The t(3;14)(q27;q32) is the most common translocation involving BCL6 in B-cell lymphoma. Although this translocation was predominantly associated with diffuse large B-cell lymphoma (DLBCL), recent studies have shown that it can also be found in follicular lymphomas (FL), often associated with a large cell component. To further investigate the relationship that might exist between this translocation and the phenotype of the tumors, we studied 34 lymphomas with a t(3;14)(q27;q32). Twenty cases were DLBCL, 14 FL and most cases, regardless of histology, were negative for the expression of CD10 (26/32, 81%). We identified the IGH switch region involved in the translocation for 32 cases. Our data indicate that in DLBCL most breakpoints involve the switch μ (17/19; 89%), whereas in FL most involve a switch γ (9/13; 70%) (P=0.0016, Fisher's exact test). This correlation between the histology and the structure of the translocated allele suggests that the lymphomas with Sμ and Sγ translocations may originate from different cells, or that the substituted regulatory regions that come to deregulate BCL6 may affect the presentation of the disease.
Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are the commonest subtypes of non-Hodgkin's B-cell lymphomas (NHL), accounting for more than 60% of cases (Jaffe et al., 2001). Both are characterized by recurrent chromosomal translocations where the expression of a proto-oncogene is deregulated by the regulatory regions of a partner locus (Willis and Dyer, 2000). The t(14;18)(q32;q21), involving BCL2, is regarded as the hallmark of FL, whereas translocations implicating BCL6 are among the most frequent abnormalities in DLBCL, with an estimated frequency of 20–40% (Bastard et al., 1994; Lo et al., 1994). However, the prognostic value of BCL6 translocations in DLBCL still remains controversial (Bastard et al., 1994; Offit et al., 1994; Barrans et al., 2002), and no clear relationship could be drawn between the observation of a translocated gene and the level of expression of the protein. Non-Hodgkin's B-cell lymphomas with BCL6 translocations are also heterogeneous at presentation, as BCL6 rearrangements were reported in a wide spectrum of B-cell NHL (Horsman et al., 1995), including up to 14% of de novo FL (Otsuki et al., 1995; Jardin et al., 2002b; Ott et al., 2002; Bosga-Bouwer et al., 2003). Finally, an important heterogeneity is observed by cytogenetics as more than 20 loci and 15 BCL6 partner genes have been identified to date (Wlodarska et al., 1995; Akasaka et al., 2000a).
Interestingly, several authors proposed that the identity of the partner and the BCL6 expression level could impact the clinical outcome in DLBCL (Akasaka et al., 2000b; Lossos et al., 2001; Ueda et al., 2002a, 2002b) or the occurrence of a histological transformation in FL (Akasaka et al., 2003). Together, these observations point to a possible relationship that may exist between the phenotype of the tumor and the identity of the translocated partner. In an attempt to clarify this issue, we compared the histology and the molecular features of two groups of NHL, one with a diffuse and the other with a follicular growth pattern, but all sharing the same t(3;14)(q27;q32) BCL6 translocation.
Molecular cloning of t(3;14) genomic breakpoints
The structures of the der(3)t(3;14)(q27;q32) are presented in Figure 1. Genomic DNA from biopsy samples was available for all 34 patients. The IGH-BCL6 junctions from seven cases, six involving the Sμ and one the Sγ3 region, were previously reported (samples #2, #5, #6, #8, #18, #22 and #24) (Jardin et al., 2003). Using the same PCR approach, we cloned 20 additional der(3) chromosomal breakpoints (Figure 2). Alignments of the sequences of the breakpoints with the IGH locus (GenBank, accession #NG001019) indicated that 18 translocations involved the Sμ, eight the Sγ3 and one the Sγ4 (Table 1 and Figure 2). As expected, most breakpoints (23/27, 85%) cluster in a 1.5 kb region starting from the 3′ end of the first exon of the gene (Akasaka et al., 2000a). However, four junctions occurred out of this cluster, three downstream, on the first intron of BCL6 (sample #3, #30 and #22) and one upstream from the first exon (sample #13).
Reverse transcriptase–PCR amplification of IGH-BCL6 transcripts expressed by the tumors
The IGH-BCL6 fusion transcripts were identified by reverse transcriptase–PCR (RT–PCR) starting from 26 available RNA. It was previously shown that different fusion transcripts can be expressed after a t(3;14), specific from the translocated switch region and differing by the substituted first exon (Figure 1) (Ye et al., 1995; Kawamata et al., 1998). We first amplified the fusion transcripts with a substituted I exon derived from the IGH sterile transcripts expressed during the class switch recombination process (Stavnezer-Nordgren and Sirlin, 1986). No amplifications were obtained when using Iα or Iɛ primers (data not shown), whereas specific products were amplified from 17 cDNAs using the Iμ or γ ones (Figure 3a). For one patient (#12), the amplified Iμ-BCL6 product was longer than expected. However, sequence analysis of the RT–PCR product validated the specificity of the amplification, and indicated that the GT splicing donor site located at the 3′ end of the Iμ exon had been disrupted by a mutation, leading to the usage of an alternative GT donor site located 123 bp dowstream of the Sμ region (Figure 3b). This result is in agreement with the observation that the 5′ end of the Sμ region is actively mutated during the transit of B cells in germinal centers (GC) (Nagaoka et al., 2002) and with our previous observations that somatic mutations can still target the IGH-BCL6 junction after a t(3;14) (Jardin et al., 2003). Finally, using a consensus JH forward primer (JHcons), we were able to amplify fusion transcripts from all the Iμ-BCL6-positive samples, in agreement with the expected structure of the der(3) chromosome (Figure 1a). These results indicated that at least two promoters, one located upstream from the J segments and the one that control the expression of the sterile Sμ transcript, deregulate BCL6 after a t(3;14) involving the Sμ.
Together, amplifications of fusion transcripts allowed us to identify the translocated S region for five lymphomas from which we had failed to clone the genomic breakpoint, three involving the Sμ and two the Sγ. Failure to clone the corresponding breakpoints could result from the structure of the translocated alleles, with rearrangements occurring outside the region explored by our PCR approach, or be explained by deletions or mutations that may prevent the hybridization of the PCR primers.
Fluorescence in situ hybridization
For two cases, neither genomic breakpoints nor fusion transcripts were obtained, but both translocations were confirmed by fluorescence in situ hybridization (FISH) experiments (data not shown). For both, a split of the telomeric portion of the probe indicated that the genomic breakpoint was located upstream from BCL6, suggesting a possible implication of the distal alternative breakpoint region (Butler et al., 2002). Starting from RNA extracted from these two biopsies, we attempted to clone by 5′ rapid amplification of cDNA ends the potential IGH-BCL6 fusion transcripts that may have been expressed by the tumors. However, we were only able to amplify wild-type BCL6 transcripts (data not shown). Although not conclusive, these results suggest that, following a translocation involving the distal ABR region, the BCL6 gene may not be deregulated by promoter substitution but rather through the juxtaposition of an IGH enhancer, a common mechanism in lymphomagenesis (Willis and Dyer, 2000; Butler et al., 2002).
Cytogenetic analysis of t(3;14)(q27;q32)-positive non-Hodgkin's B-cell lymphomas
Together, molecular biology and FISH studies allowed us to identify 34 t(3;14)-positive NHL. Complete cytogenetic data for those 34 lymphomas are provided in Table 2. Most karyotypes were complex and no t(14;18) was found. Although few cases with the two t(3;14) and t(14;18) have been described (Horsman et al., 1995; Kawakami et al., 2004), our data on a large series of lymphoma with t(3;14) indicate that the two most frequent translocations in B-cell NHL, both seen as early transforming events, are most often exclusive.
Histology and immunophenotype of t(3;14)(q27;q32)-positive non-Hodgkin's B-cell lymphomas
A part of morphological and phenotypic features in 11 of these lymphomas have previously been reported (Jardin et al., 2002a, 2002b, 2003). In our present series, 14 cases were diagnosed as FL (seven grade 2, six grade 3a and one grade 3b), three as DLBCL and FL3b (diffuse proliferation of large B cells with areas where a follicular architecture is present in the same lymph node) and 17 as DLBCL. We had previously shown that FL without t(14;18) but with BCL6 rearrangements constituted a distinct subtype with an unusual CD10− phenotype (Jardin et al., 2002b). In agreement with this observation, 9/13 (69%) FL were negative for the expression of this marker (Figure 4A). Our data now indicate that an absence of CD10 expression is also a common feature of t(3;14)-positive DLBCL, as this phenotype was also observed for 17 (89.5%) of the 19 tested lymphomas. Interestingly, a large majority of DLBCL expressed a CD10−/BCL6+/MUM1+ phenotype (12/18, 66.7%) (Figure 4B).
Histology and structure of the translocation
Our data indicate significant correlations between the histology and the location of the breakpoint on the IGH locus. Considering only the observation of a follicular growth pattern, nine FL had an Sγ translocation and seven (including the three DLBCL and FL3b) a Sμ translocation, whereas only two DLBCL showed a Sγ translocation and 14 a Sμ translocation (P=0.023; Fisher's exact test). When comparing the structure of the translocated allele and the presence of diffuse areas of proliferation of large centroblasts, nine lymphomas without diffuse areas had a Sγ t(3;14) and four a Sμ translocation, whereas 17 DLBCL (including the three DLBCL and FL3b) disclosed Sμ translocations and two a Sγ translocation (P=0.0016; Fisher's exact test). The highest correlation was obtained when comparing the translocated S region and the presence of a component of centrocytes, as 18/20 (90%) centroblastic tumors (DLBCL and/or FL3b) have a Sμ translocation, whereas 9/12 (75%) tumors comprising a component of centrocytes (FL2 and 3a) have a Sγ translocation (P<0.001; Fisher's exact test).
Translocations involving the BCL6 gene, which are usually associated witch DLBCL, are also observed in few FL cases lacking the t(14;18) translocation (Jardin et al., 2002b; Horsman et al., 2003). Follicular lymphomas are a mature B-cell neoplasm derived from GC B cells, and the WHO classification recommends their grading according to cytology (Jaffe et al., 2001). This classification allows for the distinction of three grades, the third comprising the 3a and 3b subtypes differing by the presence or absence of a preserved population of centrocytes. When the FL3a and 3b subtypes were described, it was proposed that FL3a might be more closely related to FL1-2 tumors, whereas FL3b might constitute a follicular or partly follicular variant of DLBCL (Ott et al., 2002; Katzenberger et al., 2004). This difference was substantiated by immunochemistry and also by cytogenetic, as FL3a most often express CD10 and are usually associated with the t(14;18), whereas FL3b are more heterogeneous regarding CD10 expression, most often lack the t(14;18) and are frequently associated with 3q27 structural abnormalities. Later, it was also reported that FL3b includes three subtypes, one characterized by the t(14;18) and another by 3q27 translocations, the two being mutually exclusive (Bosga-bouwer et al., 2003). Together, these observations raise important questions regarding the relations that may exist between BCL6 abnormalities and the lymphoma subtype. However, with more than 20 different partners, BCL6 translocations are highly heterogeneous and several studies suggested that the identity of the translocated partner may be associated with the phenotype of the tumor (Akasaka et al., 2000b, 2003). To get more insights into this possible association, we focused on a series of NHL with the most frequent BCL6 translocation, the t(3;14)(q27;q32), which involves the IGH locus.
Our present study confirms that the histology of NHL with t(3;14) is heterogeneous, as we found this translocation from low-grade FL2 to aggressive DLBCL. Our data also indicate that some features are shared by most t(3;14)-positive lymphomas. We had previously shown that an absence of CD10 expression is common in 3q27-positive FL (Jardin et al., 2002b), and our present data indicate that an absence of this marker is also observed in a large majority of t(3;14)-positive DLBCL. Likewise, our results indicate that most t(3;14)-positive NHL are positive for the expression of BCL6, a somehow expected result considering that the expression of the gene may be sustained by the translocation (Lossos et al., 2003). Finally, if MUM1 expression is variable in t(3;14)-positive FL, this marker is expressed in a large majority of t(3;14)-positive DLBCL. Predominantly associated with a late-stage of B-cell differentiation, MUM1 expression has been observed in a small percentage of B cells located in the light zone of the GC, in intimate contact with follicular dendritic cells (Falini et al., 2000). By contrast to normal GC B cells in which BCL6 and MUM1 expressions are mutually exclusive, the dominant CD10−/BCL6+/MUM1+ phenotype of the t(3;14)-positive DLBCL thus suggests that these lymphomas may be derived from MUM1+ late GC B cells, where BCL6 expression is maintained by the translocation itself.
The molecular analysis led us to question the structure of the translocated BCL6 allele. Interestingly, all the translocations we characterized involved either the Sμ or the Sγ regions, most often Sγ3. The most striking aspect of our results is the correlations between the S region involved in the translocation, the architecture and the cytology of the tumors. Considering histopathology, Katzenberger et al. (2004) proposed that there might be an important biological difference between FL3b (with a diffuse large cell component, made of centroblasts exclusively and where BCL6 translocations, as in DLBCL, are frequent) and FL1/2/3a (with a preserved maturation to centrocytes, which are rarely associated with BCL6 translocations). Regarding cytogenetics, we observed the same dichotomy, pointing to a possible relation between the switch region involved in the translocation and the phenotype of the tumor. These correlations may indicate different pathogenic pathways, and it can be first hypothesized that the mechanisms leading to the t(3;14) may not target the same cell in FL1/2/3a and FL3b/DLBCL. Such a difference is reminiscent of other translocations where the location of the breakpoint on the IGH locus is restricted and informs on the cell origin of the tumor. It is for example well established that the IGH-myc junctions differ in endemic and sporadic cases of Burkitt's lymphoma, involving mostly the variable regions in the first and the switch regions in the second, indicating different etiologies (Neri et al., 1988). Another hypothesis is that the presentation of the disease may differ with regard to the mechanism of BCL6 deregulation. When considering the molecular anatomy of the Sμ translocation, BCL6 is placed in close proximity with the IGH intronic enhancer, a potent regulator often involved in lymphomagenesis (Willis and Dyer, 2000). By contrast, after an Sγ translocation, BCL6 is controlled by an Iγ promoter, whose activity requires CD40 engagement and cytokines signaling to allow class switch recombination to IgG (Schaffer et al., 1999). As BCL6 is thought to be required to maintain the viability of lymphoma cells (Polo et al., 2004), it is possible that the follicular growth pattern observed in most of the Sγ-positive lymphomas reflects a requirement for the neoplastic B cells to coexist with reactive T cells and follicular dendritic cells, which might allow the Iγ promoter to drive BCL6 expression.
In conclusion, we have identified two subgroups of NHL with t(3;14) translocation that differ regarding their histopathology and the localization of the breakpoint on the IGH locus. These results suggest that the identification of either the breakpoint location within the IGH locus or of the different BCL6 partners could contribute to the understanding of the heterogeneity of B-cell lymphoma with 3q27 structural abnormalities. The clinical relevance of the two t(3;14) NHL subtypes defined by the translocated switch regions thus warrants further investigations.
Materials and methods
Thirty-four t(3;14)-positive lymphomas diagnosed between March 1986 and October 2004 were selected from the database of the Centre Henri Becquerel and included in this study. As the t(3;14)(q27;q32), involving telomeric ends of both chromosomes 3 and 14, is often difficult to detect by conventional cytogenetics, it should be emphasized that only t(3;14)-positive FL or DLBCL where the translocation could be validated either by the molecular cloning of the genomic junction, and/or by RT–PCR amplification of specific IGH-BCL6 fusion transcripts, or by FISH were retained in this study. One sample was obtained from a spleen (patient #28) and 33 from lymph nodes.
Histology and immunochemistry
All archival materials were retrospectively reviewed. Paraffin-embedded biopsies fixed in 10% formalin were available for all cases except #9 and #26. For both, slides obtained at diagnosis were reviewed. For all others, 3 μm thick sections were stained with hematoxylin and eosin, or used for immunochemistry. Immunostaining was performed with an automated indirect peroxidase method with Tecmate 500 (Dako, Glostrup, Denmark), according to the manufacturer's instructions. Antibodies to CD20 (clone L26; Dako; 1/3000 dilution), CD5 (4c7; Novocastra, Newcastle, UK; 1/75), CD10 (56c6; Dako; 1/50), Bcl6 (pg:b6p; Dako; 1/20), Bcl2 (124; Dako; 1/200) and MUM1 (MUM1p; Dako; 1/50) were used. Heat antigen retrieving was performed in citrate buffer (10 mM, pH 6.0) for CD20 and Bcl2, and in Tris/EDTA buffer (pH 9.0) for CD5, CD10, Bcl6 and MUM1. For Bcl6 and MUM1, were considered positive cases where at least 30% of the tumor cells were stained with the antibody. All slides were independently reviewed by two pathologists (JMP and PG) and all tumors were classified according to the WHO criteria (Jaffe et al., 2001).
Cytogenetic and fluorescence in situ hybridization analysis
Cytogenetic analysis was performed as previously reported (Bastard et al., 1994). R-banded metaphases were karyotyped and chromosomal abnormalities were described following the International System for Human Cytogenetic Nomenclature (Mertens et al., 1995). Fluorescence in situ hybridization using the LSI BCL6 Dual Color, Break Apart Rearrangement Probe (Vysis, Downers Grove, IL, USA) was performed on metaphases preparations according to the manufacturer's instructions.
DNA and RNA isolations
Genomic DNAs were extracted by digestion of tumor samples by proteinase K followed by a salting out procedure and ethanol precipitation. Total RNAs were isolated using the RNA NOW kit (Biogentex, P.O. Box 74, Seabrook, TX, 77586 USA). cDNA syntheses were performed by random priming starting from 1 μg of total RNA using M-MLV RT (Invitrogen, Carlsbad, CA, USA).
Molecular cloning of the t(3;14) breakpoints
PCR were performed in a volume of 50 μl using the 2 × Reddy Mix extensor PCR (ABgene, Epsom, UK), 10 pmol of each primer and 100 ng of genomic DNA. PCR protocol was 94°C 2 min, 30 cycles of amplification (94°C 10 s, 60°C 45 s and 68°C 4 min) and 68°C 7 min. Products were analysed by agarose gel electrophoresis (Seakem GTG agarose, FMC Bioproducts, Cambrex Bio Sciences, Rockland, ME, USA). Three reverse oligonucleotide primers were designed in the first intron of BCL6 to amplify the genomic breakpoints on the translocated der(3) chromosomes (BCL61R: IndexTermGCAAAATCACTCACAAAGATCTCCCT; BCL62R: IndexTermGCATCTAGCCTTACTGTCAC; BCL63R: IndexTermCGGCTCACAACAATGACAACA). These three primers were used in combination with different forward primers within the IGH locus (Jardin et al., 2003). All PCR products were isolated from agarose gels using the QIAquick Gel Extraction Kit or the QIAquick PCR purification Kit (Qiagen, Valencia, CA, USA), and sequenced using the Big Dye® Terminator v3.1 Cycle Sequencing Kit and an ABI Prism 310 DNA sequencer (Applied Biosystems, Forster City, CA, USA).
Reverse transcriptase–PCR amplification of the IGH-BCL6 fusion transcripts
PCR were performed in a volume of 50 μl using the 2 × Hot-Goldstar Red Master Mix (Eurogentec, Seraing, Belgium), 10 pmol of each primer and 5 μl of cDNA. PCR protocol was 94°C 6 min, 30 cycles of amplification (94°C 20 s, 60°C 30 s and 72°C 30 s) and 72°C 3 min. PCR products (20 μl) were analysed by agarose gel electrophoresis. For der(3) transcripts, forward oligonucleotide primers specific for the I exons of the μ, γ, α and ɛ IGH germline transcripts (Islam et al., 1994; Stavnezer-Nordgren and Sirlin, 1986) (Iμ: IndexTermAGGCTCGCAGTGACCAGG; Iγ (consensus for the four Sγ I exons): IndexTermCTCTCAGCCAGGACCAAGGA; Iα (consensus for the two Sα I exons): IndexTermTGAGGGTGGACCTGCCATGA; Iɛ: IndexTermAGCTGTCCAGGAACCCGACA), and a consensus J primer (JHcons: IndexTermGGVACMMYGGTCACCGTCTCYTCA) whose degenerate sequence allows amplifications starting from the six IGH J segments, were used in combination with a BCL6 reverse primer located in the third exon of the BCL6 gene (BCL6E3: IndexTermCGGCTCACAACAATGACAACA).
Statistical studies were performed with Statview ver. 4.57 software (Abacus Concepts, Berkeley, CA, USA). Correlations between the location of the breakpoint on the IGH locus and histology were evaluated using the Fisher's exact test.
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This work was supported by grants from the Comité de l'Eure de la Ligue Contre le Cancer.
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Ruminy, P., Jardin, F., Picquenot, J. et al. Two patterns of chromosomal breakpoint locations on the immunoglobulin heavy-chain locus in B-cell lymphomas with t(3;14)(q27;q32): relevance to histology. Oncogene 25, 4947–4954 (2006). https://doi.org/10.1038/sj.onc.1209512
- non-Hodgkin's B-cell lymphoma