits of approximately 10 and 20 kD
(Fig 1). These subunits dimerize, with the
resultant generation of a complete active site.10 The
N-terminal pro-domains (Fig 1) of some pro-caspases, which are removed
during activation, nevertheless play important roles in mediating
regulatory interactions between caspases and other proteins. The
requirement for cleavage adjacent to aspartate residues during caspase
activation, together with the aspartate specificity of caspases, raises
the possibility that cascades of caspase activation events may be
involved in apoptosis regulation (see sections 3.3 and 4.3).
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| Fig 1.
Structure and activation of caspases. The peptide
sequences that contribute to the enzymatically active caspase are shown
in cross-hatch. Asp, aspartate residues at which the inactive
pro-caspase is proteolytically cleaved with the resultant generation of
the active subunits.
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Caspases 3, 6, and 7 are terminal members of caspase cascades and
recognize critical cellular substrates, whose cleavage contributes to
the morphological and functional changes associated with
apoptosis.10 Caspase 3 substrates include poly (ADP-ribose)
polymerase,12,13 an enzyme involved in regulation of DNA
repair and gelsolin, a cytoskeletal protein.14 Caspase 3 activation also results in DNA cleavage via inactivation of an
inhibitor of DNA fragmentation factor, the endonuclease responsible for
internucleosomal cleavage of chromatin.15 Caspase 6 substrates include the nuclear structural protein, lamin.16
Thus, the cleavage of a relatively restricted set of critical caspase
substrates contributes to the apoptotic demise of cells via disassembly
of structural components, cleavage of the genetic material, and
prevention of DNA repair.
3.2. Specific protease inhibitors block cell death by targetting
terminal caspases.
In vitro studies suggest that the inhibitor of apoptosis (IAP) family
of proteins may modulate cell death via abrogation of caspase activity.
These proteins are similar to the baculovirus-encoded caspase inhibitor
p35. IAP1 and 2, XIAP (X-linked IAP) and survivin contain one to three
BIR (baculovirus IAP repeat) motifs that are essential to their
function.17 IAPs 1 and 2 and XIAP specifically target
caspases 3 and 7, which function at the distal end of proteolytic cascades. Therefore, IAP expression may serve to reprieve cells otherwise committed to apoptotic death. However, the Drosophila IAPs
(DIAP-1 and DIAP-2) block apoptosis by direct binding via the BIR
motifs to noncaspase death-inducing proteins encoded by the
reaper, hid, and grim genes.18
Therefore, it is possible that the mammalian IAPs may also inhibit cell
death by mechanisms other than binding to caspases.
The key question regarding cell death regulation concerns the
mechanisms by which caspase activation steps are triggered by apoptotic
signals. Different extracellular signals interact with the caspase
system in different ways.
3.3. Ligation of FAS or the tumor necrosis factor
(TNF) receptor results in the direct activation of
caspases.
FAS and the TNF receptor are structurally related transmembrane
receptor proteins. Their extracellular domains bind FAS ligand and TNF,
respectively, resulting in the formation of receptor trimers. The
cytoplasmic domain of FAS contains a "death domain" (Fig 2), whose elimination results in the
abrogation of cell killing.19 The death domain of FAS
recruits the death domain of the FADD (Fas-associated death domain)
protein following receptor trimerization.20 FADD also
contains a death-effector domain, which mediates interaction with
similar amino acid sequences in the pro-domain of pro-caspase 8.21,22 Trimerization of the FAS/FADD/pro-caspase 8 complex after ligand binding results in the cleavage of the pro-caspase and
generation of active caspase 8. Caspase 8 then cleaves
pro-caspase 3, probably via activation of an unidentified
intermediate caspase (Fig 2).
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| Fig 2.
Signal transduction by FAS. Protein-protein interactions
between the death domains (horizontal stripes) of FAS and FADD and the
death-effector domains (stippled) of FADD and pro-caspase 8 are shown.
Trimerization of receptor complexes after binding of FAS to FAS ligand
results in the cleavage of pro-caspase 8 and the release of active
caspase 8.
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Activation of apoptosis after TNF receptor ligation follows a similar
pattern. However, the TNF receptor does not bind FADD directly, but
does so via a linking protein, TRADD (TNF receptor-associated death
domain).19
3.4. Apoptosis induction by the perforin/granzyme system.
Killing of target cells by cytotoxic T lymphocytes plays a major role
in defense against malignant and virus-infected cells, and contributes
to transplant rejection and autoimmune disease. Killing is preceded by
the release of the contents of cytotoxic T-cell granules, which contain
perforin and the serine proteases granzymes A and B. Perforin forms a
pore in the plasma membrane of the target cell, thereby allowing entry
of granzyme B into the cytosol.23 Granzyme B cleaves and
activates caspase 3 in cell-free systems.24,25 However, the
primary target of granzyme B in intact cells is likely to be caspase
10, whose activation results in the subsequent activation of caspase
3.26 In cell-free systems, the addition of granzyme B
initiates cleavage of several apoptosis-specific substrates and also
induces chromatin condensation. Abrogation of these events by selective
inhibitors suggests that activation of caspase 3 (and possibly of
caspase 7) may be important mediators of apoptosis induction by
cytotoxic T-cell-derived granzyme B.26 However, genetic
studies have shown that the granules of cytotoxic T cells contain
additional cytotoxic components in addition to perforin and granzymes A
and B.27
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4. THE BCL-2 PROTEIN FAMILY |
4.1. The BCL-2 protein family plays a central role in the regulation of
apoptosis.
The 26-kD BCL-2 protein protects cells from the induction of
apoptosis by diverse stimuli, including the withdrawal of survival factors, heat shock, and treatment with DNA damaging
agents.28-30 BCL-2 is the prototype of a family of related
proteins. Other anti-apoptotic family members include
BCL-XL, BCL-w, MCL-1, and A1. In contrast, the BAX, BAK,
and BAD proteins are examples of pro-apoptotic BCL-2 family members
whose overexpression promotes cell killing.30 The conserved
BH1 (BCL-2 homology 1) and BH2 domains of
the anti-apoptotic proteins form a hydrophobic cleft which binds the
BH3 domains of pro-apoptotic family members, at least in
vitro.31,32
The susceptibility of cells to apoptosis is determined in part by the
relative concentrations of pro- and anti-apoptotic BCL-2 family
members. The antagonistic actions of these two groups of proteins have
been attributed to their ability to form heterodimers.33 However, at least some of the dimerization properties of the BCL-2 family may be artefacts induced by detergents in vitro.34
Furthermore, genetic studies suggest that BCL-2 and BAX function
independently of one another in the regulation of
apoptosis.35 Deletion of the BH4 domain of BCL-2 impairs
its ability to block apoptosis without affecting its dimerization with
anti-apoptotic family members.9 Deletion of the BH3 domain
of BAX, which is required for its dimerization, does not impair the
ability of the protein to increase the sensitivity of cells to
cytotoxic agents.36 Therefore, it is plausible that the
actions of pro- and anti-apoptotic members of the BCL-2 family may
determine the sensitivity of cells to apoptosis induction via binding
to a common target rather than to dimer formation.35,36
BCL-2 targets to the outer mitochondrial membrane, the nuclear
envelope, and the endoplasmic reticulum via its C-terminal hydrophobic
domain.30,37,38 However, some studies suggest that BAX
shows a largely diffuse sub-cellular localization, translocating rapidly to the mitochondria (and possibly other organelles) after the
induction of an apoptotic signal.39
The BCL-2 family regulates apoptosis induction via control of the
activation of caspases, apparently by a mechanism involving the release
of mitochondrial cytochrome c.11 However, it is unclear
whether cytochrome c release is a component of the primary apoptosis
induction pathway or a means of amplifying the death signal, as
summarized later (see sections 4.3 and 4.4). The mechanism of
cytochrome c-dependent caspase activation is discussed next.
4.2. Cytochrome c triggers caspase 3 cleavage via activation of
caspase 9.
Three proteins have been purified from the cytosol of HeLa cells which,
when recombined in the presence of adenosine triphosphate (ATP) (or
deoxy ATP), were necessary and sufficient for the cleavage and activation of pro-caspase 3. These proteins, originally designated as Apaf 1, 2, and 3 (Apaf = apoptotic
protease activating factor) have been
characterized.40,41 Apaf 1 contains a central domain with
homology to C elegans CED-4.40 The amino-terminal
domain of Apaf 1 is homologous to the CARDs (caspase
recruitment domains) of some caspases
(Fig 3). The carboxy terminus consists of
several WD repeats, which mediate interactions between certain
regulatory proteins. Apaf 2 was found to be identical to
cytochrome c,40 while Apaf 3 is identical to caspase
9.41
A model11,41,42 for the cytochrome c-dependent activation
of caspase 3 is depicted in Fig 3. In the absence of cytochrome c, the
WD repeat domain prevents interaction of Apaf-1 with pro-caspase 9. Cytochrome c binds Apaf 1, inducing a conformational change that
results in the interaction of Apaf 1 and caspase 9, mediated by the
CARD pro-domains present on both these proteins. Apaf-1 induces the
cleavage and activation of pro-caspase 9 via a mechanism involving
oligomerization of Apaf-1, thus facilitating autocatalytic cleavage of
the pro-caspase.42 Activated caspase 9 now cleaves and
activates caspase 3.
4.3. The BCL-2 protein family apparently regulates the release of
cytochrome c from mitochondria.
Cytochrome c is released from mitochondria during apoptosis induced by
diverse stimuli.11 Overexpression of BCL-2 or
BCL-XL inhibit cytochrome c release induced by etoposide,
actinomycin D, oxidative stress, Fas ligation, or interleukin-3 (IL-3)
withdrawal.43-45 The BAX protein, on the other hand,
triggers redistribution of cytochrome c in the absence of apoptotic
stimuli.46 Thus, BCL-2 and BCL-XL may prevent
apoposis by inhibiting cytochrome c release while BAX favors cell death
by promoting its relocation to the cytosol. However, it is unclear
whether these actions of the BCL-2 family result from the direct
actions of these proteins on mitochondria, which then initiate caspase
activation or whether cytochrome c release is secondary to BCL-2
family-regulated caspase activation and plays a subsequent role in
amplification of the apoptotic signal.47
Some evidence suggests a direct role for the BCL-2 family in regulating
cytochrome c release. The structure of BCL-XL resembles that of pore-forming bacterial toxins.31 BCL-2,
BCL-XL, and BAX form ion channels in
vitro.48-50 Because pores formed by BAX protein may show
high conductance values under some conditions,50 it is
possible that these channels allow the exit of cytochrome c.
Anti-apoptotic proteins including BCL-2 may block release by interfering with pore formation by BAX.50 However, channel
formation by BCL-2 family proteins has only been shown in synthetic
membranes and, in some cases, at nonphysiological pH.48-50
Therefore, it has not been established that these proteins can form
channels in cellular membranes under physiological conditions.
An alternative hypothesis suggests that BCL-2 family proteins regulate
the electrical potential gradient (  m) across the
inner mitochondrial membrane and thereby regulate mitochodrial volume.
The opening of "megachannels" in the inner membrane allows the
passage of molecules of less than 1.5 kD, resulting in the dissipation
of m. Apoptosis induced by stimuli including antineoplastic drugs and glucocorticoids is apparently preceded by
disruption of the gradient. Both the loss of m and
subsequent apoptosis induction are blocked by the megachannel
antagonist bongkrekic acid or by overexpression of BCL-2 or
BCL-XL.51,52 Therefore, changes in the
permeability of the inner mitochondrial membrane may be a central
coordinating event in the induction of apoptosis, which is inhibited by
anti-apoptotic BCL-2 family members.51 The reported ability
of BCL-2 to modulate ion fluxes across the inner mitochondrial
membrane53 is compatible with this hypothesis. The precise
mechanistic relationship between loss of m and
cytochrome c release has not been established. However, because loss of
m results in mitochondrial swelling, m loss may cause cytochrome c release as a result of
outer membrane rupture.45
It is now apparent that the BCL-2 family regulates steps in apoptotic
signaling distal to cytochrome c release. BCL-2 overexpression blocks
apoptosis in cells containing high concentrations of cytosolic cytochrome c, induced either by transient expression of
BAX54 or by direct microinjection.55 These
observations may be accounted for by the direct action of some
anti-apoptotic BCL-2 family members on caspase activation, because
BCL-XL can bind Apaf-1 directly and block its ability to
activate pro-caspase 9.56 Such a function for BCL-2 family
proteins parallels the role of the C elegans BCL-2 homologue
CED-9.57 A model that combines the putative ability of
BCL-2 family members to regulate both cytochrome c release and the
Apaf-1-mediated activation of pro-caspase 9 (the "Swiss army
knife" model47) is depicted in
Fig 4A.
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| Fig 4.
Models relating the roles of BCL-2 family proteins,
cytochrome c release, and Apaf-1-dependent caspase activation during
the induction of apoptosis. (A) "Swiss army knife" model; (B)
"death cycle" model. See text for details.
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4.4. Caspase action on mitochondria amplifies the initial apoptotic
signal via a positive feedback loop.
Caspases can themselves trigger cytochrome c release, because selective
inhibitors of these proteases can abrogate release in response to some
stimuli.45 Furthermore, death signals including ligation of
Fas, which directly activate caspases (section 4.2), may nevertheless
be amplified via caspase-mediated cytochrome c release.45
Recombinant caspases disrupt m and induce cytochrome
c release when added to isolated mitochondria.58 The
mechanism of this action of caspases is unclear.
The operation of a positive feedback loop raises the possibility that
anti-apoptotic BCL-2 family members may not play a direct role in the
modulation of cytochrome c release. The ability of these proteins to
directly inhibit Apaf-1 function56 could instead modulate
cytochrome c release indirectly via the caspase-dependent feedback
loop. This "death cycle" model47 implies that
cytochrome c release is not a component of the apoptosis-initiating
pathway but serves in the amplification of an initial signal generated via the regulation of Apaf-1 (Fig 4B).
4.5. Survival factors regulate apoptosis via phosphorylation of the
BAD protein.
The BAD protein is a pro-apoptotic member of the BCL-2
family.30,59 FL5.12 lymphoid cells depend on IL-3 for their
survival in vitro. In cells cultured in the presence of IL-3, the
BAD protein is phosphorylated on serine residues.
Phosphorylated BAD is sequestered via binding to the 14-3-3 protein and
is, therefore, unable to promote apoptosis.59 The BAD
protein rapidly becomes dephosphorylated in the absence of IL-3,
dissociates from 14-3-3, and triggers apoptosis
(Fig 5).
Recent evidence has implicated protein kinase B as the protein kinase
that mediates BAD phosphorylation in response to IL-360 and
other survival factors61 (Fig 4). IL-3 triggers activation of phosphatidylinositol 3-kinase, a lipid kinase that initiates the
eventual generation of phosphatidylinositol 3,4-bisphosphate, an
allosteric activator of protein kinase B.62
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5. THE p53 PROTEIN |
The p53 protein plays an important role in the coupling of DNA damage
to cell-cycle arrest and to the induction of apoptosis. In cells with
undamaged DNA, p53 protein levels are maintained at a low level as a
result of rapid turnover. An increase in stability after the induction
of DNA damage results in an increased level of p53.63 The
protein product of the ataxia telangiectasia (atm) gene
participates in a pathway that links the detection of DNA damage to the
upregulation of p53.64 However, the carboxy terminus of the
p53 protein itself can bind to damaged DNA,65 suggesting that both p53 and the putative damage detector may colocalize at the
site of DNA damage. The radiation resistance of thymocytes derived from
p53 "knockout" mice when compared with wild-type thymocytes66,67 emphasizes the importance of p53-dependent mechanisms in the induction of apoptosis after DNA damage induction. Upregulation of p53 also results in cell-cycle arrest. The pathways involved in this facet of p53 action have recently been
reviewed.63
5.1. Transcriptional activation by p53.
A tetramer of p53 molecules functions as a transcription factor that
binds to consensus sequences in the 5' untranslated regions of
specific target genes.63 The upstream region of the BAX
gene contains p53 consensus binding sites.68 Enforced p53
expression augments BAX expression, which is followed by apoptosis
induction.69 Genetic studies on apoptosis induction in
adriamycin-treated mouse fibroblasts suggest that BAX is an important
(but not the only) effector of p53-mediated apoptosis.70
However, thymocytes isolated from p53 "knockout" mice expressing
elevated levels of BAX are as resistant to etoposide-induced apoptosis
as are thymocytes from p53 "knockout" mice expressing normal
levels of bax.71 Therefore, mechanisms other than BAX
induction may mediate p53-dependent apoptosis, at least in some cell types.
Polyak et al72 have identified 12 mRNA species which were
rapidly induced after adenovirus-mediated transfer of the p53 gene into
p53 null colorectal carcinoma cells. These
p53-induced genes (PIGs) either encode
proteins that catalyze redox reactions and consequently generate
reactive oxygen species (ROS) or whose expression is augmented by ROS
generation. Indeed, introduction of p53 into p53 null
cells results in a burst of ROS generation that is followed by
apoptosis induction. Inhibitors of ROS generation do not interfere with
induction of PIG genes by p53 but do abrogate apoptosis induction,
suggesting that the upregulated expression of PIG genes and the
subsequent generation of ROS play a critical role in the induction of
apoptosis by p53 at least in some cell types.72 ROS can
themselves trigger cytochrome c release from mitochondria,44 possibly via modulation of ion transport
within these organelles,53,73 suggesting an additional
mechanism for the induction of apoptosis by p53.
Transient expression of p53 results in ROS generation in cells that are
susceptible to p53-mediated apoptosis but not in resistant cells,
compatible with the hypothesis that ROS are downstream mediators of
p53-induced apoptosis.74 However, the role of ROS in the
regulation of apoptosis remains controversial, because in some studies
the induction of cell death is not abrogated at very low oxygen
tension.75,76
5.2. Transcriptional repression by p53.
In addition to its transactivating properties, p53 represses
transcription from several promoters that lack p53 binding sites. BCL-2
can relieve this transcriptional repression and also protect cells from
apoptosis, suggesting that inhibition of transcription of specific but
as yet unidentified genes may contribute to the ability of p53 to
induce apoptosis.77 However, p53 is also able to induce
apoptosis via pathways that are not dependent on the regulation of gene
expression.78 Therefore, induction of apoptosis by p53 can
occur by diverse pathways depending on the cellular context. It is also
clear that some apoptotic pathways do not involve p53. For example,
thymocytes from p53 knockout mice are resistant to etoposide and
radiation but not to glucocorticoids.67 Furthermore, HL60
cells, which have lost both p53 alleles, are extremely sensitive to
apoptosis induction by drugs that induce DNA
strand-breaks.79 The p53 dependence of apoptotic pathways is also tissue dependent, because radiation-induced apoptosis is
compromised in the thymus of p53 knockout mice, but not in the
lung.80
5.3. p53 loss results in resistance to cytotoxic regimes.
When transplanted into imunodeficient mice, fibrosarcomas expressing
functional p53 show a high proportion of apoptotic cells and regress
after treatment with adriamycin or  radiation. In contrast, tumors
lacking p53 show few apoptoses and are resistant to adriamyin or
radiation.81 Therefore, inactivation of p53 can result in
the resistance of tumors to DNA damaging agents. The elevation of BAX
expression in response to radiation is only detected in human leukemia
cell lines that express p53 and that die by apoptosis in response to
DNA damage. By contrast, p53-negative lines do not elevate BAX levels
and are also resistant to radiation-induced apoptosis.82
Therefore, p53-mediated elevation of BAX contributes to the killing of
some tumor cells by cytotoxic regimes.77
5.4. The p53-related p73 gene product.
The p73 gene encodes a protein that is closely related to
p53.83 Overexpresion of p73 results in the induction of
some genes that are also targets of p53, and also induces apoptosis.
However, p73 expression is apparently not augmented after the induction of DNA damage.83 Therefore, there is at present no evidence implicating p73 in DNA damage-induced cell killing.
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6. THE PHYSIOLOGICAL ROLES OF APOPTOSIS IN THE HEMATOPOIETIC AND
LYMPHOID SYSTEMS |
During hematopoiesis, the survival of progenitor cells is regulated
both positively and negatively by a complex, interacting network of
cytokines and adhesion molecules.84 Noncycling primitive CD34+ human hematopoietic progenitors require the
continuous presence of IL-3 or granulocyte-macrophage
colony-stimulating factor (GM-CSF) for survival in vitro. In contrast,
other cytokines including IL-6 and IL-11 trigger proliferation of these
progenitors.85 Stem cell factor, Flt ligand, and IL-3
suppress apoptosis in single-cell assays designed to test the direct
actions of cytokines on primitive progenitors. Thrombopoietin is more
effective in preventing apoptosis than any of these
cytokines.86 Cytokines show target cell selectivity in
preventing apoptosis. For example, stem cell factor selectively promotes survival of primitive hematopoietic cells, whereas IL-3 blocks
cell death in more committed progenitors.87 Flt ligand is
selective for progenitors committed to the myeloid
lineage.88
Other cytokines promote the apoptotic death of both primitive and
committed progenitors.84 The flt3 ligand-mediated survival of primitive progenitors is counteracted by both transforming growth
factor- (TGF-) and TNF- .89 Interferon-
(IFN-) suppresses the survival of long-term culture-initiating
cells. The action of IFN- is more potent when this cytokine is
secreted by stromal cells in culture than when added to the medium,
stressing the importance of the hematopoietic microenvironement in
modulating survival.90 Induction of apoptosis by both
IFN- and TNF- may be mediated in part by increasing expression of
FAS on the surface of hematopoietic progenitors.91
Subsequent ligation of this death receptor then triggers cell killing.
Primitive bone marrow B-lymphoid progenitors require direct contact
with bone marrow stromal cells for survival.92 These survival-promoting interactions are dependent on interactions between
the 1 integrins VLA-4 and VLA-5 expressed on the B-cell surface and
fibronectin generated by the fibroblasts.93 It is unclear
whether interactions between these adhesion molecules directly generate
survival signals or whether the close juxtaposition of the lymphoid
progenitors to fibroblasts enhances the actions of unidentified
survival factor generated by the fibroblasts.
Apoptotic death of progenitor cells following deprivation of survival
factors is an active rather than a passive process. Hematopoietic cells
from p53 "knockout" mice are more resistant to the induction of
apoptosis after factor withdrawal than are corresponding cells from
control animals.94 Murine 32Dc13 myeloid precursor cells
depend on IL-3 for survival in vitro. Withdrawal of IL-3 results in
apoptotic death, which is dependent on the expression of wild-type
p53,95 suggesting that the activation of a cell-intrinsic
pathway involving p53 is a prerequisite for cell killing after removal
of survival factors.
Cytokines modulate both the basal survival of some leukemia cell lines
and also compromise their killing by cytotoxic
treatments.84 G-CSF, GM-CSF, IL-3, IL-6, or IFN- protect
murine myeloid leukemia cell lines from apoptotic death induced by
cytotoxic drugs.96,97 Apoptosis induced by the introduction
of wild-type p53 into a p53-negative murine AML cell line is abrogated
by IL-6,98 suggesting that cell killing on deprivation of
this cytokine proceeds via a p53-mediated pathway.
The generation of the recognition repertoires of T and B lymphocytes is
dependent on the apoptotic deletion of cells with inappropriate
specificities.99 Killing of cells after ligation of FAS or
the receptor proceeds via induction of
apoptosis.19 Activation of T lymphocytes after encounters
with cognate antigen/major histocompatibility complexes (MHC) results
in activation and concomitant upregulation of FAS ligand. Subsequent
interactions between FAS ligand and FAS induces apoptotic death of the
activated T cells, thereby downregulating the immune response.
Elimination of autoreactive B lymphocytes is also mediated by the FAS
system.19 Triggerring of specific cytotoxic T cells by
viral antigens displayed at the surface of target cells induces
expression of FAS ligand. Interaction of the ligand with FAS expressed
by the target cell initiates apoptosis.19 Cytotoxic T
lymphocytes also kill target cells via the perforin/granzyme system
(section 3.4).
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7. THE INFLUENCE OF GENETIC AND MICROENVIRONMENTAL FACTORS ON
APOPTOSIS INDUCTION IN LEUKEMIA CELLS |
Treatment of leukemia cell lines with cytotoxic drugs results in the
release of cytochrome c43-45 and the activation of
caspases.100,101 Caspases are also activated after
cytotoxic treatment of freshly isolated B chronic lymphocytic leukaemia
(B-CLL) cells.102 However, the mechanisms that couple DNA
damage to more downstream regulatory events are largely unclear.
Evidence of a largely circumstantial nature suggests that some of the
mechanisms of apoptosis control described in sections 3, 4, and 5 are
deregulated in leukemia cells, thus contributing to their abnormal
expansion and, in some cases, to drug and radiation resistance.
Deregulation of apoptosis results from translocations involving genes
that encode cell death-regulating proteins. However,
microenvironmental factors also impinge on both the basal survival of
leukemia cells and their killing by cytotoxic regimes. Some of this
evidence is summarized next.
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8. ALTERED EXPRESSION OF BCL-2 IN LEUKEMIA AND LYMPHOMA |
8.1. Translocation of the BCL-2 gene in non-Hodgkin's lymphoma (NHL).
The t(14;18) chromosomal translocation associated with NHL results in
the juxtaposition of the BCL-2 gene to the Ig heavy chain (IgH)
locus.103 Translocation results in enhanced levels of BCL-2
mRNA, which may be partially attributable to the presence of a powerful
transcriptional enhancer in the IgH locus.98 The efficiency
of splicing of BCL-2 exons is also increased as a result of their
fusion to Ig gene introns in t(14;18) cells. The resulting increase in
cellular levels of spliced BCL-2 open reading frames also contributes
to the upregulation of BCL-2 protein levels in NHL
cells.104 Transgenic mice carrying a BCL-2 gene expressed via the IgH gene enhancer overexpress BCL-2 specifically in B-lymphoid cells. These mice accumulate abnormal numbers of small,
nonproliferating B cells that show extended survival in
vitro.105,106 BCL-2 overexpression alone is insufficient
for lymphomagenesis. However, doubly transgenic mice in which
overexpression of both BCL-2 and c-MYC is targetted to B-lymphoid cells
rapidly develop tumors originating from primitive lymphoid-committed
lymphoid cells, suggesting that a second genetic event is necessary for
the malignant transformation of lymphocytes overexpressing
BCL-2.106
Enforced overexpression of the BCL-2 or BCL-XL gene in
leukemia cell lines confers increased resistance to cytotoxic
drugs.107-109 However, low-grade NHL patients with
increased BCL-2 expression respond well to chemotherapy, although
complete remissions are rare.110 Although it is likely that
overexpression of BCL-2 impairs apoptosis induction in follicular
lymphoma cells, additional microenvironemental signals are required to
maintain cell viability. NHL cells remain viable for 1 to 2 days in
culture and then die rapidly.111 Cell death is preceded by
the downregulation of BCL-XL expression, although BCL-2
expression is maintained. Both the decrease in BCL-XL and
cell death are prevented by ligation of CD40, suggesting that
continuous signaling by this cell-surface molecule is required to
maintain viability of the lymphoma cells via upregulation of BCL-XL expression.111 BCL-2 antisense
oligodeoxynucleotides have been used in the treatment of nine patients
with relapsed NHL. A reduction in tumor mass was observed in two
patients and a decrease in circulating tumor cells in two others. In
two of five samples that were studied by flow cytometry, a decrease in
BCL-2 protein levels was detected after treatment.112
NHL cells express variable levels of cell-surface FAS, but are
resistant to killing after FAS ligation. Therefore, loss of sensitivity
to this apoptotic pathway may contribute to the expansion of the
lymphoma cells by allowing their escape from normal immune regulatory
mechanisms.113
8.2. BCL-2 expression in CLL.
CLL cells show an extended life span in vivo. They proliferate very
slowly, suggesting that a failure to die by apoptosis contributes to
the accumulation of malignant cells in this disease.114 Translocations of the BCL-2 gene to Ig loci are detected in less than
2% of CLL cases.115 Nevertheless, CLL cells from some
patients express high levels of BCL-2 protein compared with
BAX.116,117 In vitro, malignant cells isolated from 30% of
CLL cases survive for several weeks in the absence of added
cytokines.118 However, malignant cells from the remaining
70% of patients undergo rapid apoptosis in culture, but are protected
by the addition of cytokines including IL-4 and IFN- or
-.118-122 IL-4 and IFN- may promote CLL cell survival
by preventing loss of expression of BCL-2 in vitro.118-120
Interaction with bone marrow stroma, which is mediated by the
1 and 2 integrins, also maintains
viability of CLL cells.123,124 Normal B cells do not adhere
to stroma and are not protected from apoptosis. Therefore, upregulation
of integrins on the surface of CLL cells relative to normal B cells may
contribute to their extended life span in vivo, via the activation of
unknown intracellular pathways.
The ratio of BCL-2 to BAX correlates inversely with the sensitivity of
B-CLL cells to cytotoxic drugs in vitro.116,117 However, in
vitro sensitivity to fludarabine failed to correlate with the achievement of clinical response.125 In a limited study of
58 CLL patients, high levels of the anti-apoptotic BCL-2 family member MCL-1 were found to correlate significantly with a failure to achieve
complete remission.125
8.3. BCL-2 expression by acute myeloid leukemia (AML) and acute
lymphoblastic leukemia (ALL) cells.
Genetic changes that directly result in augmented expression of BCL-2
have not been described in AML. However, those AML patients in which
greater than 20% of blasts express detectable BCL-2 levels show
shorter survival and lower rates of achievement of complete remission
compared with patients whose malignant cells express low BCL-2
levels.126 Immunohistochemical staining of BCL-2 is more
intense in malignant cells from AML patients who fail to achieve
remission than in those who respond to chemotherapy.127 Malignant cells from patients showing high BCL-2 expression are drug
resistant in vitro.128 Therefore, high BCL-2 expression, resulting from unknown mechanisms, may confer drug resistance on AML
cells. However, other mechanisms may also confer protection even in the
absence of high BCL-2 expression, because some AML isolates with low
BCL-2 expression are also drug-resistant in vitro.128
Elevated expression of MCL-1 at relapse suggests that cytotoxic regimes
may result in the selection of AML clones expressing high levels of
this anti-apoptotic BCL-2 family protein.129
Incubation of AML blasts with antisense oligonucleotides designed to
decrease BCL-2 expression increases their sensitivity to cytosine
arabinoside in vitro,130 emphasizing the potential importance of this protein in conferring drug resistance to these cells.
The expression of BCL-2 by the malignant cells of ALL patients at
presentation is highly variable. However, BCL-2 expression does not
correlate either with the ability of the ALL cells to survive in vitro
or with the response of the patients to intensive chemotherapy.131 Therefore, it is likely that other factors
play important roles in modulating the survival of ALL cells.
Interactions between B-lineage ALL cells and stromal fibroblasts,
mediated by interactions between 1 integrins and fibronectin,
promote the survival of the leukemia cells.92,93 The
intracellular pathways of survival promotion triggerred by these
interactions are, however, unknown.
| |
9. DELETION AND MUTATION OF THE p53 TUMOR SUPPRESSOR GENE IN LEUKEMIA
AND LYMPHOMA |
Deletion and/or mutation of p53 alleles results in the generation of
tumors with impaired expression of functional p53
protein.63 The distribution of p53 mutations in human
leukemia, which has been extensively reviewed 132, will be
briefly summarized here. In general, p53 alterations are more frequent
in aggressive disease and are associated with drug resistance and poor survival.
9.1. p53 mutations in myelodysplastic syndromes, CML, and CLL.
p53 changes are seen in 4% of myelodysplastic syndromes and are more
frequent in advanced stages.132 p53 mutations are rare in
the chronic phase of CML but are more frequent in blast
crisis.133 p53 mutations are detected in 10% to 15% of
CLL and are associated with poor response to therapy and shorter
survival.134-136 Mutations are more frequent (about 40%)
in Richter's immunoblastic transformation.137 However,
sensitivity of B-CLL cells to camptothecin analogs or fludarabine in
vitro did not correlate with the presence of p53 mutations.116
9.2. p53 mutations in lymphoma and ALL.
A high proportion (30%) of Burkitt's lymphoma and 55% of its
leukemic counterpart, L3 ALL, harbor p53 mutations in addition to
translocation and overexpression of the MYC oncogene.137
The transformation of follicular lymphoma to diffuse aggressive disease correlates with p53 mutation and decreased survival in 25% to 30% of
cases.138 p53 mutation is associated with
loss of the short arm of chromosome 17, which carries the p53 gene, in
Ph1-positive ALL.139 Overall, p53 loss is
observed in 13% of ALL.132 However, the incidence of these
changes is much lower in pediatric ALL (2%) and may correlate with the
excellent response of these childhood ALL to cytotoxic
drugs.140
9.3 p53 mutations in AML.
Genetic changes involving p53 are rare in AML, but are more frequent in
cases with deletion of chromosome 17p.141 Again, loss of
functional p53 in AML is associated with low rates of complete
remission and with decreased survival.135 The blast cells
from the majority AML patients require the addition of exogenous cytokines for both survival and growth in vitro.142,143
Factor-dependent blasts die rapidly when deprived of GM-CSF, but are
protected from apoptosis by antisense oligonucleotides that
downregulate p53 expression, suggesting that the killing of these cells
after factor deprivation is p53-dependent.143 GM-CSF and
IL-3 also protect blast cells from 70% of AML patients from apoptosis
induction by doxorubicin.144
In summary, p53 loss is relatively rare in leukemia. However, small
sub-populations of leukemia cells may harbor these genetic changes,
resulting in their relative resistance to cytotoxic regimes. p53-negative sub-populations may, therefore, survive drug treatment and
initiate relapsed disease showing a more aggressive phenotype and
increased drug resistance.
9.4. Adenoviruses lacking the E1B gene selectively kill tumor cells
lacking functional p53.
Adenovirus infection of human cells requires expression of the viral
E1B gene. The product of this gene binds to cell-encoded p53, thereby
permitting viral replication and eventual killing of the host cells.
Mutant adenoviruses lacking the E1B gene are, therefore, unable to
proliferate in normal human cells, but are able to do so in tumor cells
lacking functional p53.145 Human cervical carcinomas
carried as xenografts in immunodeficient mice regress following direct
injection of E1B-negative adenovirus. Primary infection of only 2% of
the tumor cells may be sufficient to induce regression, due to the
infectious nature of the adenovirus.145 It remains to be
established whether the strategy outlined above will result in the
selective killing of human leukemia cells.
9.5. Genetic changes involving the atm gene.
Ataxia telangiectasia patients show a high incidence of lymphoid, but
not of myeloid, malignancies.146 Sixty percent of patients with T-prolymphocytic leukemia show homozygous loss of atm
genes within the tumor cells.147 The malignant cells of
approximately 35% of B-CLL patients harbour atm mutations and
show decreased expression of the ATM protein. This subset of patients
was characterized by a more aggressive form of disease compared to
patients with normal ATM expression. In some cases, heterozygous
mutations are present in all somatic cells, suggesting a genetic
predisposition to the disease.148,149 The role of the
ATM-encoded protein in regulating apoptosis via the p53 pathway
(section 5) suggests that loss of its expression in some B-CLL may
contribute to the resistance to apoptosis characteristic of this malignancy.
| |
10. THE CHIMERIC BCR/ABL ONCOGENE IN PHILADELPHIA (Ph1)
CHROMOSOME-POSITIVE CHRONIC MYELOID LEUKEMIA (CML) AND ALL |
The Ph1 translocation [t(9;22)], is associated with CML
and results in the fusion of the bcr and abl genes. The
fusion gene encodes a 210-kD oncoprotein
(p210bcr/abl) with enhanced protein tyrosine
kinase activity compared with the normal abl-encoded
protein.150 A variant Ph1 translocation associated with ALL encodes a 185-kD BCR/ABL oncoprotein
(p185bcr/abl) with increased transforming potential
compared with p210bcr/abl.151
The normal abl-encoded protein is involved in the induction of
apoptosis in some cell types.152 By contrast, expression of p210bcr/abl protects cells from killing by
radiation, cytotoxic drugs, and ligation of FAS.153-155
p210bcr/abl protects cells from killing by
cytotoxic drugs by preventing the release of cytochrome
c156 and activation of caspase 3.156,157
Both p210bcr/abl and
p185bcr/abl activate phosphatidylinositol
3'-kinase,158,159 and this pathway is essential for
transformation by these oncoproteins.160 Kinase activation
is mediated via binding of a complex containing the CRKL and CBL
adaptor proteins to a proline-rich domain of both chimeric
oncoproteins.150,161 Because activation of
phosphatidylinositol 3-kinase results in phosphorylation of the
pro-apoptotic BAD protein via protein kinase B (section 4.5), the
anti-apoptotic actions of BCR/ABL oncoproteins may be mediated at least
in part by this route.
Drugs that selectively inhibit the bcr/abl-encoded protein
kinases may be of value in the treatment of CML and
Ph1-positive ALL. Herbimycin A162 and CGP
57148163,164 selectively inhibit the expansion of cells and
cell lines expressing bcr/abl oncoproteins. The actions of
herbimycin A on Ph1-positive cell lines is markedly
enhanced by combination with etoposide or radiation.165
Antisense oligonucleotides that suppress expression of bcr/abl
oncoproteins may also enhance apoptosis induction by drugs or
radiation.153 However, the actions of at least some
bcr/abl antisense oligonucleotides on CML cell lines may be
nonspecific.166 These nonspecific cytotoxic effects may be
attributable to the release of deoxyribonucleotides as a consequence of
exonucleolytic degradation of the oligonucleotides.167
| |
11. CHROMOSOMAL TRANSLOCATIONS INVOLVING TRANSCRIPTION FACTOR GENES
RESULT IN THE DYSREGULATION OF APOPTOSIS |
Chromosomal translocations associated with specific sub-types of acute
leukemia and lymphoma result in the rearrangement of a variety of
transcription factor genes. Some of these translocations result in
enhanced expression of the transcription factor due to the
juxtaposition of its gene next to Ig or T-cell antigen receptor loci,
which contain powerful transcriptional enhancer elements. Other
translocations involve the breakage and rejoining within introns of two
transcription factor genes. The resulting hybrid genes encode chimeric
transcription factors with novel properties which contribute to
leukemogenesis.168 Some of these chimeric or aberrantly
expressed proteins may contribute to malignant transformation via the
suppression of apoptosis. Selected examples are described here.
11.1. Translocations resulting in inhibition of apoptosis.
The t(9;14) translocation, which is associated with 50% of
lymphoplasmacytoid lymphoma, juxtaposes the paired box-containing gene
pax-5 to the IgH locus, where transcription from the pax-5 promoters is augmented due to the proximity of the powerful
Eµ enhancer.169,170 The PAX-5 protein
represses transcription of the p53 gene.171 Therefore,
decreased expression of p53 in cells bearing the t(9;14) translocation
may contribute to malignant transformation via reducing expression of p53.
The chimeric PML-RAR transcription factor is generated as a
consequence of juxtaposition of the retinoic acid receptor gene
(rar; chromosome 17) and the pml gene (chromosome
15) in acute promyelocytic leukemia. Ectopic expression of this protein in myeloid cell lines diminishes apoptotic cell death. However, a
reduced capacity to differentiate may also contribute to malignant transformation by the PML-RAR protein.172
The t(17;19) translocation, which is associated with pre-B cell
leukemia, results in the fusion of the genes encoding the transcription
factors E2A and HLF (hepatic leukemia factor). Human leukemia cells
expressing the chimeric E2A-HLF protein undergo rapid apoptotic death
after ectopic expression of a dominant negative inhibitor of E2A-HLF
function. In addition, ectopic expression of E2A-HLF in nonmalignant
pro-B lymphocytes abrogates apoptosis induction induced by IL-3
withdrawal or by p53 expression.173 Therefore, the
oncogenic action of E2A-HLF may be related to its ability to prevent
apoptosis. The similarity of the DNA binding/dimerization domains of
HLF to the CES-2 (cell death specification-2) protein of C
elegans suggests that E2A-HLF may block apoptosis via inducing transcription of a gene whose protein product blocks an early step in
the apoptotic pathway.173
The t(10;14) translocation is associated with some cases of T-cell
leukemia. The resulting juxtaposition of the hox 11 gene to the
IgH locus results in its overexpression. Disruption of the hox
11 gene in mice results in the apoptotic death of spleen cells,
again suggesting that oncogenic transformation by deregulated hox
11 expression is the result of protection from
apoptosis.174
Overexpression of the tal1(scl) gene as a result of the t(1;14)
translocation is a frequent event in T-ALL. Ectopic expression of TAL1
in an immature human T-lymphoid cell line does not perturb cell-cycle
control but results in a marked resistance to cytotoxic drugs and to
FAS ligation.175 This anti-apoptotic action is dependent on
the DNA-binding domain of TAL1, suggesting that induction of expression
of an unknown gene(s) underlies the resistance of TAL1 overexpressing
cells to cell killing.
11.2. Translocations resulting in induction of apoptosis.
By contrast, some transcription factors involved in chromosomal
translocations induce apoptotic cell death. Expression of the MYC gene
is deregulated as a result of juxtaposition to the IgH locus in
Burkitt's lymphoma and L3 ALL cells bearing the t(8;14) translocation.176 The ability of the MYC gene product to
trigger cell-cycle transit contributes to malignant transformation
induced by its overexpression. However, the MYC protein also induces
apoptosis when ectopically expressed at high levels in fibroblasts.
Although p53 is required for MYC-induced apoptosis,177 p53
"knockout" mice develop normally.178 Therefore, it is
probable that levels of MYC protein generated during normal
physiological responses do not induce apoptosis.
A net increase in cell number after enforced induction of MYC in murine
fibroblasts requires that the apoptotic pathway be blocked by
survival-inducing cytokines.179 Therefore, oncogenic transformation by deregulated MYC may require additional genetic events
that abrogate apoptosis induction and may explain the high proportion
of Burkitt's lymphoma and L3 ALL cases bearing p53 gene
lesions.137 The ability of overexpressed BCL-2 to
collaborate with MYC in promoting the generation of lymphoid tumors in
doubly transgenic mice is also consistent with the concept that
oncogenenic transformation by MYC is dependent on the suppression of
apoptosis.106
The e2a-pbx1 fusion gene results from the t(1;19) translocation
associated with B-cell precursor ALL. The protein product of this
fusion gene rapidly induces apoptosis in B-cell progenitors. The
dependence of apoptosis induction on the DNA-binding homeodomain of the
PBX1 moiety suggests that cell killing is dependent on transcriptional
activation of an unknown gene(s).180 Apoptosis induced by
E2A-PBX1 expression in cell lines is blocked by BCL-2 expression.
Therefore, oncogenic transformation by this chimeric gene may also
depend on additional genetic changes that block apoptosis
induction.180
| |
PERSPECTIVES |
Knowledge of the complex biochemical pathways involved in the
regulation of apoptosis in hematopoietic cells is advancing rapidly.
Here we have focused on aspects of apoptosis regulation with particular
relevance to the hematopoietic system. The BCL-2 protein family, the
release of mitochondrial cytochrome c, p53-mediated transcriptional
control, FAS, and the TNF receptor are involved in the control of
apoptosis induction at least in some hematopoietic cells. Diverse
regulatory mechanisms converge on a final common pathway involving
activation of the caspase family of proteases. Additional interactions
involving the BCL-2 family may also be important in apoptosis
regulation and have been reviewed elsewhere.181
Elevated expression of BCL-2, loss of functional p53, constitutive
activativation of protein tyrosine kinases, or the generation of
chimeric, oncogenic transcription factors as a result of chromosomal translocations abrogate apoptosis induction and antagonize the actions
of cytotoxic drugs or of radiation on leukemia cells. Therefore,
strategies designed to bypass blocks in the detection of apoptotic
signals or in the signal transduction phase may be of value in
overcoming resistance to cytotoxic regimes.2 However, apoptosis is a complex physiological process dependent on the integrated functioning of a large number of gene products. Therefore, any therapeutic stratagem that is dependent solely on the induction of
apoptosis will lead to the rapid evolution of clones resistant to
killing. Microenvironemental factors also influence the outcome of
cytotoxic treatments by modulating pathways of apoptosis control. Therefore, manipulation of the cytokine levels of leukemia or lymphoma
patients may also impact on the efficacy of chemotherapy or
radiation.182
Elucidation of the precise mechanisms involved in the apoptotic killing
of leukemia cells (as opposed to cell lines) and of the strategies by
which malignant cells escape killing by cytotoxic agents are major
topics for future research. It is anticipated that an understanding of
these facets of leukemia and lymphoma cell biology will lead to the
design of effective strategies for the treatment of hematopoietic
malignancies that are resistant to conventional treatment.
| |
NOTES ADDED IN PROOF |
(1) New members of the cell-surface death receptor (DR) family have
been described. DR3 triggers apoptosis consequent to binding APO 3 ligand.183 TNF-related apoptosis-inducing ligand (TRAIL) initiates cell death following binding to DR4 or DR5. The actions of
DR4 and 5 are limited by decoy receptors which bind TRAIL but are
unable to transduce apoptotic signals.183 (2) Binding of the MDM2 protein to p53 targets the latter for degradation.
Phosphorylation of p53 by the ATM protein kinase results in its
dissociation from MDM2 and consequent stabilization.184,185
(3) Phosphorylation and inactivation of caspase 9186 and of
the forkhead family transcription factor FKHRL1187 by
protein kinase B contribute to the suppression of apoptosis by
pro-survival cytokines. (4) The bcl10 gene involved in the
t(1;14)(p22;q23) translocation of mucosa-associated lymphoid tissue
(MALT) lymphoma has been cloned. Translocation results in expression of
a truncated protein which lacks the pro-apoptotic activity of the
wild-type BCL10 protein.188 (5) Mitochondria of cells
primed for apoptosis can release death-inducing proteins other than
cytochrome c. These include caspases 2 and 9 and a flavoprotein,
apoptosis-inducing factor (AIF).189
| |
FOOTNOTES |
Submitted July 15, 1998; accepted January 28, 1999.
Address reprint requests to R. Gitendra Wickremasinghe, PhD, Department
of Hematology, Royal Free and University College Medical School,
Rowland Hill St, London NW3 2PF, UK.
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INTRODUCTION
1. MORPHOLOGICAL AND...
