BCL6 rearrangement in a patient with mantle cell lymphoma

 We describe a patient with mantle cell lymphoma (MCL) associated with BCL6 gene rearrangement. MCL is a distinct subtype of non-Hodgkin's lymphoma characterized by CD5+, CD10–, CD20+, t(11;14)(q13;q32) and PRAD1/cyclin D1 overexpression. Although rearrangement of the BCL6 gene is the most frequent genetic change among diffuse lymphomas and some follicular lymphomas this is the first report of a patient with MCL associated with BCL6 rearrangement. Received: 6 January 1997 / Accepted: 17 February 1997     

The BCL11 gene family: involvement of BCL11A in lymphoid malignancies.

Many malignancies of mature B cells are characterized by chromosomal translocations involving the immunoglobulin heavy chain (IGH) locus on chromosome 14q32.3 and result in deregulated expression of the translocated oncogene. t(2;14)(p13;q32.3) is a rare event in B-cell malignancies. In contrast, gains and amplifications of the same region of chromosome 2p13 have been reported in 20% of extranodal B-cell non-Hodgkin lymphomas (B-NHL), in follicular and mediastinal B-NHL, and in Hodgkin disease (HD). It has been suggested that REL, an NF-kappaB gene family member, mapping within the amplified region, is the pathologic target. However, by molecular cloning of t(2;14)(p13;q32.3) from 3 cases of aggressive B-cell chronic lymphocytic leukemia (CLL)/immunocytoma, this study has shown clustered breakpoints on chromosome 2p13 immediately upstream of a CpG island located about 300 kb telomeric of REL. This CpG island was associated with a Krüppel zinc finger gene (BCL11A), which is normally expressed at high levels only in fetal brain and in germinal center B-cells. There were 3 major RNA isoforms of BCL11A, differing in the number of carboxy-terminal zinc fingers. All 3 RNA isoforms were deregulated as a consequence of t(2;14)(p13;q32.3). BCL11A was highly conserved, being 95% identical to mouse, chicken, and Xenopus homologues. BCL11A was also highly homologous to another gene (BCL11B) on chromosome 14q32.1. BCL11A coamplified with REL in B-NHL cases and HD lymphoma cell lines with gains and amplifications of 2p13, suggesting that BCL11A may be involved in lymphoid malignancies through either chromosomal translocation or amplification.     

Rearrangement of the chromosome 11 bcl-1 locus in centrocytic lymphoma: analysis with multiple breakpoint probes

Centrocytic lymphoma is a B-cell non-Hodgkin's lymphoma (NHL) composed of lymphocytes resembling cleaved follicular center cells (centrocytes). Previous studies have suggested an association between t(11;14) chromosomal translocations and bcl-1 rearrangement in centrocytic and related intermediate lymphocytic lymphomas. To further characterize the association between bcl-1 and centrocytic lymphoma, Southern blot analysis was performed on samples from 23 patients using four separate bcl-1 breakpoint probes spanning 63 kb of the chromosome 11 bcl-1 locus. Rearrangements were identified in six patients with the major translocation cluster (MTC) probe and in another six with probe p94PS, located about 24 kb 5' of MTC. Eleven of these 12 cases showed comigration of rearranged bcl-1 and Ig heavy chain-joining genes, consistent with the t(11;14) chromosomal translocation. No rearrangements were observed with the bcl-1 locus probes p210 or p11EH located 5' of p94PS, nor with bcl-2 or c-myc oncogene probes. No bcl-1 rearrangements were identified in B-cell follicular NHL (15), small noncleaved cell (Burkitt's and non-Burkitt's) NHL (8), T-cell NHL (4), multiple myeloma (14), and pre-B-cell acute lymphoblastic leukemia (9). One of 23 B-cell NHL of large cell type and one of 19 chronic lymphocytic leukemias or small lymphocytic NHL had MTC rearrangement. Thus, bcl-1 rearrangement occurred at MTC or p94PS in 12 of 23 centrocytic lymphomas (52%), confirming a nonrandom association and suggesting a pathogenetic role for the bcl-1 locus in this immunohistologic subtype of NHL.     

PRAD1 gene over-expression in mantle-cell lymphoma but not in other low-grade B-cell lymphomas, including extranodal lymphoma

Summary. Employing Northern blot analysis and the polymerase chain reaction, we investigated PRAD1 gene over-expression in the tumour tissues of 58 patients with B-cell lymphoma. These findings were then examined in relation to the patients' clinical and immunohistological characteristics. The over-expression of this gene was detected in 6/8 patients with mantle cell lymphoma (MCL) and in only 1/50 other lymphomas, indicating its close association with MCL. The patients with MCL had common clinical findings of advanced disease with generalized lymphadenopathy on admission, and they had a CD5+CD10–IgD+ phenotype. The patients with chronic lymphocytic leukaemia (CLL) also showed findings indicating a distinctive disease entity: a CD5+CD10–IgD+ phenotype and lack of PRAD1 over-expression. In contrast, most patients with diffuse low-grade lymphoma other than MCL and CLL had localized extranodal disease, expressed a CD5-CD10–IgD– phenotype, and lacked PRAD1 over-expression. These findings suggest that extranodal low-grade lymphomas differ from nodal MCL and are not part of the spectrum of CLL.     

Genotypic characterization of centrocytic lymphoma: frequent rearrangement of the chromosome 11 bcl-1 locus

Centrocytic lymphomas are defined in the Kiel classification as B-cell lymphomas composed exclusively of cells resembling cleaved follicular center cells (FCC). These lymphomas have been shown to be histologically, immunophenotypically, and clinically distinct from other cleaved FCC lymphomas. DNA from 18 centrocytic lymphomas (14 patients) was analyzed using Southern blotting and probes for immunoglobulin heavy (JH) and kappa light chain (JK) joining gene, T-cell receptor beta chain constant gene (CB), bcl-1, bcl-2, and c-myc gene rearrangements. All of the lymphomas had JH and JK rearrangements, confirming their B-cell origin. None of the specimens had detectable CB, bcl-2, or c-myc rearrangements. However, 4 of 14 patients (28.6%) had rearrangement of the chromosome 11 bcl-1 locus. Therefore, centrocytic lymphomas are genotypically distinguishable from the majority of other small cleaved FCC lymphomas by their lack of demonstrable bcl-2 rearrangements. This supports the distinct nature of centrocytic lymphomas and suggests the lack of importance for the putative oncogene bcl-2 in these cases. Furthermore, the frequent rearrangement of bcl-1 suggests a possible role for this locus in the pathogenesis of at least some centrocytic lymphomas.     

Coexistent Rearrangements of c-<Emphasis Type="Italic">MYC</Emphasis>,<Emphasis Type="Italic">BCL2</Emphasis>, and<Emphasis Type="Italic">BCL6</Emphasis> Genes in a Diffuse Large B-Cell Lymphoma

We present a patient with stage III de novo diffuse large B-cell lymphoma. The lymphoma cells showed mature B-cell immunophenotype but lacked surface immunoglobulin (Ig) expression. Long-distance and long-distance inverse polymerase chain reaction assays to detect the oncogene/Ig gene rearrangement revealed that the cells carried 3 independent fusion genes, namely, c-MYC/Ig heavy chain gene (IgH), BCL2/IgH, and Ig lambda light chain gene/BCL6. Thus, the lymphoma cells concurrently carried t(8;14)(q24;q32), t(14;18)(q32;q21), and t(3;22)(q27;q11), which developed in association with class switching, V/D/J recombination, and somatic hypermutation, respectively. The lymphoma responded to chemoradiotherapy, and the patient has been well for 2 years, suggesting that multiple oncogene rearrangements may not necessarily be associated with poor clinical outcome.     

The t(14;19)(q32;q13)-positive small B-cell leukaemia: a clinicopathologic and cytogenetic study of seven cases

The t(14;19)(q32;q13), involving the BCL3 locus at chromosome 19q13 and the immunoglobulin heavy chain gene at 14q32, is a rare recurrent cytogenetic abnormality identified in B-cell neoplasms, most of which have been classified as chronic lymphocytic leukaemia (CLL) in the literature. We describe the clinicopathological, immunophenotypic and cytogenetic findings in seven patients with B-cell neoplasms associated with t(14;19)(q32;q13). There were five men and two women, with a median age of 48 years (range 33-68). All had absolute lymphocytosis, six had lymphadenopathy, and one had splenomegaly. Lymphocytes in blood and bone marrow aspirate smears were predominantly small and cytologically atypical. Flow cytometric immunophenotyping showed an atypical immunophenotype with low CLL scores. The growth pattern in bone marrow biopsy specimens was interstitial to diffuse; immunohistochemical stains were positive for bcl3 and negative for cyclin D1. Lymph node biopsy specimens of two patients revealed total architectural effacement by neoplasm with proliferation centres. In addition to t(14;19), cytogenetic studies demonstrated trisomy 12 in five patients. These results suggest that B-cell neoplasms with the t(14;19)(q32;q13) present frequently as leukaemia composed of small B-lymphocytes and share many features with CLL. However, these neoplasms also differ from CLL cytologically and in their immunophenotype.     

Detection of the chromosomal translocation t(11;14) by polymerase chain reaction in mantle cell lymphomas

The t(11;14)(q13;q32) and its molecular counterpart, BCL1 rearrangement, are consistent features of mantle cell lymphoma (MCL). Rearrangement is thought to deregulate the nearby CCND1 (BCL1/PRAD1) proto-oncogene, a member of the cyclin G1 gene family, and thereby to contribute to tumorigenesis. We and others have previously shown that the BCL1 locus is rearranged in 55% to 60% of MCL patients and that, on chromosome 11, more than 80% of the breakpoints are localized within a 1-kbp DNA segment known as the major translocation cluster (MTC). We have determined the nucleotide sequence for a portion of the MTC region, and constructed chromosome 11-specific oligonucleotides that were in conjunction with a consensus immunoglobulin (Ig) heavy chain joining region (JH) primer used to perform the polymerase chain reaction (PCR) to amplify t(11;14) chromosomal junctional sequences in DNA from 16 MCL patients with breakpoints in the MTC region. 15 of the 16 breakpoints that occurred at the MTC region were amenable to PCR detection. The sizes of the amplified bands, the existence or not of a Sac I site in the PCR products, and nucleotide sequencing of the amplified DNA from four patients showed that the breakpoints share a remarkable tendency to tightly cluster within 300 bp on chromosome 11, some of them occurring at the same nucleotide. On chromosome 14, the breakpoints were localized within the Ig JH. Our findings indicate that a BCL1 rearrangement can be detected using this approach in roughly one half of the MCL patients. This has implications for both the diagnosis and the clinical management of MCL.     

Association of bcl-1 rearrangements with lymphocytic lymphoma of intermediate differentiation

Previous studies using classical cytogenetics have demonstrated the presence of the t(11;14) (q13;q32) chromosomal translocation in some cases of lymphocytic lymphoma of intermediate differentiation (IDL), a distinct type of low grade B-cell lymphoma. This finding suggested that the bcl-1 region (located at band q13 of chromosome 11) might be involved in this neoplasm. Using a genomic probe from the major breakpoint area of the bcl-1 locus, we identified rearrangements of the bcl-1 region in 10 of 19 cases, 2 of which comigrated with a rearranged allele of the immunoglobulin heavy chain gene joining region. In contrast, bcl-1 rearrangements were not found in other types of low grade B-cell lymphoma, specifically in 36 cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and 27 cases of follicular lymphoma (FL). To further assess the molecular pathology of IDL, we analyzed these cases for rearrangements of the bcl-2 proto-oncogene, which is associated primarily with follicular lymphomas. None of the 19 cases of IDL had rearrangements. Furthermore, none of the 36 cases of CLL/SLL showed bcl-2 rearrangements, whereas, as expected, 21 of 27 cases of FL had rearrangements of the bcl-2 locus. Our findings demonstrate an association between a rearranged bcl-1 region with approximately 50% of IDLs and suggest that abnormalities of this locus may be important in the pathogenesis of IDL.     

PRAD-1/cyclin D1 gene overexpression in chronic lymphoproliferative disorders: a highly specific marker of mantle cell lymphoma

The t(11;14)(q13;q32) translocation and its molecular counterpart bcl-1 rearrangement are frequently associated with mantle cell lymphomas (MCLs) and only occasionally with other variants of B-cell lymphoid malignancies. This translocation seems to activate the expression of PRAD-1/cyclin D1 gene located downstream from the major breakpoint cluster region of this rearrangement. However, the possible overexpression of this gene in other lymphoproliferative disorders independently of bcl-1 rearrangement is unknown. We have examined the overexpression of PRAD-1 gene in a large series of 142 lymphoproliferative disorders including 20 MCLs by Northern blot analysis. Cytogenetic and/or bcl-1 rearrangement analysis with 2 probes (MTC, p94PS) were performed in 28 cases. Strong PRAD-1 overexpression was observed in 19 of the 20 MCLs including 3 gastrointestinal forms and 4 blastic variants. t(11;14) and/or bcl-1 rearrangement was detected in 6 of the 12 MCLs examined. No correlation was found between the different levels of mRNA expression and the pathologic characteristics of the lymphoma. Among chronic lymphoproliferative disorders other than MCL, only 1 atypical chronic lymphocytic leukemia (CLL) with a t(11;14) translocation and bcl-1 rearrangement and the 2 hairy cell leukemias (HCLs) analyzed showed upregulation of PRAD-1 gene. The expression in the 2 HCLs was lower than in MCL, and no bcl-1 rearrangement was observed. These findings indicate that PRAD-1 overexpression is a highly sensitive and specific molecular marker of MCL but it may also be upregulated in some B-CLLs and in HCL.     

BCL2 translocations in leukemias of mature B cells

Although translocations of the BCL2 gene are frequent in B-cell non- Hodgkin's lymphomas (B-NHL) the incidence, nature, and prognostic significance of similar translocations in the phenotypically related chronic leukemias of mature B cells are unknown. Therefore, we examined 170 cases of B-cell chronic lymphocytic leukemia (B-CLL), 7 cases of B- cell prolymphocytic leukemia (B-PLL), 25 cases of hairy cell leukemia (HCL) and 22 cases of splenic lymphoma with villous lymphocytes (SLVL) with defined cytogenetic abnormalities by DNA blot using both 5' and 3' BCL2 probes to search for rearrangement of the BCL2 locus. Translocation t(14;18) (q32.3;q21.3) was detected cytogenetically in 3 cases of B-CLL. All had breakpoints in the 3' region of BCL2, mapping between the major breakpoint region (MBR) and the minor cluster region (mcr), the breakpoint clusters commonly detected in B-NHL. In 2 of the 3 cases, the breakpoint within BCL2 was mapped to a 1.0-kb EcoRI- HindIII fragment indicating a clustering of breakpoints. Two cases of B- CLL had cytogenetically detectable t(2;18)(p11;q21.3) or t(18;22)(q21.3;q11). Both had rearranged the 5' region of the BCL2 gene to the corresponding lg light-chain gene. Molecular cloning of the t(18;22)(q21.3;q11) showed that the translocation disrupted the BCL2 promoter region and the first untranslated BCL2 exon. Nevertheless, high levels of BCL2 protein were seen in this case. Only 2 other cases in whom cytogenetic analysis was not successful showed rearrangement of the 5' region of BCL2, an overall incidence of 2.3%. No cases of B-PLL, HCL, or SLVL showed either 5' or 3' BCL2 rearrangement. These data confirm the cytogenetic observations that translocations involving the BCL2 locus in all forms of leukemia of mature B cells are rare, and limited to a minor subset of B-CLL. BCL2 translocations in B-CLL involve hot spots of recombination of both the 5' and 3' regions of the BCL2 gene, which are distinct from those commonly seen in B-NHL, suggesting distinct pathogenic mechanisms.     

Deletion of 14q in non-Hodgkin's lymphoma

6 patients with non-Hodgkin's lymphoma [3 with small cell lymphocytic lymphoma of B-cell type (SL), and 1 each with follicular centroblastic/centrocytic, centroblastic, and immunoblastic lymphoma] and with the acquired cytogenetic abnormalities del(14) (q22) or del(14) (q24) are described. An evaluation of these 6 cases and 41 other lymphatic neoplasms with 14q deletion known from the literature revealed that 37 had a breakpoint in bands q22 to q24. The deletions occur significantly more often in lymphomas of SL morphology and in the leukemic counterpart, chronic lymphocytic leukemia, than in other types of lymphatic malignancies (p less than 0.001).     

PIM1 gene cooperates with human BCL6 gene to promote the development of lymphomas

Diffuse large B-cell lymphomas in humans are associated with chromosomal rearrangements (～40%) and/or mutations disrupting autoregulation (～16%) involving the BCL6 gene. Studies of lymphoma development in humans and mouse models have indicated that lymphomagenesis evolves through the accumulation of multiple genetic alterations. Based on our prior studies, which indicated that carcinogen-induced DNA mutations enhance the incidence of lymphomas in our mouse model expressing a human BCL6 transgene, we hypothesized that mutated genes are likely to play an important cooperative role in BCL6-associated lymphoma development. We used retroviral insertional mutagenesis in an effort to identify which genes cooperate with BCL6 in lymphomagenesis in our BCL6 transgenic mice. We identified PIM1 as the most frequently recurring cooperating gene in our murine BCL6-associated lymphomas (T- and B-cell types), and we observed elevated levels of PIM1 mRNA and protein expression in these neoplasms. Further, immunohistochemical staining, which was performed in 20 randomly selected BCL6-positive human B- and T-cell lymphomas, revealed concurrent expression of BCL6 and PIM1 in these neoplasms. As PIM1 encodes a serine/threonine kinase, PIM1 kinase inhibition may be a promising therapy for BCL6/PIM1-positive human lymphomas.     

Double-hit B-cell lymphomas

In many B-cell lymphomas, chromosomal translocations are biologic and diagnostic hallmarks of disease. An intriguing subset is formed by the so-called double- hit (DH) lymphomas that are defined by a chromosomal breakpoint affecting the MYC/8q24 locus in combination with another recurrent breakpoint, mainly a t(14;18)(q32;q21) involving BCL2. Recently, these lymphomas have received increased attention, which contributed to the introduction of a novel category of lymphomas in the 2008 WHO classification, "B cell lymphoma unclassifiable with features intermediate between DLBCL and BL." In this review we explore the existing literature for the most recurrent types of DH B-cell lymphomas and the involved genes with their functions, as well as their pathology and clinical aspects including therapy and prognosis. The incidence of aggressive B-cell lymphomas other than Burkitt lymphoma with a MYC breakpoint and in particular a double hit is difficult to assess, because screening by methods like FISH has not been applied on large, unselected series, and the published cytogenetic data may be biased to specific categories of lymphomas. DH lymphomas have been classified heterogeneously but mostly as DLBCL, the majority having a germinal center phenotype and expression of BCL2. Patients with DH lymphomas often present with poor prognostic parameters, including elevated LDH, bone marrow and CNS involvement, and a high IPI score. All studies on larger series of patients suggest a poor prognosis, also if treated with RCHOP or high-intensity treatment modalities. Importantly, this poor outcome cannot be accounted for by the mere presence of a MYC/8q24 breakpoint. Likely, the combination of MYC and BCL2 expression and/or a related high genomic complexity are more important. Compared to these DH lymphomas, BCL6(+)/MYC(+) DH lymphomas are far less common, and in fact most of these cases represent BCL2(+)/BCL6(+)/MYC(+) triple-hit lymphomas with involvement of BCL2 as well. CCND1(+)/MYC(+) DH lymphomas with involvement of 11q13 may also be relatively frequent, the great majority being classified as aggressive variants of mantle cell lymphoma. This suggests that activation of MYC might be an important progression pathway in mantle cell lymphoma as well. Based on clinical significance and the fact that no other solid diagnostic tools are available to identify DH lymphomas, it seems advisable to test all diffuse large B-cell and related lymphomas for MYC and other breakpoints.     

Overexpression of PRAD1 in a mantle zone lymphoma patient with a t(11;22)(q13;q11) translocation

Summary The PRAD1 gene identified from the chromosome band 11q13 region was previously demonstrated to be overexpressed in cell lines with t(11:14)(q13;q32) trans-location and was suggested to be a candidate BCL-1 gene. We report here one case of mantle zone lymphoma with a t(11;22)(q13:q11), a variant translocation at the BCL-1 locus, having the PRAD1 overexpression. By analogy with the c-myc gene in Burkitt's lymphoma and the BCL-2 gene in follicular lymphoma, this case supports strongly the idea that the PRAD1 is the candidate BCL-1 gene.     

Comparison of chromosome analysis and BCL-1 rearrangement in a series of patients with multiple myeloma

Translocation (11;14)(q13;q32) is a recurring chromosome abnormality which is found non-randomly in non-Hodgkin's lymphoma, especially of follicular type, as well as in B-cell chronic lymphocytic leukaemia, Waldenström's macroglobulinaemia and multiple myeloma. To define further the prevalence of this abnormality in multiple myeloma, we studied a series of 17 patients with this disease with concomitant chromosome analysis and Southern blotting, using a probe specific for the major translocation cluster of the BCL-1 oncogene which is located at chromosome Hq13. Karyotype analysis of 14 evaluable patients revealed three cases with abnormalities of chromosome 11q13, two of them with t(11;14)(q13:q32) and one with del (11)(q13). Southern blot analysis showed no rearrangements in BclI and HindIII digests of DNA from 17 patients including the three patients with anomaly of chromosome 11q13, using a BCL-1 specific probe. A possible restriction length polymorphism was detected in EcoRI cut DNA of five out of 11 patients studied. Therefore the chromosomal break point in our cases with abnormality of chromosome 11q13 must lie outside the major translocation cluster of the BCL-1 gene. However, in centrocytic lymphoma rearrangement of the BCL-1 oncogene has been detected in up to 50% of cases. Location of the break point may therefore be dependent on the differentiation of the transformed B-cell.     

An additional segment at 1p36 derived from der(18)t(14;18) in patients with diffuse large B-cell lymphomas transformed from follicular lymphoma

The particular translocation in follicular lymphomas (FLs) is a t(14;18)(q32;q21), recombining the immunoglobulin heavy chain (IgH) gene on chromosome 14 with the B-cell leukemia/lymphoma 2 (BCL2) gene on chromosome 18. Some low-grade FLs are aggressively transformed into diffuse large B-cell lymphomas, presumably by acquisition of secondary chromosomal changes, including chromosomal band 1p36. A common example is add(1)(p36). Because it is difficult to identify the origin of add(1)(p36) even on high-resolution G-banding analysis, we used spectral karyotyping (SKY) and double-color fluorescence in situ hybridization (DC-FISH) to define the t(14;18) and the extra band at 1p36 in two cases of diffuse large B-cell lymphoma (DLBCL). SKY revealed that the extra chromosomal segment on 1p36 was derived from chromosome 18. DC-FISH defined BCL2/IgH fusion signals at 1p36 in addition to t(14;18), suggesting that BCL2/IgH fusion at 1p36 was an evolutionary alteration following the primary BCL2/IgH translocation on der(18) in both cases. Our results indicate that IgH alleles, implicated in chromosomal rearrangement, may themselves frequently be targets for secondary translocations, suggesting that multiple IgH translocations and insertions are associated with the progression of FL.     

Gastric marginal zone B-cell lymphomas of MALT type develop along 2 distinct pathogenetic pathways.

Low-grade marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type can transform into high-grade diffuse large B-cell lymphoma (DLBCL). Up to 60% of the MALT lymphomas contain the recently described t(11;18). However, this translocation has not been detected in any DLBCL so far. To elucidate the pathogenesis of these tumors, microsatellite screening of 24 gastric MALT lymphomas was performed and the results were compared with aberrations detected in a previous study on gastric DLBCL. The most frequent aberration, found in 21% of the MALT lymphomas that were exclusively t(11;18)-negative cases, was amplification of the 3q26.2-27 region (harboring the locus of the BCL6 gene). Allelic imbalances in regions 3q26.2-27, 6q23.3-25, 7q31, 11q23-24, and 18q21 were shared by both MALT lymphoma and DLBCL. Loss of heterozygosity in regions 5q21 (APC gene locus), 9p21 (INK4A/ARF), 13q14 (RB), and 17p13 (p53) and allelic imbalances in 2p16, 6p23, and 12p12-13 occurred exclusively in DLBCL. Only one of 10 t(11;18)-positive MALT lymphomas showed an additional clonal abnormality. These tumors thus display features of a clonal proliferation characterized by the presence of the t(11;18). However, they only rarely display secondary aberrations and do not seem to transform into DLBCL. In contrast, t(11;18)-negative MALT lymphomas show numerous allelic imbalances--some of them identical with aberrations seen in DLBCL--suggesting that this group is the source of tumors eventually transforming into high-grade DLBCL.     

LAZ3 rearrangements in non-Hodgkin's lymphoma: correlation with histology, immunophenotype, karyotype, and clinical outcome in 217 patients

We have recently shown that an evolutionary conserved gene LAZ3, encoding a zinc finger protein, is disrupted and overexpressed in some B-cell lymphomas (mainly with a large cell component) that show chromosomal rearrangements involving 3q27. Because the breakpoints involved in these rearrangements are focused in a narrow major translocation cluster (MTC) on chromosome 3, we used genomic probes from this region to study the molecular rearrangements of LAZ3 in a large series of patients (217) with non-Hodgkin's lymphoma (NHL). Southern blot analysis showed LAZ3 rearrangement in 43 patients (19.8%). Rearrangement was found in 11 of the 84 patients (13%) with follicular lymphoma but was most frequent in aggressive lymphoma (diffuse mixed, diffuse large cell, and large cell immunoblastic subtypes), in which 31 of the 114 patients (27%) were affected. The highest proportion of LAZ3 alteration was observed in B-cell aggressive lymphoma (26 of 71 cases, 37%). Eleven of the 32 patients with 3q27 chromosomal abnormality had no LAZ3 rearrangement, suggesting the possibility of LAZ3 involvement outside the MTC. On the other hand, 18 of the 39 patients with LAZ3 rearrangement and available cytogenetic results did not have visible chromosomal break at 3q27, suggesting that almost a half of the rearrangements are not detectable by cytogenetic methods. No statistical association could be found between LAZ3 status and initial features of the disease or clinical outcome in either follicular or aggressive lymphomas. We conclude that LAZ3 alteration is a relatively frequent event in B-cell lymphoma, especially in those of aggressive histology. It could be used as a genomic marker of the disease, and further studies are needed to clarify clinical implications of these alterations.