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HGNC Approved Gene Symbol: BCL6
Cytogenetic location: 3q27.3 Genomic coordinates (GRCh38): 3:187,721,377-187,745,468 (from NCBI)
BCL6 functions as a transcriptional repressor and is necessary for germinal center formation. Approximately 40% of diffuse large cell lymphomas and 5 to 10% of follicular lymphomas are associated with chromosomal translocations that deregulate expression of BCL6 by juxtaposing heterologous promoters to the BCL6 coding domain (Cattoretti et al., 1995).
Chromosomal translocations involving chromosome 3q27 and immunoglobulin gene regions are among the most common rearrangements in B-cell non-Hodgkin lymphoma. Using a probe from the immunoglobulin heavy chain joining region locus (147010), Baron et al. (1993) isolated genomic clones from a bacteriophage lambda library prepared from a lymphoma characterized by a translocation t(3;14)(q27;q32). Normal chromosome 3 sequences and the reciprocal breakpoint junction were isolated. DNA probes on each side of the chromosome 3 breakpoint hybridized at high stringency to the DNA of various mammalian species, demonstrating evolutionary conservation. A probe made from partial cDNA clones isolated from a T-cell line hybridized the genomic DNA from both sides of the chromosome 3 breakpoint, indicating that the t(3;14) is associated with a break within the gene on chromosome 3. In situ chromosomal hybridization revealed that the same gene is involved in the t(3;22)(q27;q11). Preliminary nucleotide sequencing showed no identity of the cDNA to gene sequences in available data banks. Baron et al. (1993) proposed the name B-cell lymphoma-6 (BCL6) for this gene, which they presumed plays a role in the pathogenesis of certain B-cell lymphomas. Ye et al. (1993) cloned the BCL6 gene.
Kerckaert et al. (1993) reported the isolation of a gene that was disrupted in 2 patients with non-Hodgkin lymphoma and t(3;14) and t(3;4) translocations. The gene, which they called LAZ3 (lymphoma-associated zinc finger gene on chromosome 3), encodes a 79-kD protein containing 6 zinc finger motifs and sharing amino terminal homology with several transcription factors, including the Drosophila 'tramtrack' and 'Broad-complex' genes, both of which are developmental transcription regulators. LAZ3 is transcribed as a 3.8-kb message predominantly in normal adult skeletal muscle and in several non-Hodgkin lymphomas carrying 3q27 chromosomal defects. Kerckaert et al. (1993) suggested that LAZ3 may act as a transcription regulator and play an important role in lymphoma genesis.
Ye et al. (1993) cloned a gene from chromosomal translocations affecting band 3q27. They showed that the gene, BCL6, encodes a 79-kD protein that is homologous with zinc finger-transcription factors. Chromosomal translocations affecting 3q27 are common in diffuse large cell lymphoma (DLCL). In 13 of 39 DLCL samples, but not in other types of lymphoid malignancies, Ye et al. (1993) found that the BCL6 gene was truncated within its 5-prime noncoding sequences, suggesting that its expression had been deregulated. Thus, BCL6 may be a protooncogene specifically involved in the pathogenesis of DLCL. Miki et al. (1994) cloned the gene located at the 3q27 breakpoint in a patient with Burkitt lymphoma carrying a translocation t(3;22)(q27;q11). The immunoglobulin lambda light chain gene was fused to the gene on 3q27, which Miki et al. (1994) referred to as BCL5. This designation is, however, used for the gene on 17q22 (151441). The characteristics of their BCL5 gene were similar to those described by Baron et al. (1993) and Ye et al. (1993) for the so-called BCL6 gene.
Using antisera raised against N- and C-terminal BCL6 synthetic oligopeptides, Cattoretti et al. (1995) identified the BCL6 gene product as a 95-kD nuclear protein. Western blot analysis of human tumor cell lines representative of various hematopoietic lineages/stages of differentiation showed that the BCL6 protein is predominantly expressed in the B-cell lineage where it was found in mature B cells. Immunohistochemical analysis of normal human lymphoid tissues indicated that BCL6 expression is topographically restricted to germinal centers, including all centroblasts and centrocytes. The results indicated that expression of BCL6 is specifically regulated during B-cell differentiation and suggested a role for BCL6 in germinal center development or function. Because diffuse large cell lymphoma derives from germinal-center B cells, Cattoretti et al. (1995) suggested that deregulated BCL6 expression may contribute to its genesis by preventing postgerminal center differentiation.
By using a DNA sequence selected for its ability to bind recombinant BCL6 in vitro, Chang et al. (1996) showed that BCL6 is present in DNA-binding complexes in nuclear extracts from various B-cell lines. In transfection experiments, BCL6 can repress transcription from promoters linked to its DNA target sequence and this activity is dependent upon specific DNA-binding and the presence of an intact N-terminal half of the protein. This part of the BCL6 molecule contains an autonomous transrepressor domain, and 2 noncontiguous regions, including the POZ motif, mediate maximum transrepressive activity. Thus, the BCL6 protein can function as a sequence-specific transcriptional repressor and may have a role in normal lymphoid development lymphomagenesis.
Using gain-of-function and loss-of-function systems and DNA microarray screening to identify genes repressed by BCL6, Shaffer et al. (2000) found reduced expression of many lymphocyte-activation genes. In the screening, 13 arrays yielded approximately 80,000 measures of gene expression. By Northern blot, semiquantitative RT-PCR, and flow cytometry analyses, Shaffer et al. (2000) confirmed the change of mRNA and/or protein expression levels in 14 genes. The repressed target genes could be functionally linked by their roles in B-cell activation (CD69 (107273), CD44 (107269), EBI2 (605741), ID2 (600386), LEU13 (IFITM1; 604456), and STAT1 (600555)), B-cell differentiation (BLIMP1, or PRDM1; 603423), inflammation (MIP1A (SCYA3; 182283), IP10 (SCYB10; 147310), and CXCR4 (162643)), and cell cycle control (p27(KIP1) (CDKN1B; 600778) and cyclin D2 (CCND2; 123833)). Additional B-cell differentiation genes restricted to germinal center expression (CD10 (MME; 120520), AMYB (MYBL1; 159405), BCL7A (601406), CD19 (107265), and CD20 (MS4A1; 112210)) were downregulated by inhibition of BCL6 function, while CD38 (107270), a plasma cell marker, was upregulated. Shaffer et al. (2000) proposed that elevated expression of BCL6 in some B cells early in the antigen response may skew these cells toward a germinal center fate and away from a plasma cell fate. The repression of some of the differentiation and cell cycle control genes may also be critical for malignant transformation and lymphomagenesis.
BCL6, which is altered in many cases of non-Hodgkin lymphoma, shares many functional properties with PLZF (176797), which is fused with the gene of retinoic receptor alpha (RARA; 180240) as a result of a translocation in some cases of acute promyelocytic leukemia. Both inhibit cell growth, concentrate into punctate nuclear subdomains, and are sequence-specific transcriptional repressors recruiting a histone deacetylase-repressing complex. Dhordain et al. (2000) showed that BCL6 and PLZF colocalize onto nuclear dots. Moreover, truncated derivatives of one protein, which display a diffuse nuclear localization, are recruited onto nuclear dots by the full-length other. The colocalization and the reciprocal 'rescue' is the result of a direct interaction between BCL6 and PLZF, as indicated by yeast 2-hybrid assays, in vitro immunoprecipitations, and GST pull-down experiments. The data indicated that a physical interaction between these 2 proteins underlies their simultaneous recruitment onto multiprotein nuclear complexes, presumably involved in transcriptional silencing and whose integrity and/or function may be altered in oncogenesis.
Bereshchenko et al. (2002) showed that the coactivator p300 (602700) binds and acetylates BCL6 in vivo and inhibits its function. Acetylation disrupts the ability of BCL6 to recruit histone deacetylases (HDACs), thereby hindering its capacity to repress the transcription and to induce cell transformation. BCL6 is acetylated under physiologic conditions in normal germinal center B cells and in germinal center-derived B cell tumors. Treatment with specific inhibitors showed that levels of acetylation of BCL6 are controlled by both HDAC-dependent and SIR2-dependent pathways. Pharmacologic inhibition of these pathways led to the accumulation of the inactive acetylated BCL6 and to cell-cycle arrest and apoptosis in B-cell lymphoma cells. The results identified a new mechanism of regulation of BCL6 with potential for therapeutic exploration.
Tang et al. (2002) showed that HeLa cells induced to express an active form of AFX (300033) died by activating an apoptotic pathway that included a 4- to 7-fold upregulation of BCL6 expression. Examination of the BCL6 promoter identified 8 AFX binding sites, and AFX binding activated BCL6 transcription. BCL6 in turn bound the promoter of BCLX (600039), which encodes an antiapoptotic protein, and repressed BCLX transcription 1.3- to 1.7-fold. Tang et al. (2002) found that macrophages isolated from Bcl6 null mice showed enhanced survival in vitro. They concluded that AFX regulates apoptosis in part by suppressing the level of antiapoptotic BCLX through the transcriptional repressor BCL6.
Using microarray analysis of gene expression signatures, Lossos et al. (2004) studied prediction of prognosis in diffuse large B-cell lymphoma. In a univariate analysis, genes were ranked on the basis of their ability to predict survival; the strongest predictors of longer overall survival were LMO2 (180385), BCL6, and FN1 (135600), and the strongest predictors of shorter overall survival were CCND2, SCYA3, and BCL2 (151430). Lossos et al. (2004) developed a multivariate model that was based on the expression of these 6 genes, and validated the model in 2 independent microarray data sets. The model was independent of the International Prognostic Index and added to its predictive power.
Phan and Dalla-Favera (2004) reported that BCL6 suppresses the expression of the p53 gene (191170) and modulates DNA damage-induced apoptotic responses in germinal center B cells. BCL6 represses p53 transcription by binding 2 specific DNA sites within the p53 promoter region and accordingly, p53 expression is absent in germinal center B cells where BCL6 is highly expressed. Suppression of BCL6 expression via specific short interfering RNA leads to increased levels of p53 mRNA and protein both under basal conditions and in response to DNA damage. Most notably, constitutive expression of BCL6 protects B-cell lines from apoptosis induced by DNA damage. These results suggested that an important function of BCL6 is to allow germinal center B cells to tolerate the physiologic DNA breaks required for immunoglobulin class switch recombination and somatic hypermutation without inducing a p53-dependent apoptotic response. Phan and Dalla-Favera (2004) concluded that their findings also implied that deregulated BCL6 expression contributes to lymphomagenesis in part by functional inactivation of p53.
Using EMSA, Baron et al. (2007) showed that BCL6 bound directly to the PDCD2 (600866) promoter and repressed its transcription. Small interfering RNA-mediated knockdown of BCL6 in a B-cell lymphoma line resulted in increased PDCD2 protein expression. Mice overexpressing human BCL6 had minimal Pdcd2. Immunohistochemical analysis demonstrated an inverse relationship of PDCD2 and BCL6 expression in human B and T lymphomas. Baron et al. (2007) concluded that PDCD2 is a target of BCL6 and that PDCD2 repression by BCL6 is important in the pathogenesis of certain human lymphomas.
Nurieva et al. (2009) characterized the function of BCL6, a transcription factor selectively expressed in T follicular helper (T(FH)) cells. BCL6 expression is regulated by interleukin-6 (IL6; 147620) and interleukin-21 (IL21; 605384). BCL6 overexpression induced T(FH)-related gene expression and inhibited other T helper lineage cell differentiation in a DNA binding-dependent manner. Moreover, Nurieva et al. (2009) found that BCL6 deficiency in T cells resulted in impaired T(FH) development and germinal center reactions, and altered production of other effector T cell subsets.
Johnston et al. (2009) independently found that expression of the transcription factor Bcl6 in CD4+ T cells is both necessary and sufficient for in vivo T(FH) differentiation and T cell help to B cells in mice. In contrast, the transcription factor Blimp1 (603423), an antagonist of Bcl6, inhibits T(FH) differentiation and help, thereby preventing B cell germinal center and antibody responses. Johnston et al. (2009) concluded that T(FH) cells are required for proper B cell responses in vivo and that BCL6 and BLIMP1 play central but opposing roles in T(FH) differentiation.
Cerchietti et al. (2009) showed that endogenous HSP90 (HSP90AA1; 140571) interacted directly with BCL6 in diffuse large B-cell lymphomas (DLBCLs) and stabilized BCL6 mRNA and protein. HSP90 and BCL6 were almost invariantly coexpressed in the nuclei of primary DLBCL cells. HSP90 formed a complex with BCL6 at BCL6 target promoters, and pharmacologic inhibition of HSP90 derepressed BCL6 target genes.
Duy et al. (2011) reported the discovery of a novel mechanism of drug resistance that is based on protective feedback signaling of leukemia cells in response to treatment with tyrosine kinase inhibitors. Duy et al. (2011) identified BCL6 as a central component of this drug-resistance pathway and demonstrated that targeted inhibition of BCL6 leads to eradication of drug-resistant and leukemia-initiating subclones in Philadelphia chromosome-positive acute lymphoblastic leukemia cells.
Duan et al. (2012) demonstrated that BCL6 is targeted for ubiquitylation and proteasomal degradation by a SKP1-CUL1-F-box protein (SCF) ubiquitin ligase complex that contains the F-box protein FBXO11 (607871). The gene encoding FBXO11 was found to be deleted or mutated in multiple DLBCL cell lines, and this inactivation of FBXO11 correlated with increased levels and stability of BCL6. Similarly, FBXO11 was either deleted or mutated in primary DLBCLs. Notably, tumor-derived FBXO11 mutants displayed an impaired ability to induce BCL6 degradation. Reconstitution of FBXO11 expression in FBXO11-deleted DLBCL cells promoted BCL6 ubiquitylation and degradation, inhibited cell proliferation, and induced cell death. FBXO11-deleted DLBCL cells generated tumors in immunodeficient mice, and the tumorigenicity was suppressed by FBXO11 reconstitution. Duan et al. (2012) revealed a molecular mechanism controlling BCL6 stability and proposed that mutations and deletions in FBXO11 contribute to lymphomagenesis through BCL6 stabilization. The authors stated that deletions/mutations found in DLBCLs are largely monoallelic, indicating that FBXO11 is a haploinsufficient tumor suppressor gene.
Using confocal microscopy, Barnett et al. (2012) showed that after immunization, Bcl6, Il21r (605383), and Prkcz (176982) colocalized with the microtubule-organizing center in a polarized manner to 1 side of the plane of division in mouse germinal center B cells, generating unequal inheritance of fate-altering molecules by daughter cells. Germinal center B cells from mice lacking Icam1 (147840) failed to divide asymmetrically. Barnett et al. (2012) proposed that motile cells lacking constitutive attachment can receive provisional polarity cues from the microenvironment to generate daughter cell diversity and self-renewal.
Mathew et al. (2012) reported that PLZF (176797) is prominently associated with cullin-3 (CUL3; 603136) in natural killer T cell thymocytes. PLZF transports CUL3 to the nucleus, where the 2 proteins are associated within a chromatin modifying complex. Furthermore, PLZF expression results in selective ubiquitination changes of several components of this complex. CUL3 was also found associated with the BTB-ZF transcription factor BCL6, which directs the germinal center B cell and follicular T-helper cell programs. Conditional CUL3 deletion in mice demonstrated an essential role for CUL3 in the development of PLZF- and BCL6-dependent lineages. Mathew et al. (2012) concluded that distinct lineage-specific BTB-ZF transcription factors recruit CUL3 to alter the ubiquitination pattern of their associated chromatin-modifying complex. They proposed that this function is essential to direct the differentiation of several T- and B-cell effector programs, and may also be involved in the oncogenic role of PLZF and BCL6 in leukemias and lymphomas.
The BCL6 gene maps to chromosome 3q27 (Baron et al., 1993). Liao et al. (1996) mapped the mouse Bcl6 gene to chromosome 16 by interspecific backcross analysis.
The BCL6 gene is implicated in diffuse large B-cell lymphomas (DLBL). Hosokawa et al. (2000) described the molecular characterization of novel t(3;7)(q27;p12) translocations in 2 patients with DLBL. Molecular genetic analysis of the breakpoint area involving BCL6 revealed the presence of the Ikaros gene (603023). As a molecular consequence of the translocation, the 5-prime regulatory region of BCL6 was replaced by the putative 5-prime regulatory region of the Ikaros gene, probably leading to deregulated expression of the BCL6 gene throughout B-cell differentiation. RT-PCR and FISH analyses of a patient sample established that the translocation resulted in fusion of the Ikaros and BCL6 genes. The clinical features of the 2 patients with DLBL and t(3;7)(q27;p12) translocations were reported by Ichinohasama et al. (1998).
In 2 B cell-type non-Hodgkin lymphoma patients with the t(3;6)(q27;p21) translocation, Akasaka et al. (1997) found that the translocation fused the H4/m histone gene (602833) to exons 3-9 of BCL6. Since H4 gene expression is tightly coupled to DNA replication, these authors suggested that the translocation causes inappropriate expression of BCL6 during the cell cycle, leading to the development of non-Hodgkin lymphoma.
Kurata et al. (2002) studied the recurrent t(3;6)(q27;p21) translocation that occurs in non-Hodgkin lymphoma. They cloned 5 H4/BCL6 junctions from both the derivative chromosome 3 and the derivative chromosome 6. The breakpoints on H4 were distributed within the single exon or close to the terminal palindrome, and those on BCL6 were localized within or close to the translocation hypercluster. Deletions or duplications of variable numbers of nucleotides were identified at the junctions. Eight single nucleotide alterations were introduced into the translocation/mutation cluster of BCL6, whereas 4 single nucleotide substitutions were identified within a 360-bp region of H4. Thus, the somatic hypermutation mechanism was likely to target H4, resulting in a predisposition to the development of translocation with BCL6. Lymphoma cells carrying H4/BCL6 produced fusion transcripts containing both H4 and BCL6 messages; however, the cells expressed only moderate levels of BCL6 mRNA. Deletion analyses revealed that the high-level BCL6 protein expression was promoted by the H4 regulator sequences.
Chaganti et al. (1998) reported that a substantial proportion of cytogenetically detected 3q27 breaks in non-Hodgkin lymphomas do not represent BCL6-associated translocations. They suggested that alternate breakpoints may lead to BCL6 deregulation or that other genes may be involved in 3q27 translocations. In a separate report, Chaganti et al. (1998) found that BCL6 deregulation in a case of non-Hodgkin lymphoma was caused by insertion of immunoglobulin gene transcriptional regulatory sequences at the translocation junction.
The LAZ3 gene on 3q27 is nonrandomly disrupted in B-cell non-Hodgkin lymphoma by chromosomal translocations clustered within a 3.3-kb MTC (major translocation cluster) located between the 2 first noncoding exons. These translocations generally result in the expression of a chimeric mRNA transcript between the LAZ3 gene and sequences derived from the partner chromosome. Galiegue-Zouitina et al. (1999) reported the identification of L-plastin (LCP1; 153430) as a novel LAZ3 partner in chimeric transcripts resulting from a t(3;13)(q27;q14) translocation, in 2 cases of B-cell lymphoma. As a consequence of the translocation, the 5-prime regulatory region of each gene was exchanged, creating both LCP1-LAZ3 and reciprocal LAZ3-LCP1 fusion transcripts in one case, and only an LCP1-LAZ3 fusion transcript in the other. The 13q14 chromosome region is frequently disrupted in various proliferative disorders, and the LCP1 gene defines a new breakpoint site in this region. LCP1 encodes an actin-binding protein and is the second LAZ3 partner gene, with the RHOH/TTF gene (602037), involved in actin cytoskeleton organization.
Ueda et al. (2002) identified the gene for interleukin-21 receptor (IL21R; 605383) as the fusion partner with BCL6 in t(3;16)(q27;p11) translocation found in diffuse large B-cell lymphoma. They reviewed the considerable number of non-IG fusion partners of BCL6 translocations totaling a dozen or more that represented recurrent abnormalities observed in at least 2 cases and/or reported from at least 2 independent laboratories.
Migliazza et al. (1995) reported that in 22 of 30 (73%) DLCLs and 7 of 15 (47%) follicular lymphomas, but not in other tumor types, the BCL6 gene is also altered by multiple, often biallelic, mutations clustered in its 5-prime noncoding region. These mutations are of somatic origin and are found in cases displaying either normal or rearranged BCL6 alleles, indicating their independence from chromosomal rearrangements and association with immunoglobulin genes through translocation. These alterations identify a mechanism of genetic instability and malignant B cells and may have been selected during lymphomagenesis for their role in altering BCL6 expression. A panel of 123 nonhematologic tumors were screened for mutations in the sequences most frequently mutated in non-Hodgkin lymphoma using PCR/SSCP analysis, and no SSCP variant was found except for previously detected population polymorphisms. Several observations suggested to Migliazza et al. (1995) that BCL6 mutations may be the result of the IgD hypermutation mechanism acting on non-Ig loci. In 10 cases studied in detail, a total of 59 alterations were detected in the BCL6 gene, including 55 single basepair substitutions, 3 small deletions, and 1 insertion.
Capello et al. (1997) detected 5-prime mutations of BCL6 in 6 of 21 (28.6%) cases of sporadic Burkitt lymphoma and in 7 of 14 (50%) cases of endemic Burkitt lymphoma.
Somatic hypermutation in B lymphocytes had been assumed to be restricted to the immunoglobulin genes. The somatic point mutations arise between the Ig promoter and 1- to 2-kb downstream, and thus only the variable (V) region, but not the constant (C) region, of an Ig gene is affected. However, if a kappa-chain promoter is artificially inserted upstream of the C region, both C and V are mutated at equal frequencies. This suggested that initiation of transcription of Ig genes is required for somatic hypermutation and that the mutation domain is restricted to the 5-prime end of the gene because a postulated mutation factor acts early in transcript elongation. Hypermutation in B lymphocytes occurs in the immunoglobulin genes of B lymphocytes that are the precursors to memory B cells. Non-Ig promoters are permissible for the mutation process, suggesting that other genes expressed in mutating B cells may be subject to somatic hypermutation. Shen et al. (1998) found that significant mutations were not observed in MYC (190080), S14 (130620), or alpha-fetoprotein (AFP; 104150) genes, but the BCL6 gene was highly mutated in a large proportion of memory B cells of normal individuals. The mutation pattern was similar to that of immunoglobulin genes.
Posttransplantation lymphoproliferative disorders represent a heterogeneous group of Epstein-Barr virus (EBV)-associated lymphoid proliferations that arise in immunosuppressed transplant recipients. Some of these lesions regress after a reduction in immunosuppressive therapy, whereas some progress despite aggressive therapy. Morphologic, immunophenotypic, and immunogenotypic criteria are not useful in predicting clinical outcome. Cesarman et al. (1998) examined 57 lesions of the posttransplantation lymphoproliferative disorder obtained from 36 solid organ transplant recipients for the presence of mutations in the BCL6 gene. BCL6 mutations were identified in 44% of the specimens and in 44% of the patients; none was identified in the cases classified as plasmacytic hyperplasia. However, mutations were present in 43% of the polymorphic lesions and 90% of the cases diagnosed as non-Hodgkin lymphoma or multiple myeloma. BCL6 mutations predicted shorter survival and refractoriness to reduced immunosuppression and/or surgical excision. Cesarman et al. (1998) suggested that BCL6 is a reliable indicator for the division of this cluster of disorders into the biologic categories of hyperplasia and lymphoma, of which only the former can regress on immune reconstitution.
Hamblin et al. (1999) and others have demonstrated a prognostically relevant division of chronic lymphocytic leukemia (CLL) into 2 subsets, one of which has V-gene sequences in germline configuration, and the other with somatically mutated immunoglobulin V(H) genes. Sahota et al. (2000) analyzed the state of the BCL6 gene in these 2 classes of CLL. In 4 of 10 CLL cases with unmutated V(H) genes, somatic mutations were found in BCL6. In those CLL cases with somatically mutated V(H) genes, 4 of 9 showed BCL6 mutations. These data indicated that somatic mutations in the V(H) and BCL6 loci may not necessarily occur in tandem in CLL.
Gaidano et al. (1999) studied BCL6 in 26 cases of gastrointestinal MALT-NHL (mucosa-associated lymphoid tissue non-Hodgkin lymphoma), including 16 cases of low-grade histology and 10 cases of high-grade histology. Somatic mutations in BCL6 were found in 6 of 10 high-grade cases, whereas there were no mutations found in 16 low-grade cases tested (p = 0.001). The 6 cases with BCL6 mutations comprised 5 cases of gastric MALT-NHL and 1 case of jejunal MALT-NHL. Mutations were represented predominantly by single-nucleotide substitutions, which were multiple in most cases.
Kurosu et al. (2004) identified mutations in the 5-prime regulatory region of the BCL6 gene in 8 of 20 patients with pulmonary MALT lymphoma, 5 of 5 patients with human immunodeficiency virus (HIV)-related lymphocytic interstitial pneumonia (LIP), 2 of 5 patients with EBV-related LIP, and 3 of 10 patients with virus-negative LIP. BCL6 mutations in patients with HIV-LIP did not show features of Ig V(H) gene hypermutation, suggesting that immunologic reactions in HIV-related LIP result from a process different from that found in HIV-negative pulmonary lymphoproliferative disorders.
The zinc finger transcriptional repressor encoded by the BCL6 gene is normally expressed in both B cells and CD4(+) T cells within germinal centers; non-Hodgkin lymphomas are often derived from germinal center B cells. Ye et al. (1997) showed that mice deficient in BCL6 displayed normal B-cell, T-cell, and lymphoid-organ development but had a selected defect in T cell-dependent antibody responses. This defect included a complete lack of affinity maturation and was due to the inability of follicular B cells to proliferate and form germinal centers. In addition, BCL6-deficient mice developed an inflammatory response in multiple organs characterized by infiltrations of eosinophils and IgE-bearing B lymphocytes typical of a Th2-mediated hyperimmune response. Thus, Ye et al. (1997) concluded that BCL6 functions as a transcriptional switch that controls germinal center formation and may also modulate specific T cell-mediated responses. Altered expression of BCL6 in lymphoma represents a deregulation of the pathway normally leading to B-cell proliferation and germinal center formation.
Ichii et al. (2002) observed that the percentage of CD8 (see 186910)-positive T cells with a memory phenotype was lower in Bcl6 -/- mice than in wildtype mice, while the percentage of activated T cells was the same. Transgenic mice and 'rescued' Bcl6 -/- mice expressing the Bcl6 transgene specifically in T cells had levels of memory CD8 cells like those of wildtype mice. After antigenic stimulation, memory CD8 cells, which express CD44 (107269), Ly6C (see LY6D; 606204), CD122 (146710), and Bcl2 (151430), differentiated into effector cells more rapidly than nonmemory CD8 cells in wildtype mice. Analysis of CD8-positive T-cell proliferation indicated that memory-type CD8 cells proliferated through a homeostatic mechanism in a Bcl6-dependent manner in the lymphopenic environment of very young mouse spleens. Ichii et al. (2002) concluded that BCL6 is involved in the generation and maintenance of both T and B cells during immune responses.
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