Download Gene Section BCL6 (B-Cell Lymphoma 6) Atlas of Genetics and Cytogenetics

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
INIST-CNRS
OPEN ACCESS JOURNAL
Gene Section
Review
BCL6 (B-Cell Lymphoma 6)
Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
(JLH)
Published in Atlas Database: December 2012
Online updated version : http://AtlasGeneticsOncology.org/Genes/BCL6ID20.html
DOI: 10.4267/2042/50185
This article is an update of :
Knezevich S. BCL6 (B-Cell Lymphoma 6). Atlas Genet Cytogenet Oncol Haematol 2007;11(3):177-179.
Kerckaert JP. LAZ3 (Lymphoma Associated Zinc finger on chromosome 3). Atlas Genet Cytogenet Oncol Haematol 1999;3(1):1-2.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Transcription
Other names: BCL5, LAZ3, ZBTB27, ZNF51,
BCL6A
HGNC (Hugo): BCL6
Location: 3q27.3
Local order: Gene orientation: telomere - 5' BCL6 3' centromere.
3,8 kb mRNA.
Protein
Description
The protein product is 706 amino acids with an
estimated molecular weight of 78,8 kDa.
Expression
Normally expressed in germinal center B and T cells,
other lymphoid tissues, in skeletal muscle cells and in
keratinocytes.
Localisation
Nuclear paraspeckles/dots.
Function
Protein domains and functions
The protein can bind to sequence specific DNA and
repress its transcription in addition to recruiting other
protein repressors. The DNA binding is mediated
through the consensus sequence TTCCT(A/C)GAA
(see below), while the protein-protein interactions are
mediated through the BTB/POZ domain and it has been
shown to interact with other zinc finger proteins and
corepressors (including Histone Deacetylase 1
(HDAC1) and NCOR2 (Silencing Mediator of Retinoid
and Thryoid Receptor 1 (SMRT1))). The carboxy
terminus, on the other hand, is responsible for sequence
specific DNA binding through its 6 zinc fingers.
BCL6 (3q27) - Courtesy Mariano Rocchi, Resources for
Molecular Cytogenetics.
DNA/RNA
Description
The gene is encoded by 11 exons that are located on
chromosome 3q27 and is 24,3 kb. The 5' portion
encodes for the BTB/POZ domain (broadcomplex/tramtrack/bric-a-brac/pox virus/zinc finger),
while the 3' end encodes for 6 DNA binding zinc
fingers. The first ATG occurs in exon 3.
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(6)
371
BCL6 (B-Cell Lymphoma 6)
Huret JL
BCL6 is therefore essential for normal B cell
development (reviews in Albagli-Curiel, 2003; Jardin
et al., 2007; Parekh et al., 2008; Basso and DallaFavera, 2010; Pellicano and Holyoake, 2011; Wagner
et al., 2011; Basso and Dalla-Favera, 2012; Okada et
al., 2012).
- T follicular helper cells
BCL6 is essential for the development of follicular
helper T (Tfh) cells. Tfh cells are defined by the
expression of the surface markers CXCR5 and PD-1
and synthesis of IL4 and IL21. BCL6 upregulation of B
cells in the outer follicle sustains their interactions with
helper T cells and allows them to enter the germinal
centers (GC) region (Poholek et al., 2010; Kitano et al.,
2011; Baumjohann et al., 2011). ICOS induces BCL6,
and BCL6 then induces CXCR5.
Tfh cells were lost in the absence of B cells,
demonstrating a B cell requirement for maintenance of
BCL6 and Tfh cell commitment (Choi et al., 2011).
BCL6 and MAF cooperate to induce Tfh cell
differentiation (Kroenke et al., 2012).
Consensus DNA motifs recognized by BCL6
The Zn fingers of BCL6 binds to DNA and recognizes
specific DNA motifs: the M00424 motif, a consensus
sequence for the NKX-homeobox family of
transcription factors, the M2 motif, which mimics an
M00424 half site; and the M0 motif (see details in
Basso et al., 2010).
BCL6 cellular function
- BCL6 cellular function in germinal centers of
lymph nodes follicles
Mature naïve B cells migrate from the bone marrow to
lymphoid nodes, meet the antigen, they are stimulated
to proliferate and further differentiate into centroblasts
in germinal centers (GC) of lymphoid follicles.
There, cells are subjects to somatic hypermutation and
class switch recombination, to further differenciate into
memory B cells or plasma cells. This process also
requires the presence of follicular helper T cells.
BCL6 has a major role in this process. In particular,
BCL6 prevents ATM and TP53 (Phan et al., 2004) to
induce apoptosis in response to DNA rearrangements
such as those necessary for somatic hypermutation and
class switch recombination processes.
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(6)
372
BCL6 (B-Cell Lymphoma 6)
Huret JL
(which binds the PEST domain). Deacetylation of
histones leads to transcriptional repression of BCL6
targets.
BCL6 interacts with ZBTB17 to repress CDKN1A and
BCL2 (Phan et al., 2005). BCL6 has also been found to
interact with other POK family members ((POZ and
Krüppel)/ZBTB (zing finger and BTB) protein family)
such as ZBTB7A (LRF) and ZBTB16 (PLZF).
BCL6 targets
An integrated biochemical and computational approach
has recently identified thousands of BCL6 direct target
genes, including B cell receptor (BCR; note: nothing to
do with BCR, the partner of ABL1) and CD40
signaling genes (involved in signal transduction,
MAPK activation, NF-AT activation, and NF-kB
activation); T cell-mediated B-cell activation; apoptosis
(BCL2, proteins involved in positive and negative
regulation of the DISC complex and caspase activation,
suggesting a role for BCL6 in balancing pro- and
antiapoptotic programs in GC B cells); response to
DNA damage (ATM, TP53, CDKN1A, ATR, CHEK1,
TP53BP1...); interferon and cytokine signaling
(interferon-type and interleukin receptors that lead to
activation of JAK/STAT. STAT1, STAT3, and
STAT5A were also found to be directly repressed by
BCL6); Toll-like receptor signaling; TGFb receptor
signaling; and WNT signaling (Basso et al., 2010).
- Other tissues
BCL6 promotes survival of olfactory sensory neurons
(Otaki etal., 2010).
BCL6 associate to NACC1 in brain regions (Korutla et
al., 2009).
BCL6 forms a complex with BCOR on the promoters
of Notch target genes in Xenopus embryos (Sakano et
al., 2010).
BCL6-overexpression inhibits osteoclastogenesis, and
the PRDM1 (Blimp-1)/BCL6 balance is essential in
regulating the bone homeostasis by controlling
osteoclastogenesis (Miyauchi et al., 2010). BCL6
controls the expression of the CC-type chemokine
genes and attenuates allergic airway inflammation in
pulmonary epithelium (Seto et al. 2011).
BCL6 repression activity
BCL6 binds to DNA as a homodimer and recruits corepressor molecules, which, in turn, recruit class I and
II histone deacetylases. BCL6 and histone deacetylases
(HDACs) form stable complexes. BCL6 binds HDACs
both directly through its C-terminal Zn fingers and
through its N-terminal BTB/POZ domain and indirectly
by recruiting several co-repressors such as BCOR,
NCOR1, NCOR2 (which bind in a mutually exclusive
way to the BTB/POZ domain), CTBP1 (which binds
the BTB/POZ and the PEST domains), and MTA3
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(6)
373
BCL6 (B-Cell Lymphoma 6)
Huret JL
NF-kB, NF-AT, and AP-1 (Francis et al., 1995). ILF2
(NF45) and ILF3 (NF90) form the nuclear factor of
activated T-cells (NF-AT), a crucial transcription factor
essential for productive T cell activation (Kao et al.,
1994). CD40 signalling reduces BCL6 expression,
through induction of IRF4 by the NF-kB pathway
(Saito et al., 2007).
- PRDM1 (review in Crotty et al., 2010)
JUND/AP-1 and activated STATs drive high BCL6
expression in GC B cells (Arguni et al., 2006). STAT5
up-regulates BCL6 expression (Scheeren et al., 2005);
in contrast, STAT3 up-regulates PRDM1 (Diehl et al.,
2008) (the protein coded from PRDM1 is named
Blimp-1). BCL6 directly promotes the expression of
BACH2, which repress PRDM1 (Blimp-1). BCL6 also
suppresses PRDM1 (Blimp-1) through repression of
IRF4. IRF4 binds to and induces PRDM1. PRDM1
(Blimp-1) abrogates BCL6. PAX5 (protein name:
BSAP) contributes to BCL6 expression (Nera et al.,
2006; Tarlinton, 2011). PAX5 abrogates PRDM1
(Blimp-1), which abrogates PAX5. BCL6 and PAX5
promote the expression of AICDA and UNG (which
have a major role in somatic hypermutation and classswitch recombination) (Alinikula et al., 2011). BCL6
positively regulates AICDA, IRF8, and MYB via
repression of MIR155 (Basso et al., 2012). BCL6
mediates transcriptional repression by recruiting
HDACs.
BCL6 regulation
- B cell receptor
B cell receptor (BCR) induces BCL6 phosphorylation
by MAPK1 on Ser333 and Ser343, which targets BCL6 for rapid degradation by the ubiquitin/proteasome
pathway (Niu et al., 1998). FBXO11 promotes BCL6
ubiquitylation and degradation (Duan et al., 2012).
- DNA damage
After DNA damage, the kinase ATM promotes BCL6
phosphorylation; follows an interaction with PIN1
required for BCL6 degradation (Phan et al., 2007).
- EP300
EP300 binds and acetylates BCL6, which inactivates
BCL6 (acetylation disrupts the ability of BCL6 to
recruit histone deacetylases). The same two pathways
(HDAC pathway and SIRT2 pathway) that regulate
acetylation-mediated activation of TP53 also control
acetylation-mediated
inactivation
of
BCL6
(Bereshchenko et al., 2002). BCL6 represses the
expression of EP300 and its cofactor BAT3 (Cerchietti
et al., 2010). EP300 acetylates and activates PAX5 (He
et al., 2011), which enhances BCL6.
- Autoregulation
BCL6 protein binds BCL6 gene promoter, and repress
BCL6, mechanism of negative autoregulation
(Pasqualucci et al., 2003). PATZ1 interacts with BCL6
and is required for its negative autoregulation (Pero et
al., 2012).
- CD40 signaling
CD40 signaling activates various pathways, including
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(6)
374
BCL6 (B-Cell Lymphoma 6)
Huret JL
MIR155 directly targets HDAC4 and indirectly
attenuates BCL6 expression (Sandhu et al., 2012).
PRDM1 (Blimp-1) represses BCL6, and also PAX5,
MYC, and AICDA (review in Martins and Calame,
2008).
IRF8 is expressed at the high levels in germinal center
(GC) B cells. IRF8 binds BCL6 promoter and activates
BCL6 (Lee et al., 2006).
It is also to be noted that IRF4 is involved in the
t(6;14)(p25;q32) IRF4/IGH. PRDM1 (Blimp-1) is
inactivated in about 50% of the activated B cell-like
(ABC) subtype of diffuse large B cell lymphoma
(ABC- DLBCL) (Mandelbaum et al., 2010).
overall survival, especially for the non-GC phenotype
(Akyurek et al., 2012).
Implicated in
3q27 rearrangements /NHL (non
Hodgkin lymphomas)
Disease
B cell non-Hodgkin Lymphoma (B-NHL)
Prognosis
Generally considered to be a better prognosis if there is
increased expression of BCL6. The mechanism by
which its expression is increased does not seem to
matter (ie different translocation partners increasing its
expression results in the same prognosis).
Cytogenetics
3q27 rearrangements/aberrations are diverse and
include:
translocations,
micro-deletions,
point
mutations and hypermutation.
Approximately 50% of 3q27 translocations involves Ig
genes at 14q32 (IgH), 2p12 (IgK) and 22q12 (IgL) (e.g.
t(3;14)(q27;q32)). Less than half (~40%) include a
variety of other chromosomal regions (1q21, 2q21,
4p11, 5q31, 6p21, 7p12, 8q24, 9p13, 11q13, 11q23,
12q11, 13q14-21, 14q11, 15q21; 16p11...).
In addition, there are frequent bi-allelic alterations
(translocation and deletion or mutation on the nontranslocated allele).
Hybrid/Mutated gene
hybrid gene and transcripts are formed following
promoter substitution between BCL6 and its different
partners.
Chimeric transcripts are generally detected containing
the 5' part of the gene partner fused to the normal
BCL6 exon 2 splice acceptor site.
In some cases reciprocal chimeric transcripts driven by
the 5' regulatory region of BCL6 fused to the partner
gene coding region, have been characterised.
Homology
BTB/POZ - Zinc Finger proteins (PLZF, HIC1, KUP,
BAZF, ttk (drosophila), BrC (drosophila)...).
Mutations
Note
Chromosomal translocations involving BCL6 are found
in 40% of diffuse large B-cell lymphomas (DLBCL), 510% of follicular lymphomas (FL), and 50% of nodular
lymphocyte predominant Hodgkin lymphomas.
Mutations in the autoregulatory region of BCL6 leads
to a constitutive BCL6 expression (Pasqualucci et al.,
2003).
IRF4 response elements in the BCL6 gene mediate
repression of BCL6.
Mutations in the IRF4 repression region of BCL6 gene
also leads to constitutive expression of BCL6 (Saito et
al., 2007).
MYC, BCL2, and BCL6 rearrangements were detected
in 6%, 15%, and 29% respectively of diffuse large Bcell lymphoma (DLBCL) patients. Double or triple
rearrangements were detected in 3% of these patients.
MYC rearrangement was associated with a
significantly
worse
overall
survival.
BCL6
rearrangement also predicted a significantly shorter
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(6)
375
BCL6 (B-Cell Lymphoma 6)
Huret JL
- t(1;3)(q25;q27) the gene in 1q25 is GAS5
- t(2;3)(p12;q27) the gene in 2p12 is IGK
- t(3;3)(q25;q27) the gene in 3q25 is MBNL1
- t(3;3)(q27;q27) the gene in 3q27 is ST6GAL1
- t(3;3)(q27;q27) the gene in 3q27 is EIF4A2
- t(3;3)(q27;q29) the gene in 3q29 is TFRC
- t(3;4)(q27;p13) the gene in 4p13 is RHOH
- t(3;6)(q27;p22) the gene in 6p22 is HIST1H4I
- t(3;6)(q27;p21) the gene in 6p21 is PIM1
- t(3;6)(q27;p21) the gene in 6p21 is SFRS3
- t(3;6)(q27;q15) the gene in 6q15 is SNHG5
- t(3;7)(q27;p12) the gene in 7p12 is IKZF1
- t(3;7)(q27;q32) the gene in 7q32 is FRA7H
- t(3;8)(q27;q24.1) the gene in 8q24.1 is MYC
- t(3;9)(q27;p24) the gene in 9p24 is DMRT1
- t(3;9)(q27;p11) the gene in 9p11 is GRHPR
- t(3;11)(q27;q23) the gene in 11q23 is POU2AF1
- t(3;12)(q27;p13) the gene in 12p13 is GAPDH
- t(3;12)(q27;q12) the gene in 12q12 is LRMP
- t(3;13)(q27;q14) the gene in 13q14 is LCP1
- t(3;14)(q27;q32) the gene in 14q32 is IGH
- t(3;14)(q27;q32) the gene in 14q32 is HSP90AA1
- t(3;16)(q27;p13) the gene in 16p13 is CIITA
- t(3;16)(q27;p11) the gene in 16p11 is IL21R
- t(3;19)(q27;q13) the gene in 19q13 is NAPA
- t(3;22)(q27;q11) the gene in 22q11 is IGL
Abnormal protein
No fusion protein.
(prolactin) rapidly suppressed BCL6. Loss of PRLSTAT5a signaling and concomitant upregulation of
BCL6 may represent a regulatory switch facilitating
undifferentiated histology and poor prognosis (Brill et
al., 2010).
Bladder transitional cell carcinoma
Disease
BCL6 protein overexpression is observed in half of the
cases of transitional cell carcinoma.
However, BCL6 over-expression has a negative
correlation with the histological grade (Cho et al.,
2007).
Soft tissue tumors
Disease
BCL6 expression is more frequent in malignant
compared with benign/uncertain solitary fibrous
tumors, as well as in leiomyosarcomas compared with
leiomyomas (Walters et al., 2011).
Neuroblastoma
Disease
In the neuroblastic phenotype of neuroblastoma, BCL6
expression is associated with increased time to relapse
and increased overall survival (Chamdin et al., 2009).
Gastric cancer
Disease
In a study of 100 gastric cancer cases, BCL6 was
highly expressed in differentiated cancers and reduced
or absent in undifferentiated cancers. However,
survival was identical in BCL6-positive and BCL6negative cases (Hirata et al., 2009).
t(9;22)(q34;q11) leukemias
Disease
BCL6 enables Ph+ acute lymphoblastic leukaemia cells
to survive BCR-ABL1 kinase inhibition (Duy et al.
2011).
In chronic myelogenous leukemia (CML), BCL6 acts
as a critical effector downstream of FoxO in selfrenewal signaling of CML-initiating cells. Therefore,
pharmacological inhibition of BCL6 may represent a
novel strategy to eradicate leukemia-initiating cells in
CML (Hurtz et al., 2011).
Multiple myeloma
Disease
IL6 induces transcriptional up-regulation of BCL6 via
JAK/STAT3 pathway. TNF (TNF alpha) up-regulates
BCL6. BCL6 expression is mediated independantly via
both JAK/STAT3 and NF-KB pathways in multiple
myeloma cells (Hideshima et al., 2010).
Breast cancer
Breakpoints
Disease
BCL6 protein is elevated in human breast cancers,
especially in high-grade, poorly differentiated and
metastatic breast cancer cases (Bos et al., 2003;
Logarajah et al., 2003; Brill et al., 2010). PRL
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(6)
Note
Clustered in a 3,3 kb EcoRI fragment (MTC) includind
exon 1A and intron 1.
376
BCL6 (B-Cell Lymphoma 6)
Huret JL
References
Albagli-Curiel O. Ambivalent role of BCL6 in cell survival and
transformation. Oncogene. 2003 Jan 30;22(4):507-16
Kerckaert JP, Deweindt C, Tilly H, Quief S, Lecocq G, Bastard
C. LAZ3, a novel zinc-finger encoding gene, is disrupted by
recurring chromosome 3q27 translocations in human
lymphomas. Nat Genet. 1993 Sep;5(1):66-70
Logarajah S, Hunter P, Kraman M, Steele D, Lakhani S,
Bobrow L, Venkitaraman A, Wagner S. BCL-6 is expressed in
breast cancer and prevents mammary epithelial differentiation.
Oncogene. 2003 Aug 28;22(36):5572-8
Ye BH, Lista F, Lo Coco F, Knowles DM, Offit K, Chaganti RS,
Dalla-Favera R. Alterations of a zinc finger-encoding gene,
BCL-6, in diffuse large-cell lymphoma. Science. 1993 Oct
29;262(5134):747-50
Pasqualucci L, Migliazza A, Basso K, Houldsworth J, Chaganti
RS, Dalla-Favera R. Mutations of the BCL6 proto-oncogene
disrupt its negative autoregulation in diffuse large B-cell
lymphoma. Blood. 2003 Apr 15;101(8):2914-23
Kao PN, Chen L, Brock G, Ng J, Kenny J, Smith AJ, Corthésy
B. Cloning and expression of cyclosporin A- and FK506sensitive nuclear factor of activated T-cells: NF45 and NF90. J
Biol Chem. 1994 Aug 12;269(32):20691-9
Phan RT, Dalla-Favera R. The BCL6 proto-oncogene
suppresses p53 expression in germinal-centre B cells. Nature.
2004 Dec 2;432(7017):635-9
Phan RT, Saito M, Basso K, Niu H, Dalla-Favera R. BCL6
interacts with the transcription factor Miz-1 to suppress the
cyclin-dependent kinase inhibitor p21 and cell cycle arrest in
germinal center B cells. Nat Immunol. 2005 Oct;6(10):1054-60
Miki T, Kawamata N, Hirosawa S, Aoki N. Gene involved in the
3q27 translocation associated with B-cell lymphoma, BCL5,
encodes a Krüppel-like zinc-finger protein. Blood. 1994 Jan
1;83(1):26-32
Francis DA, Karras JG, Ke XY, Sen R, Rothstein TL. Induction
of the transcription factors NF-kappa B, AP-1 and NF-AT
during B cell stimulation through the CD40 receptor. Int
Immunol. 1995 Feb;7(2):151-61
Scheeren FA, Naspetti M, Diehl S, Schotte R, Nagasawa M,
Wijnands E, Gimeno R, Vyth-Dreese FA, Blom B, Spits H.
STAT5 regulates the self-renewal capacity and differentiation
of human memory B cells and controls Bcl-6 expression. Nat
Immunol. 2005 Mar;6(3):303-13
Niu H, Ye BH, Dalla-Favera R. Antigen receptor signaling
induces
MAP
kinase-mediated
phosphorylation
and
degradation of the BCL-6 transcription factor. Genes Dev.
1998 Jul 1;12(13):1953-61
Arguni E, Arima M, Tsuruoka N, Sakamoto A, Hatano M,
Tokuhisa T. JunD/AP-1 and STAT3 are the major enhancer
molecules for high Bcl6 expression in germinal center B cells.
Int Immunol. 2006 Jul;18(7):1079-89
Bereshchenko OR, Gu W, Dalla-Favera R. Acetylation
inactivates the transcriptional repressor BCL6. Nat Genet.
2002 Dec;32(4):606-13
Chen YW, Hu XT, Liang AC, Au WY, So CC, Wong ML, Shen
L, Tao Q, Chu KM, Kwong YL, Liang RH, Srivastava G. High
BCL6 expression predicts better prognosis, independent of
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(6)
377
BCL6 (B-Cell Lymphoma 6)
Huret JL
BCL6 translocation status, translocation partner, or BCL6deregulating mutations, in gastric lymphoma. Blood. 2006 Oct
1;108(7):2373-83
by the interaction with the C-terminus of pro-HB-EGF induces
cyclin D2 expression in gastric cancers. Br J Cancer. 2009 Apr
21;100(8):1320-9
Keller CE, Nandula S, Vakiani E, Alobeid B, Murty VV, Bhagat
G. Intrachromosomal rearrangement of chromosome 3q27: an
under recognized mechanism of BCL6 translocation in B-cell
non-Hodgkin lymphoma. Hum Pathol. 2006 Aug;37(8):1093-9
Korutla L, Wang P, Jackson TG, Mackler SA. NAC1, a
POZ/BTB protein that functions as a corepressor. Neurochem
Int. 2009 Mar-Apr;54(3-4):245-52
Basso K, Dalla-Favera R. BCL6: master regulator of the
germinal center reaction and key oncogene in B cell
lymphomagenesis. Adv Immunol. 2010;105:193-210
Lee CH, Melchers M, Wang H, Torrey TA, Slota R, Qi CF, Kim
JY, Lugar P, Kong HJ, Farrington L, van der Zouwen B, Zhou
JX, Lougaris V, Lipsky PE, Grammer AC, Morse HC 3rd.
Regulation of the germinal center gene program by interferon
(IFN) regulatory factor 8/IFN consensus sequence-binding
protein. J Exp Med. 2006 Jan 23;203(1):63-72
Basso K, Saito M, Sumazin P, Margolin AA, Wang K, Lim WK,
Kitagawa Y, Schneider C, Alvarez MJ, Califano A, DallaFavera R. Integrated biochemical and computational approach
identifies BCL6 direct target genes controlling multiple
pathways in normal germinal center B cells. Blood. 2010 Feb
4;115(5):975-84
Nera KP, Kohonen P, Narvi E, Peippo A, Mustonen L, Terho P,
Koskela K, Buerstedde JM, Lassila O. Loss of Pax5 promotes
plasma cell differentiation. Immunity. 2006 Mar;24(3):283-93
Cerchietti LC, Hatzi K, Caldas-Lopes E, Yang SN, Figueroa
ME, Morin RD, Hirst M, Mendez L, Shaknovich R, Cole PA,
Bhalla K, Gascoyne RD, Marra M, Chiosis G, Melnick A. BCL6
repression of EP300 in human diffuse large B cell lymphoma
cells provides a basis for rational combinatorial therapy. J Clin
Invest. 2010 Nov 1;
Ohno H. Pathogenetic and clinical implications of nonimmunoglobulin ; BCL6 translocations in B-cell non-Hodgkin's
lymphoma. J Clin Exp Hematop. 2006 Nov;46(2):43-53
Cho HY, Park HS, Lin Z, Kim I, Joo KJ, Cheon J. BCL6 gene
mutations in transitional cell carcinomas. J Int Med Res. 2007
Mar-Apr;35(2):224-30
Crotty S, Johnston RJ, Schoenberger SP. Effectors and
memories: Bcl-6 and Blimp-1 in T and B lymphocyte
differentiation. Nat Immunol. 2010 Feb;11(2):114-20
Niitsu N, Okamoto M, Nakamura N, Nakamine H, Aoki S,
Hirano M, Miura I. Prognostic impact of chromosomal alteration
of 3q27 on nodal B-cell lymphoma: correlation with histology,
immunophenotype, karyotype, and clinical outcome in 329
consecutive patients. Leuk Res. 2007 Sep;31(9):1191-7
Hideshima T, Mitsiades C, Ikeda H, Chauhan D, Raje N,
Gorgun G, Hideshima H, Munshi NC, Richardson PG,
Carrasco DR, Anderson KC. A proto-oncogene BCL6 is upregulated in the bone marrow microenvironment in multiple
myeloma cells. Blood. 2010 May 6;115(18):3772-5
Phan RT, Saito M, Kitagawa Y, Means AR, Dalla-Favera R.
Genotoxic stress regulates expression of the proto-oncogene
Bcl6 in germinal center B cells. Nat Immunol. 2007
Oct;8(10):1132-9
Mandelbaum J, Bhagat G, Tang H, Mo T, Brahmachary M,
Shen Q, Chadburn A, Rajewsky K, Tarakhovsky A,
Pasqualucci L, Dalla-Favera R. BLIMP1 is a tumor suppressor
gene frequently disrupted in activated B cell-like diffuse large B
cell lymphoma. Cancer Cell. 2010 Dec 14;18(6):568-79
Saito M, Gao J, Basso K, Kitagawa Y, Smith PM, Bhagat G,
Pernis A, Pasqualucci L, Dalla-Favera R. A signaling pathway
mediating downregulation of BCL6 in germinal center B cells is
blocked by BCL6 gene alterations in B cell lymphoma. Cancer
Cell. 2007 Sep;12(3):280-92
Miyauchi Y, Ninomiya K, Miyamoto H, Sakamoto A, Iwasaki R,
Hoshi H, Miyamoto K, Hao W, Yoshida S, Morioka H, Chiba K,
Kato S, Tokuhisa T, Saitou M, Toyama Y, Suda T, Miyamoto T.
The Blimp1-Bcl6 axis is critical to regulate osteoclast
differentiation and bone homeostasis. J Exp Med. 2010 Apr
12;207(4):751-62
Tapinassi C, Micucci C, Lahortiga I, Malazzi O, Gasparini P,
Gorosquieta A, Odero MD, Belloni E. A novel t(2;3)(p11;q27) in
a case of follicular lymphoma. Cancer Genet Cytogenet. 2007
Jan 1;172(1):70-3
Otaki JM, Hatano M, Matayoshi R, Tokuhisa T, Yamamoto H.
The proto-oncogene BCL6 promotes survival of olfactory
sensory neurons. Dev Neurobiol. 2010 May;70(6):424-35
Wang HY, Bossler AD, Schaffer A, Tomczak E, DiPatri D,
Frank DM, Nowell PC, Bagg A. A novel t(3;8)(q27;q24.1)
simultaneously involving both the BCL6 and MYC genes in a
diffuse large B-cell lymphoma. Cancer Genet Cytogenet. 2007
Jan 1;172(1):45-53
Poholek AC, Hansen K, Hernandez SG, Eto D, Chandele A,
Weinstein JS, Dong X, Odegard JM, Kaech SM, Dent AL,
Crotty S, Craft J. In vivo regulation of Bcl6 and T follicular
helper cell development. J Immunol. 2010 Jul 1;185(1):313-26
Diehl SA, Schmidlin H, Nagasawa M, van Haren SD,
Kwakkenbos MJ, Yasuda E, Beaumont T, Scheeren FA, Spits
H. STAT3-mediated up-regulation of BLIMP1 Is coordinated
with BCL6 down-regulation to control human plasma cell
differentiation. J Immunol. 2008 Apr 1;180(7):4805-15
Sakano D, Kato A, Parikh N, McKnight K, Terry D, Stefanovic
B, Kato Y. BCL6 canalizes Notch-dependent transcription,
excluding Mastermind-like1 from selected target genes during
left-right patterning. Dev Cell. 2010 Mar 16;18(3):450-62
Martins G, Calame K. Regulation and functions of Blimp-1 in T
and B lymphocytes. Annu Rev Immunol. 2008;26:133-69
Tran TH, Utama FE, Lin J, Yang N, Sjolund AB, Ryder A,
Johnson KJ, Neilson LM, Liu C, Brill KL, Rosenberg AL,
Witkiewicz AK, Rui H. Prolactin inhibits BCL6 expression in
breast cancer through a Stat5a-dependent mechanism. Cancer
Res. 2010 Feb 15;70(4):1711-21
Parekh S, Privé G, Melnick A. Therapeutic targeting of the
BCL6 oncogene for diffuse large B-cell lymphomas. Leuk
Lymphoma. 2008 May;49(5):874-82
Chamdin A, Jarzembowski JA, Subramanian C, Kuick R, Lee
JS, Kwok RP, Castle VP, Opipari AW. Bcl6 is expressed in
neuroblastoma: tumor cell type-specific expression predicts
outcome. Transl Oncol. 2009 Aug 18;2(3):128-37
Alinikula J, Nera KP, Junttila S, Lassila O. Alternate pathways
for Bcl6-mediated regulation of B cell to plasma cell
differentiation. Eur J Immunol. 2011 Aug;41(8):2404-13
Baumjohann D, Okada T, Ansel KM. Cutting Edge: Distinct
waves of BCL6 expression during T follicular helper cell
development. J Immunol. 2011 Sep 1;187(5):2089-92
Hirata Y, Ogasawara N, Sasaki M, Mizushima T, Shimura T,
Mizoshita T, Mori Y, Kubota E, Wada T, Tanida S, Kataoka H,
Kamiya T, Higashiyama S, Joh T. BCL6 degradation caused
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(6)
378
BCL6 (B-Cell Lymphoma 6)
Huret JL
Choi YS, Kageyama R, Eto D, Escobar TC, Johnston RJ,
Monticelli L, Lao C, Crotty S. ICOS receptor instructs T
follicular helper cell versus effector cell differentiation via
induction of the transcriptional repressor Bcl6. Immunity. 2011
Jun 24;34(6):932-46
Walters MP, McPhail ED, Law ME, Folpe AL. BCL-6
expression in mesenchymal tumours: an immunohistochemical
and fluorescence in situ hybridisation study. J Clin Pathol.
2011 Oct;64(10):866-9
Akyurek N, Uner A, Benekli M, Barista I. Prognostic
significance of MYC, BCL2, and BCL6 rearrangements in
patients with diffuse large B-cell lymphoma treated with
cyclophosphamide, doxorubicin, vincristine, and prednisone
plus rituximab. Cancer. 2012 Sep 1;118(17):4173-83
Duy C, Hurtz C, Shojaee S, Cerchietti L, Geng H,
Swaminathan S, Klemm L, Kweon SM, Nahar R, Braig M, Park
E, Kim YM, Hofmann WK, Herzog S, Jumaa H, Koeffler HP, Yu
JJ, Heisterkamp N, Graeber TG, Wu H, Ye BH, Melnick A,
Müschen M. BCL6 enables Ph+ acute lymphoblastic leukaemia
cells to survive BCR-ABL1 kinase inhibition. Nature. 2011 May
19;473(7347):384-8
Basso K, Dalla-Favera R. Roles of BCL6 in normal and
transformed germinal center B cells. Immunol Rev. 2012
May;247(1):172-83
He T, Hong SY, Huang L, Xue W, Yu Z, Kwon H, Kirk M, Ding
SJ, Su K, Zhang Z. Histone acetyltransferase p300 acetylates
Pax5 and strongly enhances Pax5-mediated transcriptional
activity. J Biol Chem. 2011 Apr 22;286(16):14137-45
Basso K, Schneider C, Shen Q, Holmes AB, Setty M, Leslie C,
Dalla-Favera R. BCL6 positively regulates AID and germinal
center gene expression via repression of miR-155. J Exp Med.
2012 Dec 17;209(13):2455-65
Hurtz C, Hatzi K, Cerchietti L, Braig M, Park E, Kim YM,
Herzog S, Ramezani-Rad P, Jumaa H, Müller MC, Hofmann
WK, Hochhaus A, Ye BH, Agarwal A, Druker BJ, Shah NP,
Melnick AM, Müschen M. BCL6-mediated repression of p53 is
critical for leukemia stem cell survival in chronic myeloid
leukemia. J Exp Med. 2011 Oct 24;208(11):2163-74
Duan S, Cermak L, Pagan JK, Rossi M, Martinengo C, di Celle
PF, Chapuy B, Shipp M, Chiarle R, Pagano M. FBXO11
targets BCL6 for degradation and is inactivated in diffuse large
B-cell lymphomas. Nature. 2012 Jan 5;481(7379):90-3
Kroenke MA, Eto D, Locci M, Cho M, Davidson T, Haddad EK,
Crotty S. Bcl6 and Maf cooperate to instruct human follicular
helper CD4 T cell differentiation. J Immunol. 2012 Apr
15;188(8):3734-44
Kitano M, Moriyama S, Ando Y, Hikida M, Mori Y, Kurosaki T,
Okada T. Bcl6 protein expression shapes pre-germinal center
B cell dynamics and follicular helper T cell heterogeneity.
Immunity. 2011 Jun 24;34(6):961-72
Okada T, Moriyama S, Kitano M. Differentiation of germinal
center B cells and follicular helper T cells as viewed by tracking
Bcl6
expression
dynamics.
Immunol
Rev.
2012
May;247(1):120-32
Pellicano F, Holyoake TL. Assembling defenses against
therapy-resistant leukemic stem cells: Bcl6 joins the ranks. J
Exp Med. 2011 Oct 24;208(11):2155-8
Pero R, Palmieri D, Angrisano T, Valentino T, Federico A,
Franco R, Lembo F, Klein-Szanto AJ, Del Vecchio L,
Montanaro D, Keller S, Arra C, Papadopoulou V, Wagner SD,
Croce CM, Fusco A, Chiariotti L, Fedele M. POZ-, AT-hook-,
and zinc finger-containing protein (PATZ) interacts with human
oncogene B cell lymphoma 6 (BCL6) and is required for its
negative autoregulation. J Biol Chem. 2012 May
25;287(22):18308-17
Seto T, Yoshitake M, Ogasawara T, Ikari J, Sakamoto A,
Hatano M, Hirata H, Fukuda T, Kuriyama T, Tatsumi K,
Tokuhisa T, Arima M. Bcl6 in pulmonary epithelium
coordinately controls the expression of the CC-type chemokine
genes and attenuates allergic airway inflammation. Clin Exp
Allergy. 2011 Nov;41(11):1568-78
Tarlinton DM. Bcl6: where too much complexity is barely
enough. Eur J Immunol. 2011 Aug;41(8):2148-51
This article should be referenced as such:
Wagner SD, Ahearne M, Ko Ferrigno P. The role of BCL6 in
lymphomas and routes to therapy. Br J Haematol. 2011
Jan;152(1):3-12
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(6)
Huret JL. BCL6 (B-Cell Lymphoma 6). Atlas Genet Cytogenet
Oncol Haematol. 2013; 17(6):371-379.
379