Page 235 - Williams Hematology ( PDFDrive )

210 Part IV: Molecular and Cellular Hematology Chapter 15: Apoptosis Mechanisms: Relevance to the Hematopoietic System 211

gene normally resides on chromosome 18, but it becomes merged with CASPASES
the immunoglobulin heavy-chain (IgH) locus on chromosome 14, Inactivating mutations have been described in a variety of cancers. In
probably as a result of aberrant actions of the V-D-J gene recombina- approximately 15 percent of NHLs, mutations that alter the activity of
tion machinery responsible for antibody generation in B-cells. In this caspase-10 have been reported. The resulting mutant caspase-10 pro-
context, the BCL-2 gene becomes deregulated in its expression via the teins may operate as dominant-negative inhibitors of DR-mediated
powerful cis-acting enhancer elements of the IgH locus. Chromosomal apoptosis. Although exhaustive analysis has not been performed to
79
translocations activating BCL-2 occur in most indolent NHLs (espe- date, overall mutations inactivating caspase-encoding genes appear
cially follicular B-cell lymphomas) as well as a substantial proportion to be relatively rare in hematopoietic malignancies, though epigenetic
of aggressive NHLs (perhaps commonly arising from progression of a silencing may be more common.
previously undiagnosed low-grade B-lymphoma). Gene amplification
provides another mechanism for BCL-2 gene dysregulation, and is
reported in nearly 20 percent of aggressive B-NHLs, particularly diffuse
large B-cell lymphomas (DLBCLs). Thus, by studying the cytogenetics TUMOR NECROSIS FACTOR FAMILY
of B-cell malignancies, the world’s first example of an antiapoptotic gene DEATH RECEPTORS
(BCL-2) was discovered. Somatic mutations in the FAS (CD95) gene have been found in multiple
Additionally, loss of genes encoding microRNAs (miRNAs) that myelomas (MMs) and NHLs. Missense mutations within the DD of
80
posttranscriptionally suppress BCL-2 by inducing Bcl-2 mRNA deg- Fas (CD95) were associated with retention of the wild-type allele, sug-
radation accounts for the widespread dysregulation of BCL-2 gene in gesting a dominant-negative mechanism, whereas missense mutations
B-cell chronic lymphocytic leukemia (B-CLL). In this context, approx- outside the DD were associated with allelic loss. The observation that
80
imately 90 percent of B-CLLs have homozygous loss of function muta- tumor-suppressor p53 can induce transcription of the DRs Fas (CD95)
tions or deletions involving miRNA15 and miRNA16 on chromosome and DR5 (TRAILR2) in some types of tumor cells, 81,82 suggests an addi-
13q14, thus derepressing BCL-2 gene expression. This somatic loss of tional cancer-relevant mechanism by which reductions in the expres-
miRNA15 and miRNA16 genes in CLL was the first example of miRNA sion TNF family DRs could occur in human malignancies, namely,
genes operating as tumor suppressors. secondarily to genomic lesions that inactivate p53 or that cause overex-
Genetic lesions responsible for dysregulation of other members of pression of endogenous p53 antagonists. 83
the Bcl-2 family have also been identified in various types of hemato-
logic and nonhematologic malignancies. Among these somatic genetic OTHER GENOMICALLY BASED DISEASES
mechanisms is the amplification of the BCL-X (BCL2L2) or MCL-1
(BCL2L3) gene loci, which occurs probably in one in 10 human solid INVOLVING APOPTOSIS GENES
tumors. Conversely, homozygous gene mutations that inactivate the Hereditary deficiency of XIAP is a very strong risk factor for early onset
proapoptotic BAX gene have also been identified in occasional hemato- inflammatory bowel disease (IBD). This function of XIAP is probably
poietic malignancies and some solid tumors. In this regard, deletions not related to its role in apoptosis, but rather stems from the function
or inactivating mutations in the tumor-suppressor p53 also reduce the of XIAP as a component of NACHT and Leucine rich repeat domain-
expression of several proapoptotic Bcl-2 family genes, including the containing receptor (NLR) family protein complexes involved in innate
BAX, PUMA, NOXA, and BID genes, which are direct transcriptional immunity. Causative mutations have been identified in the FAS (CD95)
76
targets of p53 (see above). The incidence of p53 gene deletions and gene of humans in patients with autoimmune lymphoproliferative syn-
84
mutations varies among hematologic malignancies, ranging from rare drome (ALPS), also known as Canale-Smith syndrome. Thus, the Fas/
(<5 percent) in T-cell leukemias and low-grade B-cell lymphomas to Fas ligand (FasL) system plays a critical role in lymphocyte homeosta-
frequent (>30 percent) in disorders such as high-grade B-cell lympho- sis in vivo. At least some of the mutant Fas proteins found in humans
mas, Burkitt lymphomas, and relapsed/aggressive acute lymphocytic with ALPS have been shown to operate as trans-dominant inhibitors of
leukemia (ALL), chronic lymphocytic leukemias (CLLs) that have wild-type Fas, probably explaining the dominant inheritance pattern of
progressed to Richter syndrome, and chronic myelogenous leukemias this disorder. Likewise, germline mutations in Fas and FasL have been
(CML) in blast crisis. 77 discovered as the underlying basis for the lymphoproliferative autoim-
mune phenotype of lpr/lpr and gdl/gdl strain mice, respectively. 85,86 In
contrast to humans, however, the mutations in the fas gene of lpr-strain
INHIBITORS OF APOPTOSIS mice produce disease with a recessive inheritance pattern. FasL, like
85
Genomic lesions involving the IAP family genes are also associ- most TNF family members, is a trimer, and the receptor also forms tri-
ated with hematologic malignancies. For example, in marginal zone mers and probably higher-order oligomers, thus explaining why some
mucosa-associated lymphoid tissue (MALT) B-cell lymphoma, the Fas mutants display dominant-negative effects on wild-type Fas while
most common of the extranodal NHLs, t(11;18)(q21;q21) chromo- others do not. Indeed, mutant versions of Fas from some patients with
somal translocations occur frequently. These translocations fuse hereditary ALPS have been demonstrated to antagonize wild-type Fas,
78
87
the three BIR domains of c-IAP2 with portions of the gene encod- probably forming mixed oligomers of wild-type and mutant molecules.
ing MALT1, a caspase-like protein. The predominant mechanism by Additionally, mutations in caspase-10 gene that produce altered pro-
which the resulting c-IAP2/MALT1 fusion protein suppresses apop- teins that interfere with Fas-induced apoptosis have been identified in
tosis appears to be hyperactivation of NF-κB. In this regard, the BIR1 patients with ALPS. 88
domain of c-IAP1 binds NF-κB–inducing E3 ligase TRAF2, and this These examples of autoimmune disorders associated with hered-
interaction has been shown to be critical for NF-κB induction by itary alternations in apoptosis-regulatory genes highlight the intricate
c-IAP2/MALT1 fusion proteins. Additionally, the C-terminal region linkages between cell death regulation and host–pathogen interactions.
of MALT1 also binds a related NF-κB–inducing E3 ligase, TRAF6, Many components of the apoptosis machinery play important roles in
making additional contributions to NF-κB stimulation. Interestingly, aspects of innate and adaptive immunity, possibly reflecting the notion
TRAF2 gene amplification has also been described in a significance that altruistic cell suicide may be the best defense against pathogens for
number of human malignancies. multicellular organisms. Moreover, a subfamily of the caspases (e.g.,

Kaushansky_chapter 15_p0203-0212.indd 210 17/09/15 6:38 pm