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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 96 No. 3 (August 1), 2000:
pp. 808-822
REVIEW ARTICLE
The role of immunoglobulin translocations in the pathogenesis
of B-cell malignancies
Tony G. Willis and
Martin J. S. Dyer
From the Academic Department of Haematology and Cytogenetics, Haddow
Laboratories, Institute of Cancer Research, Sutton, Surrey, England.
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Introduction |
Most, if not all, malignancies have recurrent and
disease-specific clonal chromosomal abnormalities, which play a pivotal role in tumor development. These comprise deletions or amplifications involving entire chromosomes or subchromosomal regions and, also, translocations. The latter represent the juxtaposition of fragments of
DNA that are usually on different chromosomes. Most translocations are
not random, involving, in a given disease, circumscribed regions of DNA
within both chromosomal partners and are furthermore, reciprocal, with
DNA being interchanged between both partners, implying that both
chromosomal ends have to be brought into close apposition.
Some chromosomal regions and localized areas within certain genes
appear to be particularly prone to chromosomal aberrations, with
specific abnormalities occurring within cells of a given lineage at
specific stages of differentiation.1 While some genes are
involved in translocations involving only one partner gene, others are
involved with multiple different partners. The MLL gene and, in particular, an 8.3-kilobase
(kb) region (the breakpoint cluster region), is recurrently involved in
a large number of different translocations, principally in acute
myeloid leukemias.2
The immunoglobulin (IG) loci show comparable promiscuity in
their translocation partners, and recently many new translocations have
been identified, using defined breaks within the IG loci to
clone the translocation breakpoint. Table 1 lists the
cloned translocations involving the IG loci; several other
recurrent IG translocations remain to be cloned.3-5
Here, we first review the IG translocations and, secondly, how
the involved genes may contribute to the pathogenesis of B-cell
malignancies.
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Cytogenetic abnormalities of the IG loci in B-cell
malignancies |
Chromosomal translocations involving the IG loci are found
in some, but not all, forms of B-cell malignancy. B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and B-cell chronic lymphocytic leukemia (CLL) have a low frequency of IG translocations, at
least at the cytogenetic level. Some IG translocations are seen
in all cases of a specific subgroup of disease. Paradigms include the involvement of MYC in all cases of Burkitt lymphoma (BL) and of cyclin D1/BCL1 in all cases of mantle cell
lymphoma.6,7 These translocations may therefore be useful
as a diagnostic marker.8
In contrast, cytogenetically identical translocations may be found in
several different types of disease. However, molecular analysis has
shown that the same translocations in different diseases may involve
different breakpoints, either within the incoming oncogene or within
the IG locus.9,10 For example, sporadic BL with
t(8;14)(q24;q32) shows a different spectrum of IGH breakpoints than those found in endemic (African) cases with the same
translocation.9 Similarly, BCL2/IG translocations
occur in both follicular lymphoma (in about 80% of cases) and, more
rarely, in CLL (about 2% of cases). The former involves the 3'
portion of the BCL2 gene on chromosome 18q21 (Figure 1
), whereas the latter usually involves the 5'
region of the same gene.10 These data indicate that
translocations, although cytogenetically identical, may arise by
different mechanisms.
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| Fig 1.
t(14;18)(q32;q21) translocation.
(A) The BCL2 gene, located at chromosome 18q21.3, consists of 3 coding exons separated by an intron of about 250 kb and is involved in
IG translocations in about 80% of follicular B-NHL and 1% to
2% of all cases of CLL. The transcriptional orientation of the gene is
from telomere to centromere. The BCL2 open reading frame is
denoted by the shaded region, and IGH switch regions are
hatched. MBR denotes major breakpoint region; mcr, minor cluster
region; vcr, variant cluster region; icr, intermediate cluster region.
(B) Typical IGH-BCL2 translocation of follicular B-NHL
involving the BCL2 MBR within the 3' UTR of the gene and
the JH segments. Note that nearly all cases of follicular
B-NHL with this translocation have undergone IGH class-switch
deletion. A BCL2-IGH fusion mRNA is produced. (C) A vcr
rearrangement typical of CLL with t(14;18)(q32;q21). Here, the 5'
portion of the BCL2 gene, which is about 250 kb centromeric of
the 3' UTR, becomes juxtaposed with the IGHJ segments in
opposite transcriptional orientation. This implies that this
translocation must be associated with inversion within either
chromosome 18 or 14 and suggests a different pathogenic mechanism. The
precise anatomy of this type of translocation remains to be
determined.
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IG translocations are usually detected by cytogenetics often
supplemented with fluorescence in situ hybridization (FISH) methods using probes that span the IG loci11; the use of
fiber-FISH is an elegant, although technically demanding, method to
define breakpoints precisely.12 Some IG
translocations, such as the t(4;14)(p16;q32) in myeloma, are
cytogenetically cryptic due to the telomeric position of the
breakpoints on the partner chromosomes and therefore need to be
demonstrated by FISH.13 Cytogenetically cryptic
translocations appear to be prevalent in myeloma.14 Whether
similarly undetectable IG translocations are present in other
diseases such as BCP-ALL remains to be determined. The use of
multicolor FISH methods including spectral karyotyping has allowed the
identification of previously unrecognized IG translocations in
myeloma, but these have yet to be applied systematically to all
diseases.15,16
IG translocations may be multiple, with different
translocations involving IGH and IGL. They may occur
early in the course of disease or may occur at the time of
transformation from low- to high-grade disease.17 Multiple
translocation events may occur at the IGH
locus.18,19 Alternatively, similar and even more complex
events may occur in the absence of cytogenetically obvious translocation and may represent insertion of IG
sequences.20,21 It has been shown recently that the
IGH locus has been inserted into the cyclin D1/BCL1
locus in a myeloma cell line, while insertion of BCL2 into the IGH locus has been observed in
patients with follicular non-Hodgkin lymphoma (NHL).22,23
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The origins, analysis, and consequences of IG
translocations |
Normal B cells undergo a series of double-stranded DNA breaks to
produce a functional IG protein with high affinity for
antigen.24 These may predispose to the targeting of
translocations to the IG loci. Although the mechanisms
underlying the pathogenesis of IG translocations remain
unclear, it is likely that errors in each of the interrelated processes
along with defects in other DNA repair genes may play a major role.
In support of this theory is the observation that most, but not all,
IG translocations are targeted to sites commonly involved in
normal recombination events (ie, the J segments, and, in the case of
IGH translocations, the S regions). Targeting of oncogenes to
the JH regions suggests that such translocations might
arise due to errors of VDJ recombination in B-cell precursors within the bone marrow. However, this is not likely: In most cases, analysis of both the productive VDJ rearrangements and both derivative chromosomes shows that translocation arises after antigen is
encountered and IGH class-switching has occurred (ie, in mature
B cells).12,25-27 Targeting of oncogenes to the J regions
in malignancies of mature B cells may in part be explained by
the reactivation of recombination activation genes (RAG) 1/2 in
germinal center (GC) B cells.28
Molecular cloning of chromosome 14q32/IGH translocations has
generally proceeded on the assumption that in most instances the
translocation will involve either the J or the S regions. However, this
is not always the case, and IG translocations may involve
rearranged and unrearranged VH/VL genes,
DH segments, and the JH-Cµ
intron, as described below and in fiber-FISH experiments on myeloma
cell lines.29
The principal molecular consequences of IG translocation are
deregulated expression and, in certain instances, mutation of the
translocated gene. First, deregulated expression of the incoming oncogene arises due to the close physical proximity of potent B-cell
transcriptional enhancers within the IG loci. This may result
in abnormally high levels of protein expression or loss of normal
mechanisms of control, such as the cell cycle-regulated expression of
MYC. Secondly, in B cells where the somatic hypermutation mechanism is active, mutation of the incoming gene may be observed and
may contribute to the neoplastic phenotype. BCL2 mutation in
cases with t(14;18)(q32;q21) has, for example, been associated with
transformation of low-grade disease.30
However, other events associated with IG translocations may
also occur, including, in the t(14;18)(q32;q21), deletion of control elements within the 5' region of the translocated BCL2
gene (some 250 kb telomeric of the breakpoint) and deletion within the
IGH locus.12,31 The consequences of these events
are not known. Similar deletions and rearrangements often hundreds of
kilobases distant from the breakpoint may be observed in other
IG translocations.7 The whole of the derivative
chromosome 14 may be destabilized, perhaps as a consequence of the
IG translocation, with additional breaks occurring centromeric
of the IGH locus, resulting in complex translocations and
amplifications.32
It had been assumed that only one gene would be targeted as a result of
IG translocations and that this gene would be found on the
derivative chromosome 14, close to the site of the
IG-associated transcriptional enhancers. However, in
translocations to S regions the intronic IG enhancer is
translocated to the other partner and this, in some instances at least,
may result in deregulated expression of another gene also. So far, this
has been shown for the t(4;14)(p16;q32) in myeloma, where a single
translocation results in deregulated expression of 2 genes (Figure
2; see also "Myeloma"); whether the same phenomenon is
found in other translocations to S regions remains
unknown.33,34
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| Fig 2.
t(4;14)(p16;q32) translocation in myeloma.
Derivative chromosomes 4 and 14 of myeloma. IGH breaks in
this malignancy are usually found within the S regions. (A)
FGFR3 expression is driven by the centromeric IGH
transcriptional enhancer (E ) on the der(14), while
MMSET expression (B) is driven by the intronic enhancer
(Eµ) on the der(4). Tel indicates telomere.
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IG translocations in B-cell malignancies |
The various IG translocations in malignant B cells are
reviewed below according to cytologic subtype of disease.8
While the acute leukemias are associated with only a single chromosomal translocation, malignancies of mature B cells often exhibit enormous cytogenetic complexity, with multiple and complex translocations, deletions, and amplifications in the 1 clone. This is consistent with
the slower natural history of these diseases. It also concurs with the
hypothesis that several genetic abnormalities including the
concurrent activation of dominant oncogenes and inactivation of tumor suppressor genesare necessary for the full neoplastic phenotype to emerge. Some of the additional changes have been associated with transformation from low- to high-grade disease.
Furthermore, while chromosomal translocations in ALL and acute myeloid
leukemia usually result in fusion of transcription factors controlling early hemopoietic differentiation and development, IG translocations involve a plethora of different molecules
that influence many different pathways. Some of these pathways are described here in detail in the context of specific chromosomal translocations.
B-cell precursor acute lymphoblastic leukemia
BCP-ALL only rarely exhibit IG translocations, which is
perhaps surprising because these malignancies constitutively express RAG1/2 enzymes. However, the frequency of IG translocations may have been underestimated by cytogenetics alone. At least 10% of cases
of BCP-ALL demonstrate deletions of the IGHJ segments, usually on one allele but sometimes on both.35 In most, both
Cµ and C are deleted with retention of
C 3. Mapping of the breakpoints revealed that these
breakpoints fell within the central portion of the intervening sequence
between C and C3. The significance of
this observation remains unknown because this portion of the
IGH locus is genetically unstable and remains uncloned. Whether
these unusual deletions represent internal IGH rearrangements or whether they mark cytogenetically cryptic translocations is not known.
t(5;14)(q31;q32)interleukin-3
(IL 3).
A distinct but rare subset of BCP-ALL is characterized by eosinophilia
and t(5;14)(q31;q32).36 Molecular cloning demonstrated juxtaposition of JH and the IL-3 gene in a
head-to-head configuration, with breakpoints occurring upstream of the
IL-3 promoter, resulting in IL-3 overexpression, which is
detectable in the serum. The granulocyte-macrophage colony-stimulating
factor gene located only 14 kb downstream of the breakpointand
therefore potentially within range of the IGH enhanceris not
overexpressed in this disease.
t(1;14)(q21;q32)BCL9.
Abnormalities of chromosome 1q21-23 are common in all forms of B-cell
malignancy and have been reported to be associated with poor response
to therapy.37 The most common abnormality is duplication of
the region: FISH analysis has shown that some of these duplications can
be complex.
The t(1;14)(q21;q32) is not specific for BCP-ALL and has been reported
in nearly all types of B-NHL as well as myeloma. However, the involved
breakpoints on chromosome 1 appear to be specific for a given disease,
and additional 1q21 breakpoints in other diseases are described below.
BCL9 was identified from the cloning of a t(1;14)(q21;q32)
translocation in a pre-B ALL cell line in which this was the sole cytogenetic abnormality.38 Breaks occurred within the
3' untranslated region (UTR) of BCL9 and within
JH. BCL9 sequence analysis predicted a protein of
1394 amino acids with no known homologies. Deregulated expression of
BCL9 was seen in the cell line carrying the translocation but
not in a panel of BL cell lines with other 1q21 abnormalities. Rearrangements of the locus were seen in 2 of 39 cases of B-NHL of
other subtypes, including 1 case with a variant t(1;22)(q21;q11) involving the IG locus. At present, the function of
BCL9 and the mechanism by which this gene may mediate B-cell
transformation remain unknown.
t(9;14)(p21;q32)cyclin-dependent kinase
inhibitor 2 (CDKN2).
Chromosome 9p21 harbors the CDKN2A/B tumor suppressor locus,
which commonly undergoes biallelic deletion in B- and T-cell precursor
ALL. In one case of BCP-ALL, the translocation t(9;14)(p21;q11) involved the T-cell receptor TCRD/A locus with this locus,
resulting in inactivation of the p16/p19 ARF gene.39 This
observation is of interest because it illustrates that some IG
translocations may involve tumor suppressor genes and result in loss of
gene expression. A parallel translocation t(9;14)(p21;q32) has been described in a BCP-ALL cell line, although whether this involves the
same gene on chromosome 9p21 remains to be determined.40
Burkitt lymphoma/B-cell ALL Fab type L3
t(8;14)(q24;q32)MYC.
BL is characterized by translocations involving the MYC gene at
chromosome 8q24.6 In 75% of cases, a reciprocal
translocation t(8;14)(q24;q32) is seen between the MYC gene and
the IGH locus while, in the remainder, the reciprocal
translocations t(8;22)(q24;q11) or t(2;8)(p12;q24) are seen,
juxtaposing MYC to one of the IG light chain loci.
These translocations are not specific for BL and are seen in many other
subtypes of B-cell malignancy. They may occur as a secondary event in
transformation of follicular B-NHL to high-grade
disease.17,41 Variant translocations involving MYC
with a variety of other non-IG loci have also been reported.
The MYC gene consists of 2 coding exons and a noncoding first
exon and, in most cases of sporadic BL, the breakpoints on 8q24.1 are
located 5' of the coding region, either in the first intron, within the first exon, or 5' of the first exon. In contrast, in most cases of endemic BL and in cases with variant translocations, the
MYC breakpoints may be considerable distances centromeric or
telomeric from the MYC coding exons. In addition to the
translocation, approximately 65% of BLs demonstrate MYC point
mutations.42
Myc expression is normally tightly linked to the early G1
phase of the cell cycle. As a result of translocation to the IG loci, control of normal Myc expression is lost, and the protein is
constitutively expressed throughout the cell cycle. Despite much work,
the precise functions and roles of Myc in oncogenesis remain
unclear. Myc can function both as transcriptional activator and transcriptional repressor, and the identification of Myc target genes remains a major goal. Myc can function as an inducer of apoptosis
and as an inducer of proliferation. These functions have been reviewed
recently.43
Mantle cell lymphoma
t(11;14)(q13;q32)BCL1/cyclin D1.
The translocation t(11;14)(q13;q32) is found in a wide variety of
B-cell malignancies, including mantle cell lymphoma (MCL), splenic
lymphoma with villous lymphocytes (SLVL), B-cell prolymphocytic leukemia, and multiple myeloma.44 All cases of MCL exhibit
the t(11;14)(q13;q32) or, rarely, variant translocations to the
IG light chains.45 The result in MCL is the
juxtaposition of the0 locus originally referred to as BCL1 on
chromosome 11q13 to an IGHJ segment. However, in some cases of
B-NHL and in multiple myeloma, translocations occur instead to
IGHS regions.46 The consequences of the
translocation are the overexpression of cyclin D1, a D-type cyclin
involved in control of the cell cycle. Although some of the breakpoints
on 11q13 fall within the major translocation cluster, most are
dispersed over a region of about 130 kb centromeric of the cyclin
D1 gene.7,44
Follicular B-NHL
t(14;18)(q32;q21)BCL2.
Approximately 80% of cases of follicular lymphoma are associated with
t(14;18)(q32;q21). This results in juxtaposition of BCL2 on chromosome 18q21.3 with IGHJ. The breakpoints
within IGH all fall within JH, while the
breakpoints on chromosome 18q21 occur mostly within the 3' region
of the gene (Figure 1). Unlike the breaks within the BCL1
locus, BCL2 breaks are clustered. Fifty percent of the 3'
BCL2 breaks falls within a major breakpoint region, a
150-breakpoint region within the 3' UTR of the gene, and another
25% falls in the minor cluster region. Others cluster within a third,
intermediate cluster region midway between the major breakpoint region
and minor cluster region,47,48 while other breakpoints have
been described scattered through this region. The remaining breakpoints
on chromosome 18 fall within the 5' noncoding region of the gene.
5' BCL2 breaks are found predominantly, although not
exclusively, in B-CLL and are involved predominantly in translocation
to the IG light chain loci.49
The result of the translocation is deregulated expression of the 26-kd
BCL2 protein, one of a family of proteins involved in the regulation of apoptosis.
t(1;22)(q22;q11)Fc gamma receptor IIB
(Fc RIIB/CD32).
A recurrent abnormality in follicular lymphoma is the t(1;22)(q22;q11)
translocation, which arises at the time of transformation to high-grade
disease.50 The target gene of this translocation is the IgG
Fc gamma receptor IIB (FCGRIIB), a member of the low-affinity IgG Fc family of transmembrane receptors. In this case, the breakpoint was located approximately 20 kb upstream of the FCGRIIB.
Diffuse large-cell lymphoma
Unlike follicular B-NHL, diffuse large-cell lymphoma (DLCL) exhibits
a plethora of different IG translocations.4 Some of these are recurrent, while others appear to be unique. The
t(14;18)(q32;q21) in about 30% of DLCL is thought to represent the
transformation of follicular B-NHL. The detection of this translocation
in DLCL appears to have little prognostic significance, but high-level BCL2 protein expression, which correlates poorly with the presence of
t(14;18), is a predictor of reduced overall and disease-free survival
in DLCL.51,52 IG translocations are found in about 50% of DLCL cases. Whether the DLCL cases that lack IG
translocations constitute a distinct histologic entity with distinctive
biological behavior remains to be determined.
t(3;14)(q27;q32)BCL6.
DLCL is frequently associated with reciprocal translocations involving
chromosomal band 3q27 and either one of the IG genes or another
partner chromosome.53 Cloning of the t(3;14)(q27;q32) translocation allowed the identification of BCL6, a zinc-finger transcription factor.54-56 Subsequent studies have
demonstrated that rearrangements of the BCL6 gene are found in
30% to 40% of DLCL, 5% to 14% of follicular lymphoma, and 20% of
acquired immunodeficiency syndrome-associated DLCL, resulting in
juxtaposition of the BCL6 coding region to heterologous
promoters.57 The 5' noncoding region of BCL6
undergoes somatic point mutation, independent of translocation, not
only in approximately 70% of DLCL and 45% of follicular lymphoma, but
also in normal GC B cells.58-60
In one series, rearrangements of BCL6 were associated with
extranodal presentation and a favorable clinical outcome.61
However, this has not been duplicated in other studies, and
BCL6 rearrangements do not seem to be associated with a
particularly bad or good clinical subgroup of DLCL.62,63
BCL6 is expressed at low levels in multiple tissues, but in B
cells its expression is tightly regulated. It is highly expressed only
in mature B cells and within the GCs of lymph nodes but not in pre-GC
cells or in differentiated plasma cells.64 However, in the
mantle zone, there is expression of BCL6 messenger RNA (mRNA)
but not protein.
BCL6 is a 92- to 98-kd nuclear phosphoprotein65 that
contains 6 Krüppel-type zinc-finger motifs in its
carboxy-terminal region and an amino-terminal POZ/BTB motif shared by
various zinc-finger proteins.66,67 The amino-terminus
contains a sequence-specific transcriptional repressor domain mediated
by a region that includes the POZ motif.68,69 B-cell
receptor (BCR)-mediated signaling via mitogen-activated
protein kinase results in phosphorylation of BCL6 at Ser333 and Ser343,
residues contained in PEST sites within the serine- and proline-rich
central region, resulting in subsequent targeting for ubiquitination
and proteosomal degradation.70,71
Gene inactivation studies have shown that BCL6 plays a key role
in the activation and proliferation of B cells within the GC.72 Loss of the normal control mechanisms regulating its
expression contributes to malignant transformation in GC-derived
lymphomas. However, overexpression of the gene results in apoptosis and
delays S-phase progression,73 and it remains unclear how
BCL6 overexpression leads to transformation. No mouse transgenic models
for BCL6 have been reported to date.
t(14;15)(q32;q11-13)BCL8.
Abnormalities of 15q11-13, including the translocation
t(14;15)(q32;q11-13), are seen in 3% to 4% of DLCL.74 A
t(14;15)(q32;q11-q13) breakpoint has been cloned from a patient with
DLCL, allowing the isolation of a new gene, BCL8, adjacent to
the breakpoint. Interestingly, in this case the breakpoint fell
upstream of a rearranged VH segment. The BCL8 locus
was rearranged in approximately 4% of cases of DLCL by Southern blot.
The gene is normally expressed only in prostate and testis, with no
detectable expression in spleen or thymus. BCL8 expression was
detected in all patients with 15q11-13 abnormalities analyzed and in
some without such abnormalities but not in normal lymphocytes.
Deregulated expression of BCL8 may therefore contribute to the
pathogenesis of a subset of DLCL cases. The functions of this gene
remain to be determined.
t(10;14)(q24;q32)NFKB2.
The chromosome band 10q24 is involved in heterogeneous aberrations,
including deletions and translocations to IGH in about 5% of
low-grade B-NHL and less frequently in intermediate- to high-grade
B-NHL.75 Molecular cloning of a t(10;14)(q24;q32) translocation breakpoint involving the C
locus led to the identification of NFKB2 adjacent to the
breakpoint.76 The NFKB2 gene encodes the protein
products p52 and p100, members of the Rel/nuclear factor
(NF)- B family.
Marginal zone lymphomas
t(9;14)(p13;q32)paired homeobox 5 (PAX5).
Lymphoplasmacytoid lymphoma (LPL)/immunocytoma is a rare subtype of
lymphoma that progresses slowly, if at all, and only rarely transforms.77 It is thought to originate from peripheral B
cells that have been stimulated to undergo plasma cell differentiation.
Translocations involving chromosome 9p13 are frequently seen in LPL and
involve various chromosome loci, including 1q25, 3q27, 7q11, 12q13,
12q21, 14q32, and 19p13.78
The t(9;14)(p13;q32) was initially reported in the DLCL cell line KIS-1
and is detectable in 50% of LPL.77 Molecular
characterization of this translocation has shown the IGH locus
to be juxtaposed in a head-to-head configuration to the PAX5
locus on chromosome 9p13, resulting in deregulated expression of
PAX5 mRNA.79,80 Five of 7 cases with 9p13
translocations demonstrated rearrangements by FISH with a YAC probe
spanning the PAX5 locus. The breakpoints, however, were highly
heterogeneous, and whether PAX5 is the sole target gene of 9p13
translocations is unclear.
t(1;14)(p22;q32)BCL10.
Lymphomas of the mucosa-associated lymphoid tissue (MALT) are the most
common form of lymphoma arising in extranodal sites, in most cases
arising in the gastric mucosa.
Low-grade MALT lymphoma is an indolent disease usually preceded by
chronic inflammation, either chronic Helicobacter pylori infection of the stomach or autoimmune disease such as Hashimoto's thyroiditis. Low-grade gastric MALT lymphoma is often initially dependent on H pylori for growth, as some cases regress with
antibiotic therapy alone.81 The molecular events leading to
the development of H pylori-independent growth and high-grade
transformation are not well understood. However, cytogenetic studies of
aggressive low-grade cases have identified abnormalities of chromosome
1p22, particularly translocation t(1;14)(p22;q32), as uncommon but
recurrent events.
Molecular analysis of the t(1;14)(p22;q32) translocation breakpoint in
MALT lymphoma allowed the identification of the BCL10 gene
juxtaposed in a head-to-head configuration with
IGHJ.82,83 The 1p22 breakpoints in other cases of
MALT lymphoma exhibiting the same translocation also map to this
region. BCL10 is widely expressed in normal tissues but is
highly expressed within lymph node GCs82 and in fetal
liver, lung, and parts of the developing neurologic
system.84
t(2;7)(p12;q21); (7;14)(q21;q32)CDK6.
A case of CLL with the translocation t(7;14)(q21;q32) originally
demonstrated the juxtaposition of IGH with a human endogenous retroviral sequence of the transposable-like human element
family.85 Cloning of t(2;7)(p12;q21) in SLVL has
subsequently revealed that the target gene for this translocation is
the CDK6 gene,86 one of the cell cycle-associated
kinases that promotes G1 to S phase transition.87 It is likely that all 7q22 translocations
involving CDK6 are specific to SLVL because chromosome 7q22 is a
recurrent breakpoint in this disease and not CLL.
Interestingly, the t(2;7)(p12;q21), the breakpoint on chromosome 2 involved an unrearranged V gene through the 3'
heptamer nanomer recombination signal sequence (RSS).
B-cell chronic lymphocytic leukemia
t(14;19)(q32;q13)BCL3.
The recurrent translocation t(14;19)(q32;q13) is a rare cytogenetic
abnormality found in CLL but is associated with a young age of
presentation and a poor prognosis. The result of the translocation is
to juxtapose BCL3 and IGH in a head-to-head
configuration, resulting in overexpression of BCL3 mRNA due to
the 3' IGH enhancer.88
t(2;14)(p13;q32)BCL11A.
The translocation t(2;14)(p13;q32) is a rare but recurrent abnormality
in what has been described as "childhood chronic lymphocytic leukemia." The translocation breakpoints for 2 such cases have been
cloned.89 Translocations involving the same breakpoint have
been observed in a subgroup of adult patients with an aggressive atypical CLL/B-NHL (Takashi Sonoki, Tony Willis, Martin Dyer, Reiner
Siebert, unpublished observations, January 2000).
t(12;22)(p13;q11)cyclin D2 (CCND2).
Transformation of CLL to high-grade B-NHL (Richter's syndrome) occurs
in about 5% of patients. A case of Richter's syndrome, which acquired
a t(12;22)(p13;q11) as a secondary event during high-grade
transformation, demonstrated juxtaposition of the IG locus
and CCND2, with the additional loss of the negative regulatory elements in the upstream segment of the CCND2
promoter.90
Myeloma
All cases of myeloma may exhibit IG translocations. Like
DLCL, these involve numerous partner chromosomes and, like DLCL, some
of these may be recurrent, while others are either unique or
rare.14-16 Consistent with the mature B-cell phenotype of
the disease and the expression of Ig isotypes other than IgM, most translocations occur to the IGH S regions.29 Many
genes have now been shown to be involved in these translocations, but
their clinical significance remains to be determined.
t(4;14)(p16;q32)FGFR3 and MMSET/WHSC1.
The karyotypically silent t(4;14)(p16;q32) translocation is detected in
approximately 20% to 25% of multiple myeloma cases and cell lines.
The effects of this translocation are unusual in that there is
deregulated expression of 2 genes (Figure 2), first, on the der(14)
chromosome of the fibroblast growth factor receptor 3 (FGFR3)91,92 and, secondly, on the der(4) of a
novel SET domain-containing gene, MMSET (multiple myeloma SET
domain), or WHSC1 (Wolf-Hirschhorn syndrome candidate
1).33,34
Cloning of the t(4;14)(p16;q32) translocation initially identified
FGFR3 on the der(14) as the target. In each case, the
breakpoint was situated 30 to 100 kb upstream of the
FGFR3 gene (Figure 2A). FGFR3 is normally expressed in
the developing central nervous system and in cartilage growth plates
but is undetectable in lymphoid tissues; the t(4;14)(p16;q32)
is associated withoverexpression of the FGFR3 transcript due to
the effects of the 3' IGH enhancer.
The FGFRs are tyrosine kinase receptors capable of binding 9 related
mitogenic fibroblast growth factors (FGFs).93 Ligand binding promotes receptor homodimerization or heterodimerization, leading to complex signaling pathways regulating cell growth, survival,
and differentiation. FGFR3 may promote or inhibit cell proliferation
depending on cell type. FGFR3 inhibits proliferation of chondrocytes,
and dominant, activating mutations in different domains of FGFR3 result
in excessive inhibition of chondrocyte proliferation, resulting in
dwarfism, including hypochondroplasia, achondroplasia, and the most
severe form, thanatophoric dysplasia.94 However,
transfection of FGFR3 into an IL3-dependent B-cell line allows
IL3-independent mitogenic stimulation.95
In some cases of myeloma with t(4;14)(p16;q32), overexpression of an
FGFR3 allele containing an activating mutation associated with
thanatophoric dysplasia have been detected.91 One of these (Lys650Glu) has been shown by transient transfection experiments to
cause ligand-independent constitutive activation of FGFR3 by autophosphorylation96 and to promote IL-6 independence in
murine IL-6-dependent B cells.97 This observation may
at least in part be explained by the finding that FGFR3
overexpression, like IL-6, upregulates BCL-xL
expression and inhibits apoptosis of IL-6-dependent B
cells.98 Deregulated expression of unmutated
FGFR3 may allow the continuous transduction of
pro-proliferative signals from bone marrow stromal cells expressing
FGFs, whereas subsequent mutation of FGFR3 would allow
FGF-independent growth.
Further analysis of the t(4;14)(p16;q32) translocation has demonstrated
that the breakpoints on 4p16 occur telomeric to and within the 5'
introns of a novel gene, MMSET or
WHSC1,33,34 which is in the opposite
transcriptional orientation to the FGFR3 gene and is also
deregulated as a result of the translocation (Figure 2B). The
MMSET gene is alternatively spliced, resulting in 2 different
transcripts. The type I transcript contains an open reading frame
coding for a 647-amino acid protein, whereas the type II transcript
encodes a protein of 1365 amino acids. IGH-MMSET hybrid
transcripts originating from the Iµ promoter were
detected in cases and cell lines demonstrating the t(4;14) translocation but would not be expected to result in fusion proteins. The functions of MMSET, and its possible contribution to myeloma pathogenesis, are unknown.
t(6;14)(p25;q32)IRF4.
The t(6;14)(p25;q32) is another recurrent translocation in myeloma,
which cannot be easily detected because of the subtelomeric position of
the 6p25 breakpoint, but it occurs in about 20% of patients.99 In the myeloma cell line SKMM1, the breakpoint
on 6p25 was located just 3' of the IRF4 (interferon
regulatory factor 4) gene.100 The IRF family of
transcription factors includes at least 6 molecules that share homology
in their amino-terminal DNA-binding domains and are active in the
regulation of gene expression in response to signaling by interferons
and by other cytokines.101 IRF4 promoted transformation in
vitro when overexpressed in fibroblasts100 and has been
shown to control the differentiation of B cells into plasma cells and
their proliferation in response to various mitogenic stimuli.
IRF4-deficient mice develop progressive generalized lymphadenopathy and
do not mount detectable antibody, cytotoxic, or antitumor responses,
indicating a requirement for IRF4 in B- and T-cell homeostasis.102
t(14;16)(q32;q23)c-MAF.
Approximately 25% of cases of multiple myeloma display the
translocation t(14;16)(q32;q23). Cloning of translocation breakpoints from 4 myeloma cell lines with this abnormality demonstrated that these
were dispersed over an approximately 500-kb region centromeric to the
C-MAF proto-oncogene at 16q23.103 A further cell
line with a variant t(16;22)(q23;q11) involving IG contained a
breakpoint telomeric to C-MAF so that the breakpoints in these
cell lines bracketed the C-MAF locus. Deregulated expression of
C-MAF mRNA of 2.3 and 4.4 kb was detected in these cell lines,
coding for predicted proteins of 403 and 373 amino acids, respectively.
C-Maf is a member of the bZIP family of transcription factors, which
includes c-Jun, c-Fos, NF-IL3, and NF-IL6. The viral homologue, v-Maf,
is an oncogene produced by an avian transforming virus, and wild type
c-Maf is able to transform fibroblast cells.104 Other
members of the basic zipper family are involved in control of many
cellular processes, including proliferation, differentiation, and
responsiveness to IL6. The mechanism whereby c-Maf might contribute to
myeloma pathogenesis is not known.
t(1;14)(q21;q32)MUM2/MUM3.
Two genes within a 20-kb region spanning the 1q21 breakpoint in a
myeloma cell line demonstrating t(1;14)(q21;q32) have been identified.105 Both genes (MUM2 and MUM3)
are normally expressed in spleen and lymph nodes and share homologies
with the FcR family of cell surface receptors: The coding region of
MUM2 is interrupted by the translocation, yielding a
structurally abnormal transcript, whereas that of MUM3 is
intact. The protein homologies and their pattern of
expression suggest that these genes may play a role in normal
B-cell development and that aberrant signaling through these proteins
may play a role in the development of a subgroup of myeloma.
| |
Pathways to B-cell malignancy |
Malignancies arising from B cells at different stages of
differentiation exhibit different spectra of genetic abnormalities. Many of the genes identified through their direct involvement in
IG translocations play pivotal roles not only in the
development of malignancy but also in the development and activation of
normal B cells, particularly within the GC. Most appear to be involved in at least 1 of 4 mechanisms of cellular regulation, including apoptosis, cell cycle progression, NF-B activation, and signal transduction pathways from cell surface receptors.
A key experiment is the creation of mouse transgenic models in which
the translocation is re-created by placing the gene of interest under
the control of the IGH intronic (Eµ) enhancer. While this results in overexpression throughout the B-cell lineage rather than just in mature B cells, such models have been useful in
defining the roles of these genes in B-cell neoplasia. Interestingly, most genes expressed in this context, including BCL2 and cyclin D1, do not alone result in B-cell neoplasia, again indicating the
necessity for the concurrent involvement of other oncogenes and tumor suppressors.
Apoptosis
Suppression of apoptosis in the context of the indolent B-cell
malignancies is a key and presumably early event, allowing the
persistence of B cells that would otherwise die within the GC. When
these cells acquire secondary genetic abnormalities, the full
neoplastic phenotype emerges. Inappropriate high-level BCL2
expression mediated either by IG translocation or by changes within the promoter plays a role in follicular B-NHL and CLL, respectively.106 However, some B-cell malignancies,
including BL and a subgroup of DLCL, fail to express BCL2, and
in these cases the mechanisms by which apoptosis is suppressed are not clear. Mutations of p53 play a role in some BL107 but,
otherwise, p53 mutations are for the most part secondary events
associated with a poor prognosis in disease of all histologic
subtypes.108
The synergistic interaction of BCL2 and MYC.
BCL2 belongs to a family of proteins containing at least 15 mammalian
homologues, all of which contain at least 1 of 4 conserved motifs known
as BCL2 homology domains (BH1 to BH4) and which may promote or inhibit
apoptosis.109,110 BCL2 prolongs cell survival by inhibiting
apoptosis in response to a wide variety of stimuli and is localized to
the intracellular organelles, including the cytoplasmic face of the
mitochondrial outer membrane.111 Its three-dimensional
structure has been determined by x-ray crystallography and nuclear
magnetic resonance spectroscopy and closely resembles those of some
types of bacterial toxins, such as the membrane insertion domain of the
diphtheria toxin and the pore-forming colicins A and E1.112
As predicted from the structure, BCL2 and BCL-xL, as well
as the proapoptotic molecule BAX, can form ion channels when they are
added to synthetic membranes.113-115 How interactions between these proteins control apoptosis has been
reviewed.109,110
E-Bcl2 transgenic mice show an
excess of mature B cells in keeping with the antiapoptotic action of
Bcl2.116,117 Similarly, overexpression of Bcl2 in a variety
of cell lines does not result in transformation but, rather, protection
from apoptosis.109,110 Eµ-Bcl2 mice do not develop
malignancies until the acquisition of secondary genetic aberrations,
including deregulation of Myc.118 Crossing of
E-Bcl2 and
Eµ-Myc mice confirms the synergistic interaction of the 2 genes, with rapid onset of lymphoid precursor malignancies.119
However, BCL2 also modulates cell cycle progression, promoting exit
into G0, an effect that appears to require critical
residues within the NH2-terminal domain and that is
dissociable from its antiapoptotic activity.120,121 This
effect may be mediated through the inhibition of p27 (KIP1)
degradation, leading to reduced CDK2 activity 122 (Figure
3). The secondary genetic abnormalities commonly seen in follicular B-NHL may therefore be necessary to overcome the cell cycle inhibitory effects of BCL2. Somatic mutations of the translocated BCL2 gene have been described in
transformed follicular B-NHL.30,123 Many of these mutations
appear to be clustered in the NH2-terminal domain, and some
have been associated with a growth advantage over wild-type BCL2 in
vitro, possibly as a result of the loss of the normal cell
cycle inhibitory effects displayed by the wild-type protein.
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| Fig 3.
Modulation of the cell cycle by IG
translocations.
A simplified diagram of the G1- to S-phase
transition. Genes that are deregulated as a result of IG
translocation are shown in yellow. Cyclin D1/CDK6:
Mitogenic signals result in transcriptional up-regulation of cyclin D1
and Akt-mediated inhibition of cyclin D1 degradation. Active cyclin
D1-CDK4/6 (represented here by CDK6 for simplicity) phosphorylates Rb.
The cell cycle inhibitors p27 (KIP1) and p21 (CIP1/WAF1) (represented
by p27 [KIP1]) are required for assembly and activation of cyclin
D-CDK4/6 complexes but mediate their inhibitory effects on the cell
cycle through inactivation of cyclin E-CDK2. Overexpression of D-type
cyclins or CDKs swings the equilibrium toward G1- to
S-phase transition by causing sequestration of p27 (KIP1) and p21
(CIP1/WAF1), allowing activation of cyclin E-CDK2. Rb is phosphorylated
further by cyclin E-CDK2, promoting its dissociation from E2F, which
then drives transcription of genes required for S-phase entry,
including cyclin E. A feedback loop operates whereby cyclin E-CDK2
phosphorylates and promotes proteolytic degradation of p27 (KIP1).
Myc: Myc mediates its effects on the cell cycle at least partly
through transcriptional up-regulation of cyclin D1/D2, which, complexed
with CDKs, sequester the cell cycle inhibitors p27 (KIP1) and p21
(CIP1/WAF1). NF-B: NF-B also promotes transition through
the cell cycle through direct up-regulation of cyclin D1 transcription.
BCL2: BCL2 appears to exert its inhibitory effects on the cell
cycle through modulation of the p27 (KIP1) degradation pathway. Ub
indicates ubiquitin; P, phosphorylation; D1, cyclin D1; E, cyclin E.
|
|
Other secondary abnormalities include deregulation of Myc, usually due
to IG translocation. In some instances, translocation of
BCL2 and MYC may occur at the one IGH allele.
As indicated above and when seen clinically, the combination of
concurrent deregulation of BCL2 and Myc results in a highly malignant
phenotype that is usually resistant to combination
chemotherapy.124
This is of some interest because Myc induces apoptosis when
overexpressed in fibroblasts.125 An important mediator of
Myc-induced apoptosis is the ARF-Mdm2-p53 pathway126
(Figure 4). Myc activation in mouse embryo
fibroblasts results in elevated p19 (ARF) (the alternative open reading
frame of the INK4A locus) and p53 levels,127 leading to apoptosis. Therefore, abrogation of Myc-induced apoptosis is
necessary to allow the full transforming potential of Myc to develop.
Transgenic mice expressing Myc under the control of the immunoglobulin
heavy chain enhancer (Eµ-Myc) accumulate large populations of undifferentiated pre-B lymphocytes and eventually develop lymphoma.128 Eµ-Myc mice
sustain spontaneous inactivation of either p53 (28%) or ARF
(24%) or overexpress Mdm2 129 and develop
lymphoma more rapidly in a hemizygous p53 or hemizygous ARF background
than in controls.130 Lymphomas arising in these hemizygous
animals have almost invariably lost the wild-type allele and are
therefore either p53-null or ARF-null, demonstrating that inactivation
of this pathway is an important step in Myc-mediated oncogenesis.
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| Fig 4.
Synergistic interaction of BCL2 and Myc.
Genes involved in these processes, which are deregulated by IG
translocations, are shown in yellow. BCL2: Central to the
control of apoptosis is the release of cytochrome c from the
mitochondrion, resulting in activation of procaspase 9. BCL2 prevents
this by maintaining ADP/ATP exchange through the voltage-dependent
anion channel (VDAC) within the mitochondrial membrane, inhibiting
H+ accumulation in the intermembrane space and subsequent
cytochrome c release. However, BCL2 also inhibits proliferation by
promoting cell cycle arrest. Myc: Myc mediates both
proliferation and apoptosis. Blocking of Myc-induced apoptosis by
genetic events, such as BCL2 overexpression or alterations in the p19
(ARF)-Mdm2-p53 pathway, results in unrestrained proliferation.
|
|
Blocking of Myc-induced apoptosis is therefore necessary for the
proliferative oncogenic potential of Myc (see below) to be realized in
B-cell malignancies. The mechanism involved is cell type-dependent.
Loss of p19 ARF usually occurs by deletion in lymphoid malignancies and
is typically seen in BCP-ALL, although it may sometimes be seen in
B-NHL at transformation to high-grade disease. Mutation of p53 is
commonly seen in BL and in B-cell prolymphocytic leukemia but,
otherwise, these mutations are usually secondary events in B-cell
malignancies.107,108 Deregulated BCL2 occurs as an
antecedent event in follicular B-NHL.
Cell cycle regulation
In mammalian cells, transition through the cell cycle is controlled
at different checkpoints. (Figure 3). Regulation is achieved through a
family of serine/threonine protein kinases consisting of regulatory
cyclin subunits that bind to and activate catalytic CDK subunits. The
cyclin-CDK complexes most closely linked to the late G1
phase checkpoint are the D-type cyclins (D1, D2, and D3) and their
partners CDK4 and CDK6. The major targets of cyclin D/CDK4 and cyclin
D/CDK6 complexes are the retinoblastoma protein (Rb) and its related
family p107 and p130.131
Activation of CDKs is regulated by a variety of mechanisms, which
include binding of cyclins, CDK inhibitors, and phosphorylation. The 7 mammalian CDK inhibitor genes identified thus far belong to 2 separate
families and are responsible for integrating many growth-inhibitory
pathways, including responses to DNA damage, senescence, and contact
inhibition.132 The INK4 family includes 4 closely related
ankyrin repeat-containing genes: p16 (INK4a), p15 (INK4b), p18 (INK4c),
and p19 (INK4d). INK4 proteins bind to CDK4 or CDK6 and prevent D-type
cyclin binding and activation. The CIP1/KIP1 family contains 3 genes:
p21 (CIP1/WAF1), p27 (KIP1), and p57 (KIP2).
p21/p27/p57 regulate multiple CDK enzymes, including CDK4/6-cyclin D,
by forming ternary complexes with CDK and cyclin proteins. Recent
evidence points to a role of p27 (KIP1) in activation of CDK4/6-cyclin
D complexes and inhibition of CDK2-cyclin E.132 Additionally, CDK2 and CDK4 are both regulated by phosphorylation and
dephosphorylation by CAK and cdc25, respectively.
Myc.
Myc is required for progression through the cell cycle, and normally
its expression correlates tightly with the proliferative state of the
cell. The functions of Myc in this regard have been recently
reviewed.43
Myc-null cell lines are characterized by a profound growth defect due
to a lengthening of both the G1 and G2 phases
of the cell cycle. The largest defect observed in these cells is a
12-fold reduction in cyclin D1-CDK4 and D1-CDK6 complexes during
G1 to S phase transition. However, the activity of other
cyclin-CDK complexes, including cyclin E-CDK2 and cyclin A-CDK2, is
also diminished, and growth rate is not restored by overexpression of
these cyclins.133 These findings are explained by the
finding that Myc directly induces expression of cyclins D1 and D2
(Figure 3), which, as cyclin-CDK complexes, sequester the cell cycle
inhibitors p27 (KIP1) and p21 (CIP1/WAF1),134,135 thereby
releasing inhibition from cell cycle control. This is at least one of
the pathways required for Myc's proliferative effects.
Cyclin D1.
Ectopic expression in G1 phase of cyclin D1 under the
control of an inducible promoter causes early phosphorylation of Rb and
acceleration of the cell cycle through G1.136 In
lymphoma cell lines carrying the t(11;14) translocation, although cyclin D1 is still regulated in its normal cyclical manner (unlike Myc
in BL), its overexpression causes acceleration through G1 phase137 (Figure 3). However, although cyclin D1
overexpression is sufficient to confer transformed properties on
established fibroblasts, it is insufficient to transform primary cells
or to induce lymphomagenesis in Eµ-cyclin D1 transgenic
mice.138 These mice demonstrated remarkably few
abnormalities in their lymphoid population. Consistent with a multistep
process of tumorigenesis, however, cyclin D1 collaborates strongly with
Myc and modestly with p21Ras in lymphomagenesis in
double transgenic animals.138,139
Cyclin D2.
Cyclin D2, like cyclin D1, is involved in control of G1 to
S phase transition (Figure 3), and its overexpression would be expected
to result in loss of the normal cell cycle control mechanisms.
CDK6.
Overexpression of CDK6 in B cells containing the translocation is
likely to contribute directly to their pathogenesis by acceleration of
the cell cycle through the G1- to S-phase transition
in a similar way to overexpression of cyclin D1/D2 or inactivating
mutations of the INK4 proteins (Figure 3). However, it is noteworthy
that SLVL, the disease in which this overexpression occurs, is
classically associated with a very low proliferative rate, suggesting
that the overexpression of CDK6 may influence other pathways.
NF-B activation
Mature B cells exhibit constitutive NF-B
activation.140 The genes leading to this activation are
frequently targets both of chromosomal translocation and
mutation.141
The Rel/NF-B family is a family of transcription factors involved in
the regulation of expression of a variety of cellular and viral genes,
including those that control immune responses, acute phase reactions,
and the replication of viruses.142 NF-B transcriptional
activity is mediated by dimeric complexes generated though the
combination of the various members of the Rel/NF-B family. These
proteins all share a highly conserved amino-terminal Rel homology
domain responsible for DNA binding, dimerization, nuclear localization
functions, and cytoplasmic association with inhibitors of the IB family.
The Rel/NF-B family can be broadly divided into 2 groups. The first
group is represented in mammalian cells by p65 (RelA), RelB, and c-Rel,
which contain the amino-terminal Rel domain and distinct
transactivation domains within their carboxy-terminal regions. The
second group contains NF-B1 (p105/p50) and NF-B2 (p100/p52),
which exist as 2 forms: (a) long (p105 and p100), containing
the amino terminal Rel homology domain, a polyglycine region, and a
carboxy-terminal ankyrin domain, and (b) short (p50 and p52),
possessing only the DNA-binding Rel domain. The ankyrin domains in both
long forms are homologous to the IB family of proteins and act in a
regulatory fashion.
In unstimulated cells, the ankyrin-containing IB proteins interact
with Rel/NF-B complexes and sequester them in the cytoplasm by
masking the nuclear localization signal (Figure
5). On stimulation, IB is
phosphorylated, ubiquitinated, and degraded. This allows NF-B to
translocate to the nucleus and bind to specific cis-acting consensus
sequences (B sites) located in the regulatory region of inducible
genes, including cytokines (eg, TNF , IL-2, IL-6, IL-8,
-interferon), adhesion molecules (eg, intracellular adhesion molecule-1, vascular cell adhesion molecule-1), genes involved in
regulation of apoptosis or response to NF-B (eg, TRAF1/2, cIAP1 and
2, TNFR1, A20, IB), and those involved in cell cycle regulation
and proliferation (eg, cyclin D1, MYC, p53, Rb).143 Activation of NF-B is thought to be necessary for transformation by
a variety of stimuli although, in some cell types, it may also lead to
apoptosis.144
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| Fig 5.
Modulation of NF-B activation by IG
translocations.
Genes involved in these processes, which are deregulated by IG
translocations, are shown in yellow. NF-B activation by
extracellular signals such as TNF is mediated via a signaling pathway
involving the death initiator signaling complex (DISC), TRAF2, NIK,
IKK, and phosphorylation and degradation of IB. NF-B2:
Truncated NF-B2 proteins as found in some lymphomas are
constitutively active transcription factors, mediating up-regulation of
NF-B target genes, including those involved in proliferation and
apoptosis, such as cyclin D1 and Bcl-xL. BCL10:
BCL10 mediates both NF-B activation, through its recruitment to the
DISC, and apoptosis via mechanisms that remain unclear. Truncated BCL10
maintains its NF-B-activating functions but loses its apoptotic
activity. BCL3: BCL3 is an IB family member, which mediates
transcriptional up-regulation of NF-B target genes through
interaction with p50/p52 homodimers.
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|
The tumor necrosis factor (TNF) signaling pathway is the most
extensively studied pathway leading to NF-B activation, but it
shares common elements with a number of other pathways, including IL-1- and CD40-mediated signaling. Binding of TNF to TNF receptor (TNFR) results in recruitment of TNF receptor-associated factors (TRAFs), particularly TRAF2, 5, and 6.145 Recruitment of
NF-B-inducing kinase (NIK) to TRAF2 results in a kinase cascade
mediated by NIK146 and IB kinases (IKK and
 ),142,147 finally resulting in phosphorylation of
IB at Ser32 and Ser36 (Figure 4). However, this is not the only
pathway to IB phosphorylation and degradation,148 and
NF-B activation can also be mediated in the absence of IB degradation, as seen in IgG+ B cells.140
NF-B-dependent signaling pathways play an essential role in B-cell
development, as evidenced by studies on knockout mice.142
NF-B2.
The result of the t(10;14)(q24;q32) is an NF-B2-C1 fusion that
retains the Rel effector and poly-G domains but is fused to an
out-of-frame and prematurely truncated C1.76
Rearrangements within the 3' region of NFKB2 have also
been reported in about 2% of other lymphoid malignancies and
particularly in cutaneous lymphomas, occurring either as a result of
other translocations or, more commonly, as a result of interstitial
deletions of chromosome 10q24.149 The rearranged
NFKB2 genes encode either truncated NF-B2 or fusion products
to heterologous molecules: These lack some or all of the ankyrin
repeats at the C-terminus but retain an intact Rel homology
domain.150 Like the p52 subunit, these mutant proteins are
constitutively localized to the nucleus, presumably through the loss of
the IB-like regulatory domain, where they are able to bind to B
sites and demonstrate transactivating properties 151
(Figure 5).
Mice lacking the C-terminal ankyrin domain of NF-B2
(p100/ mice), and therefore showing
abnormalities of NFKB2 similar to those seen in some patients
with lymphomas, demonstrate marked gastric hyperplasia, resulting in
early postnatal death.152 Both spleen and thymus are very
atrophic with abnormal architecture, whereas lymph nodes are enlarged
and the proliferative responses of B and T lymphocytes to several
mitogens are markedly enhanced. p52-deficient mice have reduced numbers
of B cells with reduced proliferative responses to antigens, reduced
numbers of follicles in spleen and lymph nodes, and impaired GC
formation.153,154
NF-B2, like BCL6, is therefore a key modulator of GC formation and
B-cell activation: Absence of the C-terminal domain may contribute to
tumor formation by allowing abnormal levels of p52-like mutant protein
to accumulate in the nucleus, resulting in enhanced NF-B-dependent
B-cell proliferation.
BCL10.
BCL10 is a 233-amino acid protein containing an amino-terminal caspase
recruitment domain (CARD),155 a motif found in a number of
proteins involved in the control and execution of apoptosis. This
domain consists of 6 tightly packed antiparallel alpha
helices156-158 and is similar in structure to the death
effector domain (DED) and the death domain (DD) contained in other
apoptotic proteins. CARDs mediate the binding between adapter molecules
and caspases: Procaspase 2 is recruited to the death initiator
signaling complex (DISC) via a CARD-CARD interaction with
RAIDD/CRADD,159,160 and procaspase 9 is activated after
binding to Apaf-1 via a homotypic CARD-CARD interaction.161
BCL10, however, is most homologous to an equine herpes virus-2 protein
E10 although this homology is limited to the CARD. The
carboxy-terminus of BCL10 is rich in serine and threonine residues
and is phosphorylated,162 which may allow regulation of
its functions.
BCL10 activates NF-B and induces apoptosis, both of which require
oligomerization via the CARD domain. However, although CARD
oligomerization is essential for both NF-B activation and apoptosis,
the CARD domain is inadequate to mediate either of these effects and
appears to function as an oligomerization motif.162 No
other CARD-mediated interactions with other proteins have been identified. NF-B activation by BCL10 is mediated via activation of
the NIK84 through TRAF2,163
leading to phosphorylation of IKK and subsequent phosphorylation and
degradation of IB (Figure 5). BCL10 may act as a transducer in the
DISC by interaction via its carboxy-terminus with the death adapter
molecule TRADD.163
BCL10 may mediate its apoptotic activity through the binding of its
carboxy-terminal domain to procaspase 9, resulting in autoproteolytic
activation of the caspase precursor to its active form.164
However, other studies have demonstrated a lack of binding to
procaspase 9 and, therefore, the significance of this finding remains
unclear.84,162,163 Importantly, like other proapoptotic genes, BCL10 may also act as a tumor suppressor, suppressing the transformation of primary rat embryo fibroblasts by synergistic combinations of various nuclear oncogenes.82 Whether this
activity is dependent on apoptosis or on other mechanisms remains to be elucidated.
Some MALT lymphomas demonstrating the t(1;14)(p22;q32) translocation
and other lymphoid tumors in which the translocation is absent contain
genomic mutations of the BCL10 coding
sequence.82,165 Most of these are frameshift mutations
resulting in premature truncation of the protein distal to the CARD
and, functionally, in loss of apoptotic activity, retention of NF-B
activation, and a "gain of function" ability to enhance
transformation in rat embryo fibroblast assays.82 Other
missense mutations identified reside within the carboxy-terminus and
would be expected to result in loss of some of the key biological
functions of BCL10.
However, not all MALT lymphomas exhibiting the t(1;14)(p22;q32)
translocation exhibit mutations, and it seems likely that in these
cases the apoptotic/transformation suppressor pathways are blocked by a
different mechanism than loss of the carboxy-terminus. Interestingly,
all cases with the t(1;14)(p22;q32) translocation, whether they contain
mutated BCL10, demonstrate strong nuclear BCL10 staining
different from the normal cytoplasmic pattern seen in normal B cells
and in other MALT cases.166 The mechanism behind this
finding is presently unknown. Overexpression of BCL10 may therefore,
like some of the mutant forms of NF-B2, result in constitutive
nuclear expression. The localization of at least some isoforms of BCL10
within the nucleus suggests that this gene may have functions other
than the regulation of apoptosis. Not all CARD-containing proteins are
involved solely in apoptotic regulation: Some isoforms of ARC
(apoptosis repressor with CARD)/Nop30 are involved in RNA
processing.167,168
BCL10 is likely to play a role in the normal development of the GC,
where lymphocytes proliferate in response to antigen or undergo
apoptosis. Truncated BCL10 is likely to contribute to oncogenesis through the uncoupling of apoptosis from the proliferative effects of NF-B activation.
BCL3.
BCL3 is a member of the IB family of proteins that regulate the
Rel/NF-B family of transcription factors.169-171 The
IB family includes at least 5 different members: IB, IB,
IB, IB , and BCL3. Each of these proteins has different
specificities for interaction via the centrally located ankyrin repeat
domain with the N-terminal Rel homology domains of different
Rel/NF-B homodimeric or heterodimeric complexes.142 BCL3
is unique among the IB family in that it is a nuclear
protein172 containing amino- and carboxy-terminal transactivation domains.173 It specifically associates with
homodimers of p50 or p52 subunits174,175 (Figure 5). p50
and p52 subunits are similar in their primary structures. They have no
defined transactivation domains and, as homodimers, may competitively inhibit the binding of transactivating NF-B dimers to consensus DNA
binding (B) sites.
BCL3 can act as an antirepressor to remove homodimers from B sites
so that transactivating NF-B dimers can bind,176 act as
a transactivator by forming complexes with homodimers at B sites,173,177 or enhance homodimer binding to B
sites.178
These functions are at least partly dependent on the phosphorylation
status of BCL3.179 BCL3 also interacts with other nuclear cofactors, including the BRCA-1-binding protein Bard1 and the histone
acetylase Tip60.180 These interactions may modulate
its function.
Mice lacking Bcl3 show impaired GC formation, loss of follicular
dendritic cell networks, and defects in their normal antibody responses, findings similar to those seen in NF-B2-deficient mice.181,182 However, both NF-B2- and Bcl3-deficient
lymphocytes can form GCs and generate at least some T-cell-dependent
antibody responses when adoptively transferred into RAG-1-deficient
mice, suggesting that accessory cells such as follicular dendritic
cells may be required for these functions. On the other hand,
Eµ-Bcl3 transgenic mice are characterized by an
accumulation of mature B cells in bone marrow, lymph nodes, and
peritoneal cavity.183 They demonstrate a hyperresponsive
humoral immunity as evidenced by an increased sensitivity to BCR
cross-linking, increased levels of autoantibody to double-stranded DNA,
and a threefold increase in the number of germinal cells in lymph
nodes. Transgenic mice also show decreases in serum IgM and IgG3 but
increases in IgG1 and IgA, consistent with the involvement of
Rel/NF-B complexes in Ig class switching. However, no lymphoid
neoplasms are seen in transgenic animals.
The mechanisms underlying NF-B-mediated transformation remain
unclear. Two pathways of direct relevance to oncogenesis have emerged.
First, NF-B is able to mediate a protective role in apoptosis
induced by chemotherapeutic drugs, TNF, and by certain oncogenes,
including Ras.184-186 This effect is likely to be mediated via antiapoptotic target genes, including
Bcl-xL.187 Secondly, NF-B is closely
associated with the cell cycle. B cells from NF-B-deficient mice
show delays in cell cycle progression from G1 to S phase,
and expression of a dominant negative mutant of IB results in
retarded phosphorylation of the Rb protein and G1/S phase transition.188,189
NF-B activates cyclin D1 transcription via NF-B binding sites
within its promoter, which induces G1/S transition.190,191 NF-B activation may therefore have
dual roles in suppression of apoptosis and in cell cycle progression.
In certain situations and in certain cell types, however, NF-B
enhances apoptosis. It is likely that in B-cell malignancies this
aspect will have been blocked by prior genetic events such as
BCL2 overexpression.
B-cell receptor signaling
Stimulation of B cells by antigen-mediated cross-linking of the BCR
induces tyrosine phosphorylation of a number of proteins, including the
CD19 and CD22, the BCR signaling proteins CD79a (Ig) and CD79b
(Ig), and the kinases Syk, Lyn, PI3-K, and Btk, together with other
proteins, including phospholipase C (PLC), Shc, Grb2, and
Vav192 (Figure 6). Binding of
antibody to Fc receptor can result in activation, inhibition, or
apoptosis. Activation responses are mediated by the immunoreceptor
tyrosine activation motif (ITAM) found in FcRI and FcRIII.
Inhibitory responses are mediated via the immunoreceptor tyrosine
inhibitory motif (ITIM)193 found in
FcRIIB. B cells express only the inhibitory receptor FcRIIB.
View larger version (86K):
[in this window]
[in a new window]
| Fig 6.
Modulation of antigen receptor signaling by IG
translocations.
Genes that are deregulated as a result of IG translocation are
shown in yellow. Antigen binding to the BCR results in B-cell
activation via multiple effectors, including Ras, Btk, JNK, and PLC.
Pax5: Pax5 transcriptionally up-regulates 2 key molecules in
the BCR complex, CD79a and CD19, allowing enhanced B-cell
proliferation. FcRIIB: In normal B cells, FcRIIB mediates
its inhibitory signal via 1 of 2 pathways. (1) Simultaneous
cross-linking of FcRIIB with the BCR by immune complexes results in
phosphorylation of the FcRIIB ITIM and subsequent recruitment of
SHIP, which, by hydrolyzing PIP3, results in dissociation from the
membrane and, therefore, inactivation of Btk. (2) Alternatively,
cross-linking of FcRIIB alone results in apoptosis mediated via
direct activation of Btk. In cases of follicular lymphoma demonstrating
the t(1;22)(q22;q11), the t(14;18) is a prior event, resulting in
overexpression of BCL2, which blocks apoptosis and may allow
proliferative signals to go unhindered.
|
|
FcRIIB.
The FCGRIIB gene encodes 2 isoforms, FcRIIb1, which is the
major species expressed on the surface of B cells, and IIb2, which are
identical except for a 19-amino acid insertion in the cytoplasmic domain of IIb1.194 Most experimental work has been carried
out on the IIb1 isoform; however, the IIb2 isoform is preferentially expressed as a result of the translocation t(1;22)(q22;q11). Whether the key biologic functions with regard to oncogenesis of these 2 isoforms are significantly different remains to be determined.
FcRIIB mediates inhibitory signaling in normal B
cells195 (Figure 6). Cross-linking of BCR and FcRIIB
results in tyrosine phosphorylation of the ITIM motif
of FcRIIB and the recruitment of the Src-homology-2
(SH2)-containing inositol polyphosphate 5-phosphatase
(SHIP).196,197 SHIP, by hydrolyzing phosphatidylinositol 3,4,5-trisphosphate (PIP3), leads to dissociation of Bruton's tyrosine
kinase (Btk) from the membrane198,199 and decreased activity of the survival-associated protein kinase,
Akt.200,201 Btk is essential for B-cell activation and
proliferation, mediating its effects through activation of PLC,
which promotes intracellular calcium influx.202
Overexpression of an inhibitory Fc receptor might not appear to be
compatible with lymphomagenesis. However, cross-linking of FcRIIB
alone results in apoptosis and activation of c-Jun N-terminal kinase
(JNK), mediated via Btk, an effect that requires the transmembrane
domain of FcRIIB.203 This apoptotic response is
diminished in Bcl2 transgenic mice, resulting in cell
proliferation,204 presumably through uncoupling of the
apoptosis effector arm from proliferative signals.
Such dissociation might provide a rationale for the acquisition of the
t(1;22)(q22;q11) as a secondary abnormality in follicular lymphoma:
Overexpression of BCL2 provides the necessary environment in
which the apoptotic response to FcRIIB is abrogated, allowing JNK
activation or other stimulatory signals to drive proliferation.
Pax5.
Transcription of PAX5 is initiated from 2 promoters on 9p13,
resulting in the splicing of 2 alternative untranslated first exons (1A
or 1B) to the coding sequences (exons 2-10). PAX5 codes for the
50-kd transcription factor B-cell-specific activator protein (BSAP),205 which recognizes its target genes via the
conserved paired domain contained in exons 2 and 3. Pax5 is expressed
after birth only in B lymphocytes and testis. During normal B-cell
lymphopoiesis, Pax5 is expressed from the earliest B-lineage committed
precursor cell up to the mature B-cell stage but is subsequently
down-regulated during plasma cell differentiation. Overexpression of
Pax5 results in an enhanced proliferative response in splenic B cells
to lipopolysaccharide (LPS) stimulation, whereas addition of antisense
oligonucleotides to such cells results in an impaired LPS
response,206 demonstrating that Pax5 plays a role in the
regulation of activation and proliferation of mature B cells.
Pax5 plays a key role in the regulation of CD19, CD79a, and N-Myc
expression: All 3 genes are down-regulated significantly in the absence
of Pax5. Both CD19 and CD79a synergize with other B-cell surface
receptors to transduce stimulatory signals (Figure 6), resulting in
activation of a variety of signaling pathways, including the Src family
phosphotyrosine kinases (Fyn, Lyn, and Lck), serine-specific protein
kinases (eg, protein kinase C), p21Ras,
NF-B, and mitogen-associated protein
kinase.207 CD79a, together with CD79b, serves as the
signaling subunits of the BCR by establishing binding and activation
sites for SH2 domain-containing molecules at phosphorylated tyrosine
residues within their ITAMs. CD19 appears to function as a regulatory
component central to the multiple signaling pathways activated by BCR
signaling by providing docking sites for other signaling effector
molecules. Overexpression of CD19 results in enhanced proliferative
responses to LPS and other stimuli similar to those seen with Pax5 overexpression.
Deregulated expression of PAX5 as a result of the
t(9;14)(p13;q32) in LPL may therefore contribute to malignant
transformation by interfering with normal inactivation of PAX5
transcription during plasma cell differentiation, resulting in enhanced
proliferative signaling via the BCR.
| |
Future prospects |
MYC was first shown to be involved in the t(8;14)(q24;q32)
of BL in 1982. The subsequent 18 years have seen the isolation of
pathogenic genes from many other IG translocations, but raw cytogenetic data alone would suggest that more remain to be cloned. The
widespread use of multicolor FISH methods, along with polymerase chain
reaction methods for cloning translocation breakpoints and the
resources made available by the genome sequencing project, will
expedite this analysis. While these translocations may be rare, it is
possible that the genes isolated by this approach will also be involved
in mutations in cases lacking the translocation. Furthermore, cloning
of IG translocations suggests new functions for previously
cloned molecules and may define new therapeutic targets.
Many questions relating to the origin of the IG translocations
remain unanswered. Study of mutant mice may allow some of the key genes
involved in this process to be identified.208 However, it
is unclear how the intimate associations of specific IG
translocations with specific stages of B-cell differentiation and
specific B-cell diseases might arise. The spatial arrangement and
precise positioning of chromosomes and genes (8% of normal lymphocytes
have MYC and IGH loci in close apposition) during the
cell cycle may have a role to play.209,210
Are these translocations a feature of normal B-cell development? The
t(14;18)(q32;q21) is present at low levels in many apparently normal
individuals,211 and MYC translocations have been
demonstrated in phenotypically normal mice.212 These data
indicate that IG translocation alone is insufficient to
generate disease. Whether other IG translocations are found at
comparable frequency in normal B cells in human beings is not known.
Application of sensitive polymerase chain reaction and FISH
technologies and analysis of mouse models should allow these and other
questions to be answered. If the rate at which IG
translocations occur in normal individuals determines the propensity to
develop B-cell malignancy, it may be possible to detect at-risk
individuals long before the emergence of frank disease.
Note added in proof.
Two groups have recently reported the cloning of a case of
extranodal DLCL with t(1;14)(q21;q32) and shown that this case directly involved the MUC1 gene on chromosome1q21.
MUC1, located within a gene-rich region of chromosome
1q21, was specifically deregulated as a consequence of this
translocation. MUC1 also appeared to be the target gene of some
amplifications of this region. MUC1 overexpression occurs
frequently in human epithelial cancers and is associated with tumor
progression and poor clinical outcome, but these are the first reports
of this gene involved in the pathogenesis of B-cell malignancies. How
this protein, which is normally expressed only in plasma cells of the
B-cell lineage, contributes to B-cell transformation is not clear.
| |
Footnotes |
Submitted August 9, 1999; accepted February 16, 2000.
Supported in part by grants from the Leukaemia Research Fund, the Kay
Kendall Leukaemia Fund, and the Cancer Research Campaign.
Reprints: Martin J. S. Dyer, Academic Department of Haematology
and Cytogenetics, Haddow Laboratories, Institute of Cancer Research,
Sutton, Surrey, UK SM2 5NG; e-mail: mdyer{at}icr.ac.uk.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
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Introduction
Cytogenetic abnormalities of...