Disease relevance of BCL6

• Specific peptide interference reveals BCL6 transcriptional and oncogenic mechanisms in B-cell lymphoma cells [1].
• BCL6 is frequently activated in non-Hodgkin's lymphoma, but its mechanism of action has remained unclear [2].
• We report here that, in 22/30 (73%) DLCL and 7/15 (47%) follicular lymphoma (FL), but not in other tumor types, the BCL6 gene is also altered by multiple (1.4 x 10(-3) -1.6 x 10(-2) per bp), often biallelic, mutations clustering in its 5' noncoding region [3].
• The BCL6 gene encodes a zinc-finger transcription factor and is altered by chromosomal arrangements in its 5' noncoding region in approximately 30% of diffuse large-cell lymphoma (DLCL) [3].
• In contrast, high-growth fraction lymphomas are characterized by an enhanced proliferative activity, as a result of the deregulation of oncogenes with cell cycle regulatory functions, such as BCL6, in large B-cell lymphoma, or c-myc, in Burkitt lymphoma [4].

High impact information on BCL6

• MTA3 is expressed in the same pattern in germinal centers as BCL-6 [5].
• The transcriptional repressor BCL-6 regulates B lymphocyte cell fate during the germinal center reaction by preventing terminal differentiation of B lymphocytes into plasma cells until appropriate signals are received [5].
• Remarkably, exogenous expression of BCL-6 in a plasma cell line leads, in an MTA3-dependent manner, to repression of plasma cell-specific transcripts, reactivation of the B cell transcriptional program, expression of B lymphocyte cell surface markers, and reprogramming of cell fate [5].
• BCL-6 physically interacts with Mi-2/NuRD and this interaction is sensitive to BCL-6 acetylation status [5].
• This indicates that these syndromes are likely to result from defects in alternative functions of BCOR, such as interactions with transcriptional partners other than BCL-6 [6].

Chemical compound and disease context of BCL6

• In the present study, we established Daudi and Raji B-cell lymphoma cell lines that overexpress BCL6 or its mutant, BCL6-Ala333/343, in which serine residues required for degradation through the proteasome pathway in B-cell receptor-stimulated cells are mutated [7].
• To directly address this issue, we used a tetracycline-regulated system in human U2OS osteosarcoma cells and thus found that BCL6 mediates growth suppression associated with impaired S phase progression and apoptosis [8].
• Resveratrol induces apoptosis in transformed follicular lymphoma OCI-LY8 cells: Evidence for a novel mechanism involving inhibition of BCL6 signaling [9].
• The N-ethyl-N-nitrosourea-induced lymphomas spread widely, were exclusively T cell, expressed the BCL6 protein, and occurred only in the transgenic mice [10].
• We hypothesize that increased BCL-6 in breast cancer cells might block tamoxifen resistance by repressing AP-1, eventually resulting in apoptosis [11].

Biological context of BCL6

• In BCL6-positive lymphoma cells, peptide blockade caused apoptosis and cell cycle arrest [1].
• The BTB/POZ transcriptional repressor and candidate oncogene BCL6 is frequently misregulated in B-cell lymphomas [1].
• A senescence rescue screen identifies BCL6 as an inhibitor of anti-proliferative p19(ARF)-p53 signaling [2].
• The BCL6 proto-oncogene encodes a transcriptional repressor required for the development of germinal centers (GCs) and implicated in the pathogenesis of GC-derived B cell lymphoma [12].
• In addition, these findings imply that T-B cell interactions may be disrupted in B cell lymphoma expressing deregulated BCL6 genes [12].

Anatomical context of BCL6

• We show that BCL6 expression also dramatically extends the replicative lifespan of primary human B cells in culture and induces cyclin D1 expression, indicating that BCL6 has a similar activity in lymphoid cells [2].
• BCL6 efficiently immortalizes primary mouse embryonic fibroblasts and cooperates with RAS in oncogenic transformation [2].
• BCL6 encodes a transcription factor that represses genes necessary for the terminal differentiation of lymphocytes within germinal centers, and the misregulated expression of this factor is strongly implicated in several types of B cell lymphoma [13].
• The results suggest that BCL6 may directly control the ability of B cell to interact with T cells during normal GC development [12].
• The BCL6 nuclear phosphoprotein is expressed in a variety of tissues and is up-regulated particularly in lymph node germinal centers [14].

Associations of BCL6 with chemical compounds

• Meta-analysis demonstrated that the preferentially altered sequence motifs of BCL6 in PMBL were TA (p=0.002) and AT (p=0.0008) dinucleotides and TAT trinucleotides (p=0.001) [15].
• Finally, ultrastructural analyses in UTA-L cells exposed to BrdU for various times reveal that replication progresses just around, but not within, BCL6 subdomains [16].
• The antiproliferative effects of vorinostat are believed to be due to drug-induced accumulation of acetylated proteins, including the core nucleosomal histones and other proteins (e.g., BCL6, p53 and Hsp90) [17].
• These results demonstrate for the first time that resveratrol inhibits a BCL6-linked pathway and suggest that loss of BCL6 expression may represent a key event underlying the anti-proliferative activities of resveratrol on LY8 cells [9].
• In addition, a general and specific inhibitor of HDACs, trichostatin A, did not alleviate the HIC-1- and gammaFBP-B-mediated transcriptional repression, as previously shown for BCL-6 [18].

Physical interactions of BCL6

• We have identified a 17 residue fragment from SMRT that binds to the BCL6 BTB domain, and determined the crystal structure of the complex to 2.2 A [13].
• These differences may also explain why LRF interacts with BCL6 but not with PLZF [19].
• The POZ domains of BCL-6 and several other POZ proteins interact with corepressors N-CoR and SMRT [20].
• Here we report an alternative mechanism by which BCL6 controls the transcription of genes lacking a BCL6 binding site and show that this mechanism was required for the prevention of tumor suppressor p53-independent cell cycle arrest in germinal center B cells [21].
• Strikingly, BCoR interacts selectively with the POZ domain of BCL-6 but not with eight other POZ proteins tested, including PLZF [20].

Enzymatic interactions of BCL6

• In this study, we show that BCL-6 is phosphorylated by mitogen-activated protein kinase (MAPK) in vitro at the sites phosphorylated in vivo [22].

Regulatory relationships of BCL6

• These results raise the possibility that BCL6 may regulate apoptosis by means of its repressive effects on PDCD2 [14].
• BCL6 is regulated by p53 through a response element frequently disrupted in B-cell non-Hodgkin lymphoma [23].
• The transactivating ability of IRF-4 is blocked by the repressor factor BCL-6 [24].
• The ARF tumor suppressor inhibits BCL6-mediated transcriptional repression [25].
• These expression patterns of BAZF mRNA suggest that BAZF may regulate differentiation in stages or lineages that are different from those regulated by BCL6 [26].

Other interactions of BCL6

• Immunohistochemistry reveals the anticipated inverse relationship between BCL6 and PDCD2 expression in human tonsil [14].
• Alterations in 2p, 3q, 13, and 18q were not associated with N-MYC, BCL6, RB, or BCL2 alterations, respectively, suggesting that other genes may be the targets of these genetic abnormalities in MCLs [27].
• Other amplifications also affected genes for which a pathogenetic role in pancreatic carcinoma has not been described, such as BCL10 and BCL6, two members of the BCL family [28].
• SIRT1 and other NAD-dependent deacetylases have been implicated in control of cellular responses to stress and in tumorigenesis through deacetylation of important regulatory proteins, including p53 and the BCL6 oncoprotein [29].
• Overexpression experiments showed that BCL6 and HDAC4, -5, or -7 are intermingled onto common nuclear substructures and form stable complexes [30].

Analytical, diagnostic and therapeutic context of BCL6

• We studied the genomic status of BCL6 in 23 cases of nodular lymphocyte predominance Hodgkin lymphoma (NLPHL) and 40 cases of classical Hodgkin lymphoma (cHL), using dual-color interphase fluorescence in situ hybridization (FISH) [31].
• We studied BCL6 gene rearrangement by the methodology of long-distance inverse polymerase chain reaction (LDI-PCR) [32].
• BCL6 mRNA and protein levels increased after chemotherapy/radiotherapy in human but not in murine tissues [23].
• Microarray analysis identified BCL6 as a primary target of p53 [23].
• Nevertheless, CD10 expression was a predictor of favorable outcome, whereas high bcl-2 expression and BCL6 rearrangement were adverse predictors of disease-free survival [33].

References