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FLASH GENE

Symbol

BCL6

contributors: mct/pgu - updated : 10-04-2016

HGNC name	B-cell CLL/lymphoma 6
HGNC id	1001

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001706 10 - 3575 NP_001697 78 706 - 2008 18675787 containing a different 5'UTR compared to variant 2 but encoding the same isoform isoform 1 NM_001130845 10 - 3662 NP_001124317 78 706 - 2008 18675787 isoform 1 NM_001134378 8 - 3086 NP_001128210 - 650 - 2008 18675787 lacks exon 7 that encodes the first two zinc fingers could form homodimers or heterodimers with BCL6 and could bind to classical BCL6-binding sites compact repressor that may have a functional role in normal and neoplastic germinal center B cells isoform 2

EXPRESSION

Type	restricted

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Lymphoid/Immune lymph node           tonsils

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular striatum skeletal

cells

System Cell Pubmed Species Stage Rna symbol Lymphoid/Immune B cell

cell lineage	B cells lineage
cell lines
fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a BTB/POZ (zinc finger N-terminal) domain, encoded by sequence starting at exon 3
	a PEST domain, the second repression domain (RDII) in the middle, interacts with the corepressor MTA3 (function of BCL6 may be modified by phosphorylation or acetylation of this domain)
	six Krueppel-type (C2H2 type) C-terminal zinc finger motifs,
	six C2H2-type ZFs encoded by exons 7 to 10, interacting with the corepressors NCOR1, NCOR2 and BCOR

HOMOLOGY

interspecies	homolog to murine Bcl6
	homolog to rattus LOC303836

Homologene

FAMILY

CATEGORY

regulatory , transcription factor , protooncogene

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,nucleus,nucleoplasm
text	BCL6 and FBXO11 co-localized in the nucleus where they showed overlapping, punctate staining throughout the nucleoplasm

basic FUNCTION	zinc finger transcriptional repressor or activator required for germinal center development and regulating B lymphocytes cell fate during the germinal center reaction by preventing terminal differentiation of B lymphocytes
	supresses the expression of TP53 by binding two specific DNA sites in the p53 promoter region and modulates DNA damaged-induced apoptotic responses in germinal-centre B
	recruiting a SMRT/SIN3A/histone deacetylase complex to mediate transcriptional repression
	regulating gene expression to control inflammation, lymphocyte differentiation, and lymphomagenesis through repression of AP-1
	transcriptional repressor, implicated in the pathogenesis of lymphomas, especially the diffuse large B-cell type
	nuclear phosphoprotein that is the master regulator in germinal center (GC) formation and GC B-cell differentiation and survival
	can also repress genes indirectly through binding to other transcription factors, such as peroxisome proliferator-activated receptor (PPARD and ZBTB17)
	BCL6 and BCL6B regulate hematopoietic progenitor cells (HPC) homeostasis by an indirect pathway involving CD8 T cell
	is required to prevent TP53-dependent apoptosis that results from hypermutation and chromosome rearrangement in germinal center B cells
	having an important function in facilitating apoptosis of germinal center B cells via suppression of BCL2, and blocking this pathway may be critical for lymphomagenesis)
	can suppress target gene expression by directly binding to specific DNA sequences or by interacting with PIAS2 or AP1 factors, which in turn bind DNA direct
	required for programming of T follicular helper cell generation
	transcriptional repressor that is essential for the germinal center (GC) reaction and important in lymphomagenesis
	controls the transcription of a variety of genes involved in B-cell development, differentiation and activation
	BCL6 and PIM1 are both protooncogenes that play roles in the pathogenesis of lymphoma
	BCL6 protects senescent cells from accumulation of adenosine-targeted DNA mutations induced by ADAR
	BCL6 and BACH2 cooperate to orchestrate gene expression patterning in germinal center (GC) B cells through both transcriptional and biochemical mechanisms, which collectively determine the proper initiation and timing of terminal differentiation
	in addition to its well-recognized roles in immune regulation, BCL6 plays likely a role in regulatory events of lipid metabolism, and in the absence of BCL6, lipid metabolism in liver and adipose tissue is dysregulated
	is a transcriptional repressor and critical mediator of the germinal center reaction during a T-cell-dependent antibody response

CELLULAR PROCESS	cell life, proliferation/growth
	nucleotide, transcription, regulation

PHYSIOLOGICAL PROCESS

inflammation

PATHWAY

metabolism

signaling

a component	PATZ1 and BCL6 form a complex in mammalian cells, and the POZ domain of PATZ1 is necessary for such interaction
	complex comprising BCOR-BCL6-IRF8 modulates BCL6-associated transcriptional regulation of germinal center B cell function
	BCL6-CUL3 complexes also provide essential negative feedback regulation during both thymocyte development and T cell activation to restrain excessive T follicular helper (Tfh) responses

INTERACTION

DNA	binding to the p53 promoter region

RNA

small molecule	metal binding,
	ion Zn2+ binding

protein	PDCD2
	LRF binding
	I3 SMRT/SIN3A/histone deacetylase complex binding
	BTB-POZ transcriptional repressor constituting a potential therapeutic target for B cell lymphomas
	interactions among BCL6, PDCD2, and other regulatory factors are likely to be very important in the development of B and T cell lymphomas
	binds to the BCL2 promoter region by interacting with the transcriptional activator PIAS2 and suppresses PIAS2-induced activation of BCL2 expression)
	transcriptional repressor of the POZ/BTB zinc-finger protein family, which binds to specific DNA sequences
	interacting with PRDM1 (BCL6 and PRDM1 are powerful antagonistic master regulators of germinal center B cell differentiation and plasma cell differentiation)
	interacting with BCOR through BTB domain despite the fact that BCOR has no detectable sequence similarity to the other two corepressors
	interaction with PRL (inhibits BCL6 expression in breast cancer through a STAT5A-dependent mechanism)
	targeted for ubiquitylation and proteasomal degradation by a SKP1–CUL1–F-box protein (SCF) ubiquitin ligase complex containing FBXO11
	FBXO11 mediates the ubiquitylation and degradation of BCL6
	PATZ1 interacts with BCL6 and negatively modulates its expression
	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
	HDAC4 may play an important role in suppressing cancers in conjunction with corepressors like BCL6 that recruit HDAC4 for repressing oncogenes
	PRKAA2 exerts its anti-inflammatory effects through PARP1 and BCL6
	likely HDAC1 functionally interacts with BCOR during eye development and, along with BCL6, act together to mediate normal optic cup formation by preventing colobomata
	STAT3 increases expression of BCL6 and enhances recruitment of RNA polymerase II phosphorylated at a site associated with transcriptional initiation, but STAT5, represses BCL6 expression below basal levels and decreases the association of RNA polymerase II at the gene
	BCL6-mediated transcriptional repression of LITAF may inhibit autophagy in B cells during the germinal centre reaction sorting
	ZXDC is a regulator in the process of myeloid function and is responsible for CCL2 gene de-repression by BCL6
	ZBTB33 is a key regulator of spleen germinal center formation by repressing BCL6 expression in splenocytes
	BCL6 does not bind directly or indirectly to SLC22A6 promoter but increases the protein expression of HNF1A and thereby indirectly enhances SLC22A6 gene transcription
	PELI1 directly interacted with the oncoprotein B cell chronic lymphocytic leukemia (BCL6) and induced lysine 63-mediated BCL6 polyubiquitination
	activities of PIAS2 are altered by its interaction with the POZ-domain transcriptional repressors BCL6 and NACC1, and these interactions have been implicated in tumourigenesis in B-cell lymphomas and in ovarian serous carcinomas
	BCL6 specifically binds to the interferon-regulatory factor IRF7 loci and restrains its transcription, thereby functioning as a negative regulator for interferon IFNB1 production and antiviral responses
	IL4 and IL21 cooperate to induce the high BCL6 protein level required for germinal center formation
	STAT3 and the Ikaros zinc finger transcription factors IKZF3, IKZF1 cooperate to regulate BCL66 expression

cell & other

REGULATION

repressed by

binding of a repressive complex formed of ZEB1 and CTBP, to an E-box in the promoter

Other

regulated by PDCD2

ASSOCIATED DISORDERS

corresponding disease(s)

FL3B

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral   translocation     in B cell lymphomas, translocations t(3;14), t(3;13),t(2;3),t(3;22),t(3;4),t(3;11)and others tumoral fusion       in primary diffuse large B-cell lymphomas of the central nervous system with poor prognosis tumoral fusion       fused with histone H4 in t(3;6)(q27;p21), in non-Hodgkin's lymphoma tumoral   translocation     with HSPCA and GAPD in primary diffuse large B-cell lymphomas of the central nervous system tumoral   translocation     alternative translocation breakpoint cluster region associated with follicular lymphoma grade 3B tumoral somatic mutation       somatic point mutations in non-Hodgkin lymphomas (NHL) tumoral     --other   expressed in systemic anaplastic large cell lymphomas

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer hemopathy   combination modalities targeting the multiple oncogenic activities of BCL6 and the anti-apoptotic function of BCL2 may represent a rational approach for the treatment of a subset of DLBCL cancer hemopathy   dual targeting of oncogenic tyrosine kinases and BCL6-dependent feedback represents a novel strategy to eradicate drug-resistant and leukaemia-initiating subclones in tyrosine-kinase-driven leukaemia

ANIMAL & CELL MODELS