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208 Part IV: Molecular and Cellular Hematology Chapter 15: Apoptosis Mechanisms: Relevance to the Hematopoietic System 209

BCL-X gene as at least one of their mechanisms of suppressing apop- activates the human BAX gene promoter. Loss of p53 activity occurs in
tosis. Examples with relevance to hematopoietic system include ery- many human malignancies by a variety of mechanism, including gene
thropoietin-mediated stimulation of survival of erythrocyte precursors deletion, gene mutations that result in mutant p53 proteins lacking
and interleukin (IL)-3 and IL-7-mediasted stimulation of survival of transcriptional activity, and MDM2 gene amplification. Small molecule
B-lymphocyte progenitors (pro/pre–B-cells). Additionally, Jak family drugs that block Mdm2 protein interaction with p53 have shown prom-
nonreceptor protein tyrosine kinases are capable of stimulating phos- ising preclinical activity against hematopoietic malignancies.
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phatidylinositol 3’-kinase (PI3K) activity, which, in turn, causes acti- Interestingly, in addition to its role as a nuclear transcription fac-
vation of Akt family kinases. The murine gene encoding Akt was first tor, evidence has emerged suggesting that p53 may promote apoptosis
discovered by virtue of its similarity to the v-akt oncogene found in also via nontranscriptional mechanisms under some circumstances.
some murine leukemia viruses and through its activation in thymomas Specifically, a cytoplasmic pool of p53 reportedly associates with mito-
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caused by retrovirus insertions near the c-akt gene. Humans contain chondria, directly inducing activation of the Bax and inhibiting Bcl-2
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three AKT genes. Akt can phosphorylate multiple proteins within the and Bcl-X . Importantly, even mutant p53 is capable of activating this
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core apoptosis machinery. For example, the proapoptotic Bcl-2 family cell-death pathway, raising hopes of finding pharmacologic interven-
member Bad is a target of Akt, where phosphorylation of Bad causes tions that would entice mutant p53 to attack mitochondria and trigger
its sequestration by 14–3–3 family proteins, thus inhibiting Bad from apoptosis of cancer cells in which this important tumor-suppressor gene
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heterodimerizing with Bcl-X . Akt also can phosphorylate human product has suffered somatic mutations that inactive its nuclear (tran-
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caspase-9, blocking apoptosis downstream of mitochondria. Another scriptional) functions.
substrate of Akt that is relevant to apoptosis is forkhead transcription
factors (FKHD). Some FKHD family members appear to control apop-
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tosis, perhaps by affecting transcription of the gene encoding FasL. HEMATOLOGIC DISEASES AND
Phosphorylation of FKHD by Akt prevents its entry into the nucleus.
APOPTOSIS
CYTOKINES Either insufficient or excessive apoptosis plays important roles in a wide
diversity of hematologic diseases. Convincing evidence has gathered to
Several cytokines stimulate the activation of NF-κB (REL) family tran- support a major role for insufficient apoptosis in the context of most (if
scription factors. NF-κB directly binds the promoters and induces not all) hematologic malignancies, where defects in apoptosis prolong
expression of several antiapoptotic genes, including the BCL-2 fam- cell life span and thereby promote cell accumulation, as well as com-
ily members BCL-X and BFL-1, the IAP-family member C-IAP2, and plementing the proapoptotic effects of certain oncogenes (e.g., C-MYC;
C-FLIP. Thus, elevations in NF-κB activity can increase cellular resis- CYCLIN-D1), permitting growth factor independent cell survival,
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tance to apoptosis, affecting (1) the Intrinsic (mitochondrial) pathway and promoting resistance to chemotherapy, radiation, and immune-
through elevations in antiapoptotic Bcl-2 family proteins, (2) the extrin- mediated cell killing. Defects in apoptosis also seem to underlie some
sic (TNF family DR) pathway through upregulation of c-Flip, and (3) aspects of autoimmunity, where a failure to eradicate autoreactive lym-
downstream common pathways involving effector caspases as a result phocytes occurs. Conversely, excessive apoptosis has been implicated in
of overexpression of c-IAP2. the depletion of CD4+ T-lymphocytes seen in chronic HIV infection,
The first example of NF-κB involvement in malignancy was pro- bacteria-mediated killing of macrophages, myelodysplastic disorders
vided by studies of the avian Rev-T retrovirus, a transforming retrovi- where marrow failure occurs resulting in anemia and failed myelopoie-
rus that causes rapidly fatal lymphomas in young chickens and which sis, and many other conditions. Some examples of the human diseases
carries the v-Rel oncogene. The cellular homologue of this viral onco- that have been linked to genomic alterations of apoptosis genes are
gene is C-REL, which encodes the p65 subunit of NF-κB. Amplifica- highlighted here, without an attempt to be comprehensive.
tion of the C-REL gene has been reported in non-Hodgkin lymphomas
(NHLs), occurring particularly in diffuse large B-cell lymphoma and
commonly associated with extranodal presentation. Other genetic ALTERNATIONS IN APOPTOSIS GENES IN
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alterations associated with dysregulation of NF-κB include chromoso- HEMATOLOGIC MALIGNANCIES
mal translocations involving the I-κB family member BCL-3 in B-CLL. Defects in apoptosis (cell death) are recognized as one of the hallmarks
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I-κB family proteins bind and sequester NF-kB complexes, preventing of essentially all cancers. Not surprisingly, therefore, myriad examples
the transcription factor from entering the nucleus. Typically, I-κB of alternations in genes regulating the core apoptosis machinery have
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is regulated by ubiquitin-mediated turnover by the 26S proteasome. been delineated in human cancers. Hematologic malignancies have, in
Mutations in I-κB thus may enhance NF-κB activity, either by produc- fact, revealed many of the first and most striking examples of the criti-
ing unstable proteins or reducing the affinity of I-κB for NF-κB. The cal importance of cell death as a constraint to inappropriate cell expan-
anticancer activity of drugs that inhibit the proteasome, approved for sion and accumulation. Here, some illustrative examples are provided
multiple myeloma, may be attributable in part to suppression of I-κB without an attempt to be comprehensive, particularly focusing on the
degradation, thereby inhibiting NF-κB induction. 71 families of apoptosis-regulating genes outlined above with emphasis on
genomic alterations. Additionally, myriad epigenetic mechanisms mod-
GENOTOXIC STRESS ulate the expression of apoptosis genes in hematologic malignancies,
which are not covered here.
Gamma-radiation and many DNA-damaging anticancer drugs potently
stimulate apoptosis of hematopoietic cells. The principal mediator of
apoptosis induced by genotoxic stress is p53. The p53 protein is a tetram- BCL-2 FAMILY
eric transcription factor, whose levels are controlled by the E3 ligase The Bcl-2 family derives its name from discovery of the founding
Mdm2. This transcription factor directly induces expression of BH3- member as a result of its involvement in B-cell lymphomas and leu-
only proteins Noxa (APR), Bid, and PUMA, 72–74 thus linking p53 to the kemias. The human BCL-2 gene is involved in t(14;18) chromosomal
death machinery. Additionally, p53 directly binds and transcriptionally translocations found commonly in NHLs. In this regard, the BCL-2

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