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Advances in Brief |
First Division, Department of Internal Medicine, Faculty of Medicine [H. A., T. A., M. K., C. U., T. U., H. O.], and Center for Molecular Biology and Genetics [T. A., A. S.], Kyoto University, Kyoto 606-8507, Japan
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light chain gene in 1, and IG 
light chain gene
in 7. In contrast, 23 cases affected non-IG loci,
including the H4 histone gene, heat shock protein genes
HSP89
and HSP90ß, and
PIM-1 proto-oncogene. On der(3) chromosomes, complete
sets of the promoters of these partner genes replaced that of
BCL6 in the same transcriptional orientation. These
results suggest that BCL6 gene affected by the
translocation is transcriptionally activated by a variety of stimuli,
including cell cycle control, changes in the physical environment, and
response to cytokines. Break points on BCL6 occurred
within the major translocation cluster, and we identified a 120-bp
hyper-cluster region a short distance from the 3' end of exon 1. Gel
mobility-shift assay suggested the presence of a protein(s) that bound
to this particular region. |
Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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We have developed a LD-PCR method capable of detecting IG/oncogene junctions of up to 30 kb (12 , 13) . Our previous study showed that LD-PCR successfully detected three IG/BCL6 translocations [i.e., t(2;3)(p12;q27), t(3;22)(q27;q11), and t(3;14)(q27;q32)], which had been well characterized at the molecular level. For cases in which partner loci were not determined, we have developed a LDI-PCR method, which amplifies unknown fragments flanked by known BCL6 sequences. Here, we report the cloning and sequencing of a number of BCL6 translocations from a large series of B-cell tumors using these two LD-PCR-based assays. The purpose of the present study was to explore the diverse molecular anatomy of BCL6 translocations and to find structural and functional consequences of the juxtaposition of the BCL6 gene to a wide variety of partner genes.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Southern Blot Hybridization.
Genomic DNA extracted from lymphoma specimens was digested with
appropriate restriction enzymes and electrophoresed through 0.8%
agarose gels. DNA was transferred onto nylon membrane filters
(GeneScreen Plus; NEN Research products, Boston, MA) and hybridized
with probes labeled with 32P using a random
labeling system. The F372 probe for the MTC region of the
BCL6 gene was a 2.3-kb XhoI/BamHI
fragment (5)
.
LD-PCR.
Designations and sequences of the oligonucleotide primers to detect
IG/oncogene fusion genes were listed in our previous studies
(12
, 13)
. Each PCR reaction mixture (50 µl) contained
100 ng of genomic DNA, reaction buffer, dNTP mixture, 20 pmol of each
primer, and 2.5 units of LA Taq DNA polymerase (Takara
Shuzo, Kyoto). PCR cycling variables for long DNA targets were
previously described in detail (13)
. Aliquots of the PCR
products were analyzed by agarose gel electrophoresis and visualized
under UV illumination after EtBr staining.
LDI-PCR.
High molecular weight genomic DNA was digested with XbaI or
BamHI and purified by standard methods. The DNA was diluted
to a concentration of 1 µg/ml and incubated at 16°C overnight in
the presence of T4 DNA ligase to facilitate intramolecular
ligation (15)
. The self-ligated circular DNA was used as a
template for a nested PCR; the circular DNA was not reopened. The
position and orientation of the primers are illustrated in Fig. 1A
. The sequences were: 08,
5'-CAGCTTGGGACTTTCAGCACCTGGTTTGGGGTCAT-3'; 09,
5'-TTCGCCAGGGTTCCAATAACACGGCATCAT-AAAGG-3'; 28,
5'-GCCAGTGTTCATTGGAAACCGCTCCCCAGCAG-TCT-3'; 29,
5'-GCCAGAATTTGCTCCACAACAGTTCCTCCGTAAAG-3'; 36,
5'-CCTGGCAAAGCGGGGGAGTGGGGAGTCGGGTATGG-3'; 37,
5'-GGGGCCGTTCCTGGTTTCCACTGGGGCAAAGAGAA-3'; 38,
5'-AGGAACGGCCCCTCCCAACCCTCCCGATGTCCACT-3'; 39,
5'-AAGACCATACCCGACTCCCCACTCCCCCGCTTTGC-3'; 40,
5'-AGCAAAGCGCACTCCCCCTCTTATGTCACCGAATA-3'; 41,
5'-AGAATTCCAGAG-GCCGAGCTTTGCTACAGCGAAGG-3'; 42,
5'-TGAGGGAGGCCCACA-TAGTGATGCCAACTGGATAC-3'; 45,
5'-GGAGAGCATAAGAGAGG-GAGGCAGAGAGGAGAGAA-3'; 46,
5'-ATTTGAAGTCAGAGGAAAAA-GCAGATGAGGAGTTT-3'; 47,
5'-GCTGAGGTGGGAAGATCACTTG-AGACCAGGGATTC-3'; 48,
5'-AGTAAGACCCTGTCTCAAAATAAA-GAAAGAAATAA-3'. The components of
LDI-PCR reaction mixture (50 µl) were identical to those of LD-PCR.
The first PCR reaction was carried out as described (13)
,
although the annealing and extension time were shortened to 6 min. An
aliquot of 1 µl of the first PCR product was subjected to a second
PCR using the nested primers.
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Gel Mobility-Shift Assay.
Nuclear extracts were prepared by the method of Schreiber et
al. (16)
. Binding reactions were performed in a total
volume of 10 µl containing 2 µl of extract, 2 µl of 5x binding
buffer [20% glycerol, 5 mM
MgCl2, 2.5 mM EDTA, 2.5
mM DTT, 250 mM NaCl, 50
mM Tris-HCl (pH 7.5), and 0.25 mg/ml
poly(dI-dC)/poly(dI-dC); Promega, Madison, WI], and 1 µl of
double-stranded, 32P-end-labeled probes.
Incubations were carried out for 20 min at 20°C, and the resulting
complexes were resolved on 4% nondenaturing polyacrylamide gels in
0.5x Tris-borate EDTA. For competition experiments, incubations were
performed with a 100-fold-excess of unlabeled probe.
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Results |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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). Fifteen patients had a follicular lymphoma with varying
degrees of mixtures of small cleaved and large cells, and 39 patients
had diffuse large cell lymphomas. The other histologies, according to
the REAL classification (14)
, included small
lymphocytic lymphoma and Burkitt-like lymphoma. The remaining two cases
were not classified.
IG/BCL6 Translocations Revealed by
LD-PCR.
To detect IG/BCL6 junctions, we performed LD-PCR
using primers for BCL6 exon 2 (BCL6 primer),
approximately 4 kb upstream of exon 1 (5'-BCL6 primer), and
constant region genes of the three IGs (C
primers; Refs. 12
and 13
). Of the 58 cases
carrying a BCL6 rearrangement, 18 were positive for LD-PCR
amplification (Fig. 2A)
. The sizes of these LD-PCR products ranged from 4.3–14 kb
and were unique to each tumor specimen. C/BCL6
fusions were demonstrated in five cases, and three had a
t(3;22)(q27;q11) on cytogenetic analysis. A
C/BCL6 fusion was detected in a case carrying
both t(14;18)(q32;q21) and t(2;3)(p11;q27) (6)
. The
5'-BCL6/CH primer pairs amplified fragments,
including a junction on der(14)
t(3;14) from 12 cases; four had a
5'-BCL6/Cµ fusion, and eight had a
5'-BCL6/C
fusion.
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switch sequences, followed those of
5'-BCL6. The sequences immediately adjacent to the break
points sometimes showed considerable complexity. For instance, a 412-bp
fragment identified at the 5'-BCL6/S junction
of case 726 contained sequences that were identical to those from
chromosome band 11q23, in addition to those showing sequence homology
to the VH3–11 variable gene (data not shown).
On the other hand, the IGL/BCL6 fusion
involved the 5' side of a member of VIV family (GenBank
accession no. HS2 M7VK4) that was associated with the J4
segment (Fig. 3A)
. The break points of IGL/BCL6
fusions occurred upstream of the V2–11/J2
complex (one case), at a point between the V2–1, which
is the most 3' V gene of IG and the
J1 segment (one case) and between the J and
C segments (three cases; Fig. 3, A and B
). Thus, the positions of break points on the
IGLs were not related to the regions in which
V/J recombination normally occurs.
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, nested primer pairs in inverse
orientation were designed corresponding to sequences 5' and 3' of the
MTC. The LDI-PCR products, therefore, included regions from unknown
sequences involved in each translocation, which were flanked by the
known BCL6 sequence. The 3' primer pairs amplified junctions
on the der(3)
chromosome, whereas junctional sequences on the partner
chromosomes, der(partner), were obtained using the 5' primer pairs.
We applied LDI-PCR to a total of 40 LD-PCR-negative cases and obtained
amplified fragments corresponding to either or both the der(3)
and the
der(partner). Fig. 2B
shows representative results of
EtBr-stained agarose gel electrophoresis of LDI-PCR products. All
materials showed a unique PCR product ranging from 1.4–9.4 kb in size,
which were the expected sizes from the results of Southern analysis and
the distance of the primers used. The LDI-PCR products encompassing
junctional points were cloned into plasmids and sequenced with primers
from the known BCL6 sequences. The sequences appearing
beyond the artificial XbaI or BamHI site
represented those from the partners. Homology search of the GenBank
database revealed that LDI-PCR products from an additional 12 cases
included sequences from IGs; ten cases involved
IGH, and IGL was the partner in two cases. In
the latter fusions, the two translocations involved the 5' side of the
V2–1 gene (Fig. 3B
, 883 and 908).
In contrast, 23 cases involved non-IG loci as partners. We
previously reported that a novel H4 histone gene was linked
to BCL6 in two B-NHL cases carrying t(3;6)(q27;p21.3)
(10)
. The present LDI-PCR study revealed that an
additional three cases involved this particular H4, which
has been recently demonstrated to be included in a PAC clone form
6p21.31–6p22.1 (no. HS86C11). Nucleotide sequencing of the break
points demonstrated that the translocation was reciprocal at the
nucleotide level, and the break points on H4 from the total
of five cases were distributed within the single exon to 3' of the
terminal palindrome (Fig. 4A
and
Fig. 5A
).
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and HSP90ß, and PIM-1
proto-oncogene. The HSP89 gene is composed of 11 exons,
and exons 2 through 11 encode the Mr
89,000 protein (17)
. The breakage occurred within intron
1, resulting in exchange of the first noncoding exons of
BCL6 and HSP89 (Fig. 4B)
. Three
heat shock response elements composed of contiguous inverted repeats of
a 5-bp sequence, the consensus of which was defined as nGAAn (n is any
nucleotide; Ref. 18
), were identified in -448 to -439,
-429 to -420, and -123 to -114 bp of the break point; all were in
the tail-to-tail orientation (Fig. 5B)
. On the other hand,
HSP90ß mapped to 6p12 was composed of 12 exons, and the
translation initiation codon lay at the 5' end of exon 2 (Fig. 4C
; Ref. 19
). The break point was close to the
5' end of exon 3, and three heat shock elements, nGAAnnTTCn, were
localized within intron 1 (Fig. 5C)
. The PIM-1
proto-oncogene consists of 6 exons (Fig. 4D)
and has been
mapped to 6p21 (20)
. The gene has a characteristic
G+C-rich housekeeping promoter that lacks TATA or CAAT sequences (Fig. 5D
; Refs. 20
and 21
); however,
more distant elements have been presumed to regulate tissue-selective
expression (21)
. The breakpoints on der(3)
and der(6)
were
localized within intron 1, both of which were downstream of the
translation initiation site.
Other partner sequences registered in the database were TTF
(9)
, transferrin receptor gene (TFRC),
-NAC transcriptional coactivator gene (22)
,
and MHC class II transactivator gene CIITA
(23)
. Two cases had two independent
non-IG/BCL6 translocations. The sequences of 11
partners are currently uncharacterized. The remaining five cases did
not have a rearrangement with other loci; three had a deletion of
1.0–2.2-kb segments within the MTC, and two had nucleotide
substitutions leading to generation of additional XbaI sites
(Fig. 1)
. Table 1
summarizes partner loci identified by the two LD-PCR-based assays.
Fifty-two percent of cases involved IG loci as partners, and
the major locus was IGH. These frequencies were in agreement
with those of 3q27 translocations determined by cytogenetic analysis
(24)
.
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, the vast majority of break points
were further clustered a short distance downstream of exon 1. Fig. 1B
shows the nucleotide sequences of intron 1 and the
positions of break points of 19 cases. Of the 19 break points, 12
involved IG genes as partners, and the remaining break
points were associated with non-IG loci. A 120-bp region
containing 16 break points was designated as a hyper-cluster region;
the region lacked known sequences that have been observed at other
IG/oncogene junctions.
Gel Mobility-Shift Assay Suggesting the Presence of a Protein(s)
Capable of Binding to the Break Point Hyper-Cluster Region.
We prepared a 30-mer double-stranded oligonucleotide probe (probe 6162;
Fig. 1B
) included in the hyper-cluster and studied the
presence of a sequence-specific DNA-binding protein(s). Nuclear
extracts from hematological cell lines were mixed with the end-labeled
probe and subjected to gel mobility-shift assay. Fig. 6
shows representative results for protein/DNA complexes. Sifted bands
were prominently observed in a diffuse large cell lymphoma cell line
and an EBV-transformed lymphoblastoid cell line, and their specificity
was confirmed by competition experiments using excess amounts of
unlabeled probe. As indicated in Fig. 1B
, 10 break points
were within or close to this probe, suggesting that this particular
fragment could include sequences that are related to the underlying
mechanism of BCL6 translocation.
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Because translocations involving IGs almost certainly occur as the result of errors of the recombination process (1) , the positions of break points on IGs can reflect B-cell stage where the translocation develops. In analogous to t(8;14)(q24;q32) of the sporadic type of Burkitt’s lymphoma, IGH/BCL6 translocation invariably involves switch regions of IGH. Therefore, this translocation is most likely associated with the isotype class switching process following completion of V/D/J assembly and occurs at the mature B-cell stage in the germinal center of lymphoid tissues.
However, this "miss-class switch" mechanism may not be applicable
to the variant IGL/BCL6 translocations. In the
present study, we cloned a total of eight
IGL/BCL6 fusions. Sequencing analysis showed that
four break points were 5' of V genes and two of the four
were associated with a J segment, indicating that these
translocations involved IGL alleles that had already
completed V/J assembly. On the other hand, the
remaining four break points were distributed within the
IGL gene and had no apparent association with
V/J joining. Therefore, it is likely that
these translocations involved an IGL gene with the germ
line configuration. Because there is a clear order of events in the
formation of an IGL gene (i.e., the
IGL gene is rearranged first, and the IGL
gene is not affected by the rearrangement process when the
IGL successfully forms an active gene), our findings led
to the conclusion that IGL/BCL6 translocation
occurs at the mature B-cell stage when normal V/J
assemblies of the two IGLs have been completed. The
mechanisms responsible for the illegitimate recombination between these
particular regions of IGL and BCL6 gene remain to
be elucidated.
Partner Genes Involved in Non-IG/BCL6 Translocations
are Transcriptionally Activated by a Variety of Stimuli.
The common molecular features of non-IG/BCL6
translocations include: (a) the gene fusion occurs in the
same transcriptional orientation; (b) the break point on the
partner gene is localized in close proximity to its promoter sequence;
and (c) the complete set of the promoter is fused upstream
of the coding region of BCL6 on the der(3)
chromosome. It
should be noted also that a portion of the 5' exon(s) of the partner
gene, which may or may not include coding regions, was invariably
included in the non-IG/BCL6 junction, potentially
leading to generation of fusion mRNAs. This may be of functional
significance, because it could have substantial impact on the stability
and/or translatability of the resulting fusion transcripts. On the
other hand, coding exons of the partner gene were interrupted by the
upstream sequences of BCL6 in the
BCL6/H4, BCL6/HSP90ß, and
BCL6/PIM-1 fusions, but remained intact in the
BCL6/HSP89 fusion. Thus, it seems that partner
genes on the translocated allele may not be important although they are
fused with the BCL6 promoter.
Expression of the BCL6 gene is tightly regulated during B-cell differentiation; its expression increases in mature B-cells in the germinal center and then decreases during their differentiation into plasma cells (25) . Thus, it is conceivable that inappropriate expression of BCL6 may result in transcriptional repression of genes involved in terminal differentiation or in apoptosis, thereby leading to neoplastic cell growth of B cells. In the present study, we identified four unique non-IG/BCL6 fusions in which the pattern of transcriptional regulation of the partner genes has been well studied. The Site II equivalent of the present H4 gene contains consensus binding sites for two transcription factors (i.e., histone nuclear factor D and IFN regulatory factor 2; Ref. 10 ). histone nuclear factor D is a multicomponent protein containing cyclin A, CDC2, and an RB-related protein, which apparently links H4 gene regulation directly to cell cycle control (26) . The regulation of HSP gene expression in eukaryotes is mediated by the conserved HSF (18) . HSF acts through the HSEs composed of three contiguous inverted repeats of a 5-bp sequence. On heat stress, HSF binds to the HSEs as a trimer, and all three repeats are required for high-affinity interaction (18) .
The PIM-1 proto-oncogene encodes a serine/threonine protein
kinase and plays a role in the signal transduction events associated
with lymphocyte activation (27)
. The basal level of
PIM-1 expression seems to be regulated in a cell
type-specific manner (i.e., highest in myeloid and B cell
lines and lowest in T cell lines; Ref. 21
). On the other
hand, inducible PIM-1 expression has been observed in
response to a wide variety of mitogens and cytokines (27)
.
Interleukin-3-induced PIM-1 expression is suppressed by
dominant-negative Stat5 mutants, suggesting that PIM-1 is
regulated by Jak-Stat pathways (28)
. Indeed, a canonical
IFN-activated site-like motif was identified in the promoter region
(27)
.
In summary, our observation suggested that partner genes are
transcriptionally activated by a variety of stimuli, including cell
cycle control, changes in the physical environment, and response to
cytokines. Involvement of the transactivator gene CIITA, the
expression of which is induced by IFN- (23)
, is another
example of this observation. Thus, it seems that alteration of
BCL6 expression resulting from
non-IG/BCL6 translocation is much more elegant
than simple overexpression or constitutive expression. As germinal
center B cells proliferate rapidly in response to antigen stimulation,
it is likely that the BCL6 gene affected by the
translocation is inappropriately expressed during the B-cell
proliferation, although the possible links between the deregulated
BCL6 expression and ultimate development of lymphoma remain
to be established.
The Intronic Sequence Immediately 3' of BCL6 Exon 1 Is the Target
for Somatic Mutation and Chromosomal Translocation.
Somatic mutations within the 5' noncoding region of BCL6
have been described in B-cell tumors of the germinal
center/postgerminal center type (29
, 30)
. The majorities
of the mutations are clustering 3' of exon 1, which has been referred
to as the MMC (31)
. These mutations are often multiple,
are frequently biallelic and are independent of BCL6
translocation or linkage to IGs (29
, 30)
. On
the other hand, somatic mutations within the MMC were recently reported
in a large proportion of memory B cells isolated from normal
individuals as well as germinal center B cells from a reactive tonsil
(32)
.
The present study clearly showed that the break point hyper-cluster was affected by a variety of BCL6 translocations and the MMC overlap. Thus, the two somatic events (i.e., mutations and chromosomal translocation) are apparently related. It is possible that mutations occurring within the MMC might alter the chromatin structure of this particular region, thereby being prone to rearrangement with other independent genes. This may partly account for the lack of known characteristic sequences that potentially mediate chromosome translocations within this region. In this context, we are currently investigating whether binding of the protein(s) identified by the gel mobility-shift assay is enhanced for the hyper-cluster sequence that carries mutations.
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FOOTNOTES |
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1 Supported by grants-in-aid from the Ministry of
Health and Welfare (7-29 and 9-10) and from the Ministry of Education,
Science, Sports and Culture (11670994), Japan. 
2 These two authors equally contributed to this
work. T. A. is a fellow in Cancer Research of the Japan Society for
the Promotion of Science and a recipient of the Award for Young
Investigators from the American Association for Cancer Research.
3 To whom requests for reprints should be
addressed, at First Division, Department of Internal Medicine, Faculty
of Medicine, Kyoto University, 54-Shogoin-Kawaramachi, Sakyo-ku, Kyoto
606-8507, Japan. Phone and fax: 81-75-751-3155; E-mail: hohno{at}kuhp.kyoto-u.ac.jp
4 The abbreviations used are: IG,
immunoglobulin gene; IGH, IG heavy chain gene;
IGL, IG light chain gene; IGL,
light chain gene; IGL, light chain gene;
V, variable; D, diversity;
J, joining; S, switch; C,
constant; B-NHL, B-cell non-Hodgkin’s lymphoma; MTC, major
translocation cluster; LD, long-distance; LDI, LD inverse; EtBr,
ethidium bromide; HSF, heat shock transcription factor; HSE, HS
response elements; MMC, major mutation cluster.
Received 8/30/99. Accepted 3/17/00.
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REFERENCES |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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I. S. Lossos, Y. Jacobs, M. L. Cleary, R. Levy, T. Akasaka, and H. Ohno Correspondence re: Akasaka, H., et al., Molecular Anatomy of BCL6 Translocations Revealed by Long-Distance Polymerase Chain Reaction-based Assays. Cancer Res., 60: 2335-2341, 2000. Cancer Res., October 1, 2001; 61(19): 7363 - 7364. [Full Text] [PDF]
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T. Akasaka, C. Ueda, M. Kurata, H. Akasaka, H. Yamabe, T. Uchiyama, and H. Ohno Nonimmunoglobulin (non-Ig)/BCL6 gene fusion in diffuse large B-cell lymphoma results in worse prognosis than Ig/BCL6 Blood, October 15, 2000; 96(8): 2907 - 2909. [Abstract] [Full Text] [PDF]
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