Affinage

BCL6

B-cell lymphoma 6 protein · UniProt P41182

Length
706 aa
Mass
78.8 kDa
Annotated
2026-06-09
100 papers in source corpus 39 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BCL6 is a sequence-specific transcriptional repressor that orchestrates germinal center B-cell and follicular helper T-cell programs and is dysregulated in lymphoma through 3q27 chromosomal translocations that substitute heterologous promoters for its own, driving overexpression of a structurally normal protein (PMID:8220427, PMID:8557040). The N-terminal BTB/POZ domain acts as an autonomous repression module that mediates homomerization, targets the protein to punctate nuclear foci, and recruits corepressors—most directly SMRT—through a lateral groove whose structural basis was defined by a peptide/BTB co-crystal mimicking the BcoR WVVP motif (PMID:9019154, PMID:8545127, PMID:9380707, PMID:27856253). Through its zinc-finger DNA-binding domain BCL6 binds consensus elements and silences a broad target set spanning immune effectors and cell-cycle/DNA-damage genes, including IL-18, granzyme B, CHEK1, NLRP3, and antiviral ISGs, and it can also be recruited to AP1- and STAT-motif loci via physical interaction with AP1 complexes, subverting TCR-driven gene activation (PMID:9380707, PMID:12817026, PMID:17125145, PMID:18346918, PMID:25824819, PMID:28550121). In lymphocyte differentiation BCL6 enforces the GC/Tfh fate—cooperating with BACH2 to repress PRDM1 and antagonizing BLIMP1—while controlling Tfh–B cell contact and CD40L-mediated help, and balancing CD8+ T-cell stemness against terminal differentiation (PMID:24277074, PMID:34464595, PMID:37862431). BCL6 abundance and activity are tightly tuned by post-translational control: p300-mediated acetylation inactivates corepressor recruitment, FBXO11-SCF directs ubiquitin-proteasomal degradation, PELI1 confers stabilizing K63-ubiquitination, and PRKD2 phosphorylation enforces cytoplasmic retention (PMID:12402037, PMID:22113614, PMID:25295537, PMID:31980486). These properties make BCL6 a pharmacological target: BTB-groove inhibitors derepress its targets, and BI-3802 induces BCL6 polymerization coupled to SIAH1-dependent degradation (PMID:27856253, PMID:33208943).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1994 High

    Establishing what BCL6 is at the molecular level: cloning revealed a Krüppel-like zinc-finger protein with an N-terminal BTB/POZ domain whose gene is recurrently disrupted by 3q27 translocations in lymphoma, framing it as a candidate transcription factor oncogene.

    Evidence cDNA/genomic cloning, sequencing, in vitro transcription/translation, Southern/Northern blot in lymphoma samples

    PMID:8057668 PMID:8220427 PMID:8274740

    Open questions at the time
    • DNA-binding specificity and target genes not yet defined
    • Mechanism of repression not established
  2. 1995 High

    Defining the translocation mechanism: breakpoints juxtapose IgH germline promoters upstream of intact BCL6 coding exons, showing that lymphoma deregulation is by promoter substitution rather than protein alteration.

    Evidence Breakpoint mapping and chimeric transcript analysis in DLCL biopsies and cell lines

    PMID:8557040

    Open questions at the time
    • Downstream oncogenic targets of overexpressed BCL6 not identified
  3. 1996 High

    Establishing BCL6 as a transcriptional repressor and localizing the activity: the BTB/POZ domain is an autonomous, distance- and promoter-independent repression domain that also mediates homomerization and targeting to nuclear foci.

    Evidence GAL4-fusion reporter assays with deletion mutagenesis, yeast two-hybrid, immunofluorescence in transfected cells

    PMID:8545127 PMID:8607866 PMID:9019154

    Open questions at the time
    • Corepressor partners not yet identified
    • DNA target sites in the genome not mapped
  4. 1997 High

    Identifying the repression machinery: the BTB/POZ domain directly recruits the corepressor SMRT, linking BCL6 silencing to histone deacetylation and a mechanism shared with nuclear hormone receptors.

    Evidence Yeast two-hybrid screen, in vitro binding, co-IP/co-localization, reporter assays

    PMID:9380707

    Open questions at the time
    • Full corepressor complex composition not enumerated
    • Endogenous target genes not defined
  5. 2002 High

    Discovering a switch that inactivates BCL6: p300 acetylates BCL6 and disrupts HDAC recruitment, defining acetylation as a reversible inhibitory modification with therapeutic implications in lymphoma.

    Evidence Co-IP, in vivo acetylation and HDAC-recruitment assays, deacetylase-inhibitor treatment, transformation assays

    PMID:12402037

    Open questions at the time
    • Acetylated residues and deacetylase identity not fully resolved
  6. 2006 High

    Extending BCL6 function beyond B cells: direct binding and repression of IL-18 and granzyme B promoters showed BCL6 controls innate and cytotoxic immune effector genes.

    Evidence ChIP, gel shift, promoter reporters with binding-site mutation, KO macrophages, overexpression in CD8+ T cells with cytotoxicity assays

    PMID:12817026 PMID:17125145

    Open questions at the time
    • Signal-dependent modification altering DNA occupancy not molecularly defined
  7. 2013 Medium

    Linking BCL6 to DNA-damage checkpoint suppression: direct repression of CHEK1 (and inferred control of ATR/TP53/CDKN1A) explained how BCL6 permits tolerance of genotoxic stress in GC and lymphoma B cells.

    Evidence ChIP, promoter binding, BCL6 peptide inhibitor rescue in DLBCL cells

    PMID:18346918

    Open questions at the time
    • Direct binding to all checkpoint targets (ATR, TP53) inferred rather than each ChIP-validated
  8. 2012 High

    Establishing how BCL6 levels are terminated: FBXO11-SCF directly ubiquitylates BCL6 for proteasomal degradation, and its loss in DLBCL stabilizes BCL6, defining a tumor-suppressor brake.

    Evidence SCF reconstitution, ubiquitylation/degradation assays, disease-mutant analysis, xenograft models

    PMID:22113614

    Open questions at the time
    • Degron and signals triggering FBXO11 engagement not mapped
  9. 2013 High

    Defining the GC fate-determining network: BCL6 co-occupies targets with BACH2, represses PRDM1, and modulates BACH2 stability, with genetic epistasis showing the pair governs GC formation versus plasma-cell differentiation.

    Evidence ChIP-seq, double-heterozygous mice, gene expression profiling

    PMID:24277074

    Open questions at the time
    • Mechanism of BCL6 control over BACH2 protein stability unresolved
  10. 2012 High

    Defining BCL6 as the master Tfh program inducer: ectopic BCL6 in primary human CD4+ T cells drives a coherent migration/effector gene module and cooperates with c-Maf.

    Evidence Gain-of-function in primary human CD4+ T cells, flow cytometry, expression analysis

    PMID:22427637

    Open questions at the time
    • Direct versus indirect target assignment within the module not resolved at this stage
  11. 2015 High

    Revealing non-canonical genomic recruitment: BCL6 binds AP1- and STAT-motif loci by physically interacting with AP1, allowing it to subvert TCR-driven activation rather than acting only at BCL6 consensus sites.

    Evidence Cistrome ChIP-seq in primary human Tfh cells, motif analysis, BCL6-AP1 co-IP

    PMID:25824819

    Open questions at the time
    • Generality of AP1-dependent recruitment across cell types not established
  12. 2020 High

    Adding spatial post-translational control: PRKD2 directly binds and phosphorylates BCL6 to retain it in the cytoplasm, and BCL6 represses Prkd2, forming a feedback loop that locks in Tfh commitment.

    Evidence Forward genetic screen, Prkd2-null mice, binding/phosphorylation assays, localization analysis, ChIP-seq

    PMID:31980486

    Open questions at the time
    • Phosphosites mediating cytoplasmic retention not mapped
  13. 2014 Medium

    Demonstrating stabilizing ubiquitination: PELI1 confers K63-linked polyubiquitination that stabilizes rather than degrades BCL6, providing an oncogenic counterweight to FBXO11.

    Evidence Co-IP, K63-linkage ubiquitination assays, transgenic mice, DLBCL sample correlation

    PMID:25295537

    Open questions at the time
    • Single-lab finding; ubiquitinated lysines and structural basis of stabilization undefined
  14. 2016 High

    Providing the structural basis for inhibitor design: a sub-nanomolar peptide bound at the BTB corepressor groove mimicking the BcoR WVVP motif confirmed the lateral groove as the druggable corepressor-interaction surface.

    Evidence X-ray crystallography of F1324/BCL6(5-129), SPR, ELISA, mammalian two-hybrid

    PMID:27856253

    Open questions at the time
    • Cellular efficacy of groove-blocking peptides across tumor contexts not addressed here
  15. 2020 High

    Establishing a degradation-based therapeutic mechanism: BI-3802 induces specific reversible BCL6 polymerization into filaments that recruits SIAH1 for proteasomal degradation, surpassing inhibition alone.

    Evidence Cryo-EM of drug-induced polymer, ubiquitination assays, SIAH1 interaction studies, cell assays

    PMID:33208943

    Open questions at the time
    • Endogenous physiological role of SIAH1-mediated BCL6 turnover unclear
  16. 2022 High

    Placing BCL6 within oncogenic signaling and replication control: MAPK/ERK/ELK1 downstream of mutant KRAS drives BCL6 transcription, and BCL6 sustains pre-RC components, making KRAS-mutant tumors dependent on BCL6 for replication fork stability.

    Evidence KRAS activation in mouse lung, ELK1 ChIP-seq at BCL6 promoter, conditional BCL6 KO, inhibitor treatment, replication fork assays

    PMID:36377663

    Open questions at the time
    • Direct BCL6 occupancy at each pre-RC target gene not fully mapped
  17. 2023 High

    Positioning BCL6 at a signaling nexus for T-cell stemness: TGF-β-SMAD2 induces and IL-2-STAT5 represses BCL6, which antagonizes BLIMP1 to favor progenitor over terminal CD8+ T-cell fate.

    Evidence Bcl6 conditional KO in CD8+ T cells, tumor models, ChIP-seq/transcriptome, signaling perturbation, Prdm1 KO comparison

    PMID:37862431

    Open questions at the time
    • Direct integration of SMAD2/STAT5 inputs at the BCL6 locus not structurally resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse post-translational inputs (acetylation, FBXO11 vs PELI1 ubiquitination, PRKD2 phosphorylation) are coordinately integrated to set BCL6 dosage and subcellular distribution in a given cell state remains unresolved.
  • No unified quantitative model of competing modifications
  • Cell-state-specific modification crosstalk undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0003677 DNA binding 5 GO:0060089 molecular transducer activity 3
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 7 R-HSA-1643685 Disease 5 R-HSA-392499 Metabolism of proteins 5 R-HSA-74160 Gene expression (Transcription) 5
Partners
BACH2FBXO11NCOR1P300PELI1PRKD2SIAH1SMRT
Complex memberships
BCL6-SMRT/NCoR corepressor complexSCF(FBXO11) ubiquitin ligase complex (substrate)

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 BCL6 (LAZ3) encodes a 79 kDa protein containing six zinc-finger motifs and an N-terminal BTB/POZ domain, structurally homologous to Drosophila transcription regulators tramtrack and Broad-complex; the gene is disrupted by recurring chromosomal translocations at 3q27 in non-Hodgkin's lymphoma. cDNA cloning, nucleotide sequencing, Southern blot Nature genetics High 8220427
1994 BCL6 (BCL5/ZNF51) encodes a Krüppel-like Cys2-His2 zinc-finger protein of ~78.8 kDa confirmed by in vitro transcription and translation; the gene is activated by translocation at 3q27, with breakpoints in the 5' region leaving the protein-coding exons intact. cDNA cloning, in vitro transcription/translation, nucleotide sequencing Blood High 8274740
1994 The BCL6 gene spans ~26 kb with nine exons; the translation start site is in exon 3, the zinc-finger motif is encoded by exons 6–9, and the large intron 1 (9 kb) is not efficiently spliced, generating minor 10–12 kb transcripts in addition to the major 3.8 kb transcript. Translocation breakpoints cluster around exon 1, removing putative regulatory regions and causing BCL6 overexpression. Genomic cloning, Southern blot, Northern blot analysis Leukemia High 8057668
1995 BCL6 (LAZ3) is a sequence-specific transcriptional repressor; the BTB/POZ domain functions as an autonomous transcriptional repression domain, and deletion of the BTB/POZ domain reduces but does not abolish repression. Repression is distance-independent and largely promoter-independent. Transient transfection with GAL4-fusion constructs, luciferase reporter assays, deletion mutagenesis Cell growth & differentiation High 9019154
1995 The BCL6 BTB/POZ domain mediates homomerization in vivo, as shown by yeast two-hybrid, and targets the protein to punctate nuclear dots (nuclear substructures); deletion of the BTB/POZ domain abolishes nuclear dot localization while the protein remains nuclear. Yeast two-hybrid, immunofluorescence in transfected COS-1/NIH3T3 cells, fusion with oestrogen receptor ligand-binding domain Oncogene High 8545127
1995 Chromosomal translocations t(3;14) juxtapose IgH germline transcript promoters (Iμ or Iγ3) upstream of BCL6 coding exons, generating chimeric IgH-BCL6 transcripts that produce a structurally normal BCL6 protein; deregulated expression results from promoter substitution, not protein alteration. Breakpoint mapping, cDNA analysis, RNA expression analysis in DLCL biopsies and tumor cell lines The EMBO journal High 8557040
1996 Multiple domains of BCL6 participate in transcriptional repression; the BTB/POZ domain plays an important but non-exclusive role, and repression occurs at long distances (1.6 kb) in a largely promoter-independent manner, ruling out steric hindrance. GAL4-BCL6 chimera transient transfection, luciferase reporter assays with domain deletions Biochemical and biophysical research communications Medium 8607866
1997 The BCL6 BTB/POZ domain directly interacts with the corepressor SMRT in vitro and in vivo; DNA-bound BCL6 recruits SMRT, and both proteins co-localize in nuclear dots. Overexpression of SMRT enhances BCL6-mediated transcriptional repression, indicating that BCL6 represses transcription via SMRT recruitment and histone deacetylation (shared mechanism with nuclear hormone receptors). Yeast two-hybrid screen, in vitro protein binding assays, co-immunoprecipitation/co-localization in transfected cells, transcription reporter assays Proceedings of the National Academy of Sciences of the United States of America High 9380707
1999 Overexpressed BCL6 triggers apoptosis, delays S phase progression, and co-localizes with sites of ongoing DNA synthesis (replication foci) in human U2OS cells; these effects depend on the ability of BCL6 to engage protein-protein interactions (BTB/POZ domain-dependent), not solely on its DNA-binding activity. Tetracycline-regulated BCL6 expression in U2OS cells, BrdU incorporation assays, immunofluorescence co-localization, growth/apoptosis assays with domain-deletion mutants Oncogene Medium 10490843
2000 BCL6 (LAZ3) and PLZF directly interact through both POZ/POZ contacts and zinc-finger/zinc-finger and cross-domain contacts; they co-localize on nuclear dots, and full-length protein of one can recruit truncated (diffusely nuclear) forms of the other onto nuclear dots, indicating formation of multiprotein nuclear complexes. Yeast two-hybrid, in vitro immunoprecipitation, GST pull-down, immunofluorescence co-localization in transfected CHO cells Oncogene High 11175338
2002 The coactivator p300 binds and acetylates BCL6 in vivo, disrupting BCL6's ability to recruit HDACs and thereby inhibiting its transcriptional repression activity and cell-transforming capacity. BCL6 acetylation is controlled by both HDAC-dependent and SIR2-dependent deacetylase pathways; pharmacological inhibition of these pathways accumulates inactive acetylated BCL6, inducing cell-cycle arrest and apoptosis in B-cell lymphoma cells. Co-immunoprecipitation, in vivo acetylation assays, HDAC recruitment assays, pharmacological inhibitor treatments, transformation assays Nature genetics High 12402037
2003 BCL6 directly binds to a consensus element in the IL-18 promoter and represses IL-18 transcription in macrophages; Bcl6 binding to the IL-18 promoter is lost upon LPS stimulation without change in total BCL6 protein levels, indicating functional modification of BCL6 post-stimulation. BCL6-deficient macrophages show strikingly elevated IL-18 expression. Gel retardation assay, chromatin immunoprecipitation (ChIP), luciferase reporter assay, BCL6-deficient mouse macrophages, dominant-negative BCL6 transfection Journal of immunology High 12817026
2006 BCL6 directly represses the granzyme B gene in CD8+ T cells by binding to a BCL6 consensus sequence in the granzyme B promoter; overexpression of BCL6 in CD8+ T cells reduces granzyme B expression and cytotoxic killing activity. ChIP, luciferase reporter assay with BCL6-binding sequence requirement, overexpression in CD8+ T cells, cytotoxicity assays European journal of immunology High 17125145
2008 BCL6 directly binds to a consensus element in the CHEK1 promoter and represses CHEK1 expression in normal and malignant B cells; a BCL6 peptide inhibitor (BPI) that disrupts corepressor binding to the BCL6 BTB domain reactivates CHEK1 in DLBCL cells, suggesting BCL6 suppresses multiple nodes of the DNA damage sensing/transduction pathway (ATR, TP53, CDKN1A, CHEK1). ChIP, promoter binding assays, BCL6 peptide inhibitor (BPI) treatment, gene expression analysis in DLBCL cells Blood cells, molecules & diseases Medium 18346918
2012 FBXO11, an F-box protein, directly targets BCL6 for ubiquitylation and proteasomal degradation as part of an SCF ubiquitin ligase complex; FBXO11 is deleted or mutated in DLBCL, leading to BCL6 stabilization. Tumor-derived FBXO11 mutants are impaired in inducing BCL6 degradation, and reconstitution of FBXO11 in deleted cells promotes BCL6 ubiquitylation, inhibits proliferation, and induces apoptosis. SCF complex reconstitution, ubiquitylation assays, degradation assays, FBXO11 mutant functional analysis, tumor xenograft models Nature High 22113614
2012 BCL6 introduced into primary human CD4+ T cells induces a core set of migration and effector genes defining follicular helper T cell identity (CXCR4, CXCR5, CCR7, EBI2, SAP, CD40L, PD-1, ICOS, CXCL13), while not altering IL-21 or IL-4 expression. Maf (c-Maf) separately induces IL-21 and CXCR5, and cooperates with BCL6 to induce CXCR4, PD-1, and ICOS. Ectopic expression of BCL6 and Maf in primary human CD4+ T cells, flow cytometry, gene expression analysis Journal of immunology High 22427637
2013 BCL6 and BACH2 cooperate to repress germinal center B cell terminal differentiation: they co-occupy ~30% of shared genomic targets including the PRDM1 locus. BCL6 also modulates BACH2 protein stability, with their protein levels positively correlated in GC B cells. Double-heterozygous Bcl6+/−Bach2+/− mice show profound reduction in GC formation and accelerated plasmacytic differentiation, revealing genetic epistasis. ChIP-seq, genetic epistasis in double-heterozygous mice, gene expression profiling, ChIP Blood High 24277074
2013 BCL6 directly represses LITAF transcription by binding to the LITAF promoter in B cells; BCL6 silencing increases LITAF expression. LITAF promotes autophagy, and its BCL6-mediated repression inhibits autophagy responses in B-cell lymphoma cells. ChIP, luciferase reporter assay, BCL6 knockdown gene expression analysis, autophagy assays, immunofluorescence British journal of haematology Medium 23795761
2014 BCL6 directly represses IL-9 transcription in Th9 cells by binding to the Il9 promoter; BCL6 and STAT5 bind to adjacent motifs in the Il9 promoter and compete functionally (BCL6 binding correlates with repressive histone marks; STAT5 binding with permissive marks). BCL6 represses STAT5-mediated Il9 transactivation in a luciferase reporter assay. ChIP, luciferase reporter assay, BCL6 overexpression/knockdown in Th9 cells, flow cytometry, EAE in vivo model Journal of immunology High 24879792
2014 PELI1 (pellino 1) E3 ubiquitin ligase directly interacts with BCL6 and induces K63-linked polyubiquitination of BCL6, stabilizing rather than degrading BCL6; PELI1 overexpression positively correlates with BCL6 expression in DLBCL. Co-immunoprecipitation, ubiquitination assays (K63-linkage specificity), transgenic mouse model, DLBCL patient sample analysis The Journal of clinical investigation Medium 25295537
2015 BCL6 primarily acts as a transcriptional repressor in Tfh cells, controlling migration and repressing alternative T cell fates. BCL6 binds genomic loci bearing AP1 or STAT motifs (not just BCL6 consensus sequences) by physically interacting with AP1 complexes, and depends on AP1 for recruitment to AP1-motif loci, thereby subverting TCR-driven AP1 activity. BCL6 cistrome mapping (ChIP-seq) in primary human GC Tfh cells, motif analysis, direct BCL6-AP1 co-immunoprecipitation The Journal of experimental medicine High 25824819
2015 BCL6 promotes osteoblastogenesis by directly repressing Stat1 transcription; ChIP demonstrates BCL6 binding to the Stat1 promoter in osteoblasts. Mice lacking both Bcl6 and Stat1 (DKO) exhibit significant rescue of bone mass and osteoblastic parameters compared with Bcl6-deficient mice, establishing genetic epistasis. ChIP, genetic double-KO mouse model, in vitro osteoblastogenesis assays, bone phenotype analysis Biochemical and biophysical research communications High 25597995
2016 BCL6 inhibitory peptide F1324 binds the BCL6 BTB domain at sub-nanomolar affinity (KD = 0.57 nM) at the corepressor (BcoR/SMRT) binding groove; crystal structure of the F1324/BCL6(5-129) complex shows the WRVP C-terminal motif of F1324 mimics the WVVP motif of BcoR, structurally confirming the corepressor-binding lateral groove as the key interaction surface. X-ray crystallography, surface plasmon resonance (SPR), cell-free ELISA, mammalian two-hybrid (M2H) assay Biochemical and biophysical research communications High 27856253
2016 TCF1 induces Bcl6 expression in CD8+ T cells, and the TCF1-Bcl6 axis counteracts type I interferon signaling to maintain progenitor-like (TCF1high) CD8+ T cells during chronic infection; cell-intrinsic TCF1 deficiency abolishes this progenitor subset and leads to viremia. Conditional TCF1-KO mice, chronic LCMV infection model, retroviral overexpression, adoptive transfer, flow cytometry, gene expression analysis Science immunology High 28018990
2017 BCL6 represses wild-type p53 expression and its target genes in glioblastoma cells; BCL6 transcriptionally activates AXL (a receptor tyrosine kinase), which mediates BCL6 effects on MEK-ERK and S6K-RPS6 signaling axes. Targeted inhibition of the BCL6/NCoR1 corepressor complex by a peptidomimetic inhibitor decreases AXL expression and these downstream signals. BCL6 knockdown/overexpression in GBM cells, transcriptome analysis, peptidomimetic inhibitor, KrasG12V transgenic glioma mouse model, ChIP inference Proceedings of the National Academy of Sciences of the United States of America Medium 28356518
2017 BCL6 represses NLRP3 transcription by binding to the NLRP3 promoter in renal tubular epithelial cells; BCL6 overexpression attenuates Ang II- or LPS-induced NLRP3 inflammasome activation and reduces mature IL-1β levels. ChIP (BCL6 binding to NLRP3 promoter), BCL6 overexpression/shRNA knockdown in HK-2 cells, lentiviral delivery in SHR rats Cell death & disease Medium 29072703
2019 Thpok (a CD4+-lineage transcription factor) directly binds a Thpok-responsive element in the first intron of Bcl6 and promotes Bcl6 expression during Tfh differentiation; Thpok also promotes Maf expression independently of Bcl6, and Maf cooperates with Bcl6 to mediate Tfh differentiation. ChIP (Thpok binding to Bcl6 intron 1), conditional Thpok-KO mice, reporter assays, gene expression profiling Immunity High 31422869
2019 MLL-AF4 and MLL-ENL fusion oncoproteins directly bind the BCL6 promoter (by ChIP-seq) and upregulate BCL6 expression in B-ALL; BCL6 in turn maintains elevated MLL mRNA (positive feedback). BCL6 represses BIM (PMAIP1) to curb MLL-induced proapoptotic signaling, and BCL6 inhibition restores BIM expression and sensitizes MLL-rearranged ALL cells to chemotherapy. ChIP-seq, inducible BCL6 expression, conditional BCL6 deletion, pharmacological BCL6 inhibition (RI-BPI, FX1), gene expression analysis, transplant leukemia models Genes & development High 31395741
2020 The small molecule BI-3802 binds the BCL6 BTB domain and induces highly specific, reversible polymerization of BCL6 into supramolecular filaments; this drug-induced polymerization sequesters BCL6 into cellular foci and triggers SIAH1 E3 ubiquitin ligase-dependent ubiquitination and proteasomal degradation of BCL6, achieving greater pharmacological activity than other BCL6 inhibitors. Cryo-electron microscopy (structural determination of BI-3802/BCL6 polymer), ubiquitination assays, SIAH1 interaction studies, cell biological assays Nature High 33208943
2020 PRKD2 (protein kinase D2) directly binds BCL6 and phosphorylates BCL6, constraining BCL6 to the cytoplasm and thereby limiting Tfh cell development. Conversely, BCL6 transcriptionally represses Prkd2 expression in activated CD4+ T cells, forming a mutually inhibitory positive feedback loop that controls stable transition to Tfh fate. Forward genetic screen, targeted Prkd2 null mutation in mice, direct Prkd2-Bcl6 protein binding assay, phosphorylation assays, subcellular localization analysis, Bcl6 reporter, ChIP-seq Science immunology High 31980486
2020 Bcl6 in thymocytes is required for efficient DN-to-DP differentiation during pre-TCR signaling, and attenuates Notch1 activation; conditional Bcl6 deletion increases Notch1 activation and Notch-mediated transcription in DP thymocytes. Conditional Bcl6 deletion in thymocytes, flow cytometry, gene expression analysis for Notch target genes Development Medium 32907850
2021 BCL6 in Tfh cells controls calcium signaling and physically mediates Tfh cell entanglement with B cells and CD40L delivery to B cells; BCL6 haploinsufficiency inhibits GC formation and Tfh cell maintenance, and this can be rescued by CD40L overexpression, placing BCL6 upstream of CD40L-mediated contact help. BCL6 haploinsufficient mice, intravital imaging (Tfh-B cell interactions), calcium signaling assays, CD40L overexpression rescue experiments Immunity High 34464595
2021 BCL6 binds IFN-stimulated gene (ISG) loci (MX2, IFITM3) in Tfh cells and inhibits their expression, accounting for diminished antiviral resistance of Tfh cells; inhibition of the BCL6 BTB domain increases ISG expression and suppresses HIV infection/replication in Tfh cells. ChIP (BCL6 binding to ISG loci), BCL6 BTB-domain inhibitor treatment, HIV infection assays, flow cytometry Journal of leukocyte biology Medium 28550121
2022 The MAPK/ERK/ELK1 signaling axis downstream of mutant KRAS directly regulates BCL6 transcription; BCL6 in turn maintains expression of prereplication complex (pre-RC) components, and BCL6 inhibition stalls replication forks causing DNA damage and growth arrest in KRAS-mutant lung cancer cells. KRAS activation in mouse lung tissue, ChIP-seq (ELK1 binding to BCL6 promoter), BCL6 conditional KO in LSL-KrasG12D mice, pharmacological BCL6 inhibition, DNA damage markers, replication fork assays The Journal of clinical investigation High 36377663
2023 BCL6 transcriptionally represses Tterm cell-associated genes and induces Tprog cell-related genes in CD8+ T cells in a manner antagonistic to BLIMP1; BCL6 expression is upregulated by TGF-β-SMAD2 signaling and downregulated by IL-2-STAT5 signaling, placing BCL6 at the nexus of two opposing pathways controlling CD8+ T cell stemness vs. terminal differentiation. Bcl6 conditional KO in CD8+ T cells, tumor models, ChIP-seq/transcriptome analysis, TGF-β and IL-2 signaling pathway perturbation, BLIMP1 (Prdm1) KO comparison Science immunology High 37862431
2024 IL-4 cytokine signaling in GC B cells directly downregulates BCL6 via negative autoregulation (BCL6 locus contains IL-4-responsive elements), promoting GC B cell exit and memory B cell formation; both increasing and limiting IL-4 signaling disrupts memory B cell selection stringency. IL-4 cytokine perturbation in GC B cells, BCL6 reporter, genetic and pharmacological IL-4 signaling manipulation, memory B cell quantification Immunity Medium 38513666
2013 In zebrafish, Bcl6a acts downstream of Vax1/Vax2 transcription factors during optic cup development; bcl6a is a direct transcriptional target of Vax2 (by ChIP), and Bcl6a functions cooperatively with Bcor, Rnf2, and Hdac1 to repress p53 expression and prevent p53-dependent apoptosis during optic cup formation, thereby preventing colobomata. Zebrafish bcl6a morpholino knockdown, ChIP (Vax2 binding to bcl6a), genetic epistasis with vax1/vax2 mutants and p53 mutants, Bcor/Rnf2/Hdac1 co-knockdown Human molecular genetics High 23669349
2017 SIRT1 (a histone deacetylase) co-localizes with BCL6 in nuclei and both proteins bind to and suppress the GLI1 promoter (a progesterone action mediator) by ChIP analysis in endometrial cells; KRAS activation increases SIRT1 expression, which cooperates with BCL6 to repress progesterone target genes. ChIP (BCL6 and SIRT1 binding to GLI1 promoter), conditional KRAS activation mouse model, immunolocalization, gene expression analysis Scientific reports Medium 28754906
2011 BCL6 directly promotes Bach2 expression and suppresses Blimp-1 through direct binding to the IRF4 gene, as well as by promoting MITF expression (a suppressor of IRF4); BCL6 also appears to directly activate AID and UNG expression required for somatic hypermutation and class-switch recombination. ChIP (BCL6 binding to IRF4 and other loci), gain/loss-of-function in DT40 B cells, gene expression analysis European journal of immunology Medium 21674482

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 The TCF1-Bcl6 axis counteracts type I interferon to repress exhaustion and maintain T cell stemness. Science immunology 524 28018990
2010 Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation. Nature immunology 428 20084069
1993 LAZ3, a novel zinc-finger encoding gene, is disrupted by recurring chromosome 3q27 translocations in human lymphomas. Nature genetics 402 8220427
2012 Roles of BCL6 in normal and transformed germinal center B cells. Immunological reviews 351 22500840
2002 Acetylation inactivates the transcriptional repressor BCL6. Nature genetics 342 12402037
2012 Bcl6 and Maf cooperate to instruct human follicular helper CD4 T cell differentiation. Journal of immunology (Baltimore, Md. : 1950) 300 22427637
1997 Corepressor SMRT binds the BTB/POZ repressing domain of the LAZ3/BCL6 oncoprotein. Proceedings of the National Academy of Sciences of the United States of America 291 9380707
1994 LAZ3 rearrangements in non-Hodgkin's lymphoma: correlation with histology, immunophenotype, karyotype, and clinical outcome in 217 patients. Blood 286 8167331
2010 BCL6: master regulator of the germinal center reaction and key oncogene in B cell lymphomagenesis. Advances in immunology 254 20510734
2012 FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas. Nature 242 22113614
1995 Chromosomal translocations cause deregulated BCL6 expression by promoter substitution in B cell lymphoma. The EMBO journal 240 8557040
2010 In vivo regulation of Bcl6 and T follicular helper cell development. Journal of immunology (Baltimore, Md. : 1950) 233 20519643
1996 BCL-6 expression during B-cell activation. Blood 231 8652841
2012 Bcl6 expression specifies the T follicular helper cell program in vivo. The Journal of experimental medicine 223 22987803
2015 BCL6 orchestrates Tfh cell differentiation via multiple distinct mechanisms. The Journal of experimental medicine 220 25824819
2020 Small-molecule-induced polymerization triggers degradation of BCL6. Nature 214 33208943
1994 Gene involved in the 3q27 translocation associated with B-cell lymphoma, BCL5, encodes a Krüppel-like zinc-finger protein. Blood 158 8274740
2014 Breaking bad in the germinal center: how deregulation of BCL6 contributes to lymphomagenesis. Trends in molecular medicine 156 24698494
2021 Bcl6-Mediated Transcriptional Regulation of Follicular Helper T cells (TFH). Trends in immunology 151 33663954
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2012 miR-155 targets histone deacetylase 4 (HDAC4) and impairs transcriptional activity of B-cell lymphoma 6 (BCL6) in the Eμ-miR-155 transgenic mouse model. Proceedings of the National Academy of Sciences of the United States of America 112 23169640
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2014 BCL6 controls Th9 cell development by repressing Il9 transcription. Journal of immunology (Baltimore, Md. : 1950) 49 24879792
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2011 Alternate pathways for Bcl6-mediated regulation of B cell to plasma cell differentiation. European journal of immunology 48 21674482
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2013 LITAF, a BCL6 target gene, regulates autophagy in mature B-cell lymphomas. British journal of haematology 38 23795761
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