Bcl-6 mediates the germinal center B cell phenotype and lymphomagenesis through transcriptional repression of the DNA-damage sensor ATR

Ranuncolo, Stella Maris; Polo, José M.; Dierov, Jamil; Singer, Michael; Kuo, Tracy C.; Greally, John M.; Green, Roland; Carroll, Martin; Melnick, Ari

doi:10.1038/ni1478

Cited by 239 publications

(292 citation statements)

References 51 publications

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“…Recent work revealed that Bcl6 is also needed for follicular T helper cell development [10][11][12]. Analyses of Bcl6 target genes in B cells indicate that suppression of apoptosis and cell cycle arrest responses occur through p53, p21 and CHEK1 and Bcl6 also regulates DNA damage responses by controlling ATR [13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Alternate pathways for Bcl6‐mediated regulation of B cell to plasma cell differentiation

et al. 2011

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The transcription factor Bcl6 regulates germinal center formation and differentiation of B cells into high-affinity antibody-producing plasma cells. The direct double-negative regulatory circuit between Bcl6 and Blimp-1 is well established. We now reveal alternative mechanisms for Bcl6-mediated regulation of B-cell differentiation to plasma cells and show with DT40 cells that Bcl6 directly promotes the expression of Bach2, a known suppressor of Blimp-1. Moreover, Bcl6 suppresses Blimp-1 expression through direct binding to the IRF4 gene, as well as by promoting the expression of MITF, a known suppressor of IRF4. We also provide evidence that Bcl6 is needed for the expression of AID and UNG, the indispensable proteins for somatic hypermutation and class-switch recombination, and UNG appears to be a direct Bcl6 target. Our findings reveal a complex regulatory network in which Bcl6 acts as a key element dictating the transition of DT40 B cells to plasma cells. Supporting Information available online See accompanying Commentary by Tarlinton IntroductionThe transition of activated B cells into high-affinity antibodyproducing plasmablasts, plasma cells and memory B cells in the germinal centers (GCs) is a biologically unique process involving rapid B-cell proliferation coupled with a high rate of mutation in the variable regions of immunoglobulin (Ig) genes. Considering that the majority of B-cell lymphomas originate from the GC B cells [1], a comprehensive understanding of the transcriptional regulation controlling the transition of B cells to plasma cells is essential. The transcription factors Blimp-1, Xbp-1 and IRF4 have been identified to be critical regulators promoting the Ig secretion and plasma cell phenotype, whereas Pax5, Bcl6, MITF and Bach2 are the known inhibitors of plasma cell development [2].Previous studies have shown that the downregulation of B-cell identity factor Pax5 occurs before the induction of the plasma cell transcription program [3,4], and that the loss of Pax5 expression [4] leads to the downregulation of BCL6. Furthermore, B-cell receptor (BCR) signaling of sufficient affinity leads to rapid phosphorylation and degradation of Bcl6 protein [5], while Bcl6 can also be functionally inactivated by acetylation [6]. These features of Bcl6 make it a prominent molecular trigger that controls the plasma cell differentiation.The transcription factor Bcl6 has been demonstrated to be essential for GC B-cell development, as Bcl6 knockout mice fail to develop GCs and do not produce high-affinity antibodies [7][8][9]. Recent work revealed that Bcl6 is also needed for follicular T helper cell development [10][11][12]. Analyses of Bcl6 target genes in B cells indicate that suppression of apoptosis and cell cycle arrest responses occur through p53, p21 and CHEK1 and Bcl6 also regulates DNA damage responses by controlling ATR [13][14][15][16]. Thus, Bcl6 appears to function as a factor permitting rapid B-cell 2404proliferation and tolerance for DNA damage in GCs. Bcl6 also represses genes that are involve...

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Section: Introductionmentioning

confidence: 99%

Alternate pathways for Bcl6‐mediated regulation of B cell to plasma cell differentiation

et al. 2011

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“…Structural studies revealed that SMRT, NCoR, and BCoR all bind to a lateral groove in the POZ domain through a stretch of 17 amino acids (1). Using a cell-permeable BCL6 peptide inhibitor, BPI, designed to block POZ lateral groove corepressor recruitment, we have shown that SMRT/NCoR/BCoR control cell proliferation and survival in GC-derived B cells by mediating BCL6-dependent repression of genes such as ATR, TP53, and CDKN1A (32,35,37). The RDII corepressors, HDAC2 and MTA3/NuRD, bind to BCL6 in an acetylation-sensitive manner and are dissociated from BCL6 when the KKYK motif within RDII is acetylated (4, 15).…”

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“…GC are dynamic and specialized structures in the secondary lymphoid organs within which B cells undergo immunoglobulin class switch recombination and somatic hypermutation to produce diverse, high-affinity antibodies (17,26). Widely considered to be the master regulator of the GC stage of B-cell development, BCL6 maintains the GC-specific gene expression program by silencing genes involved in B-cell activation (CD69, CD80, and NF-B1), response to DNA damage (TP53 and ATR), cell-cycle regulation (CCND2, CDKN1B, and CDKN1A), and plasma cell differentiation (PRDM1) (25,29,34,37,38,40,41). Thus, neither the memory nor the plasma cell differentiation program can be initiated until expression and activity of BCL6 are extinguished by GC exit signals.…”

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CtBP Is an Essential Corepressor for BCL6 Autoregulation

Mendez¹,

Polo

Yu³

et al. 2008

Molecular and Cellular Biology

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The transcription repressor BCL6 plays an essential role in the formation and function of germinal centers (GCs). While normal B cells promptly shut off BCL6 when they exit the GC, many GC-derived B-cell lymphomas sustain BCL6 expression through chromosomal translocations and activating mutations. We have previously shown that a common effect of lymphoma-associated BCL6 gene alterations is to bypass a negative autoregulatory loop that controls its transcription. In this study, we report that BCL6 autoregulation is independent of several known corepressor complexes including silencing mediator for retinoid and thyroid hormone receptors, nuclear receptor coreceptor, BCL6 corepressor, and MTA3/NuRD. Furthermore, we show that BCL6 can interact with the CtBP (C-terminal binding protein) corepressor both in vitro and in vivo and that CtBP is recruited by BCL6 to its 5 regulatory region. In lymphoma cell lines carrying BCL6 translocations, small interfering RNA-mediated CtBP knock-down selectively relieved the previously silenced wild-type BCL6 allele but not the translocated alleles, which are driven by heterologous promoters. These results demonstrate that CtBP is a novel BCL6 corepressor and suggest that a unique corepressor requirement for BCL6 autoregulation may allow GC B cells to differentially control the expression of BCL6 and other BCL6 target genes in response to environmental stimuli during the GC stage of B cell development.BCL6 is a sequence-specific transcription repressor that is required for the formation of germinal centers (GC), and its deregulated expression underlies development of many GCderived B-cell lymphomas (12,44,47). Expression of BCL6 is developmentally regulated such that in the B-cell lineage, high levels of BCL6 are restricted to the GC stage. GC are dynamic and specialized structures in the secondary lymphoid organs within which B cells undergo immunoglobulin class switch recombination and somatic hypermutation to produce diverse, high-affinity antibodies (17,26). Widely considered to be the master regulator of the GC stage of B-cell development, BCL6 maintains the GC-specific gene expression program by silencing genes involved in B-cell activation (CD69, CD80, and NF-B1), response to DNA damage (TP53 and ATR), cell-cycle regulation (CCND2, CDKN1B, and CDKN1A), and plasma cell differentiation (PRDM1) (25,29,34,37,38,40,41). Thus, neither the memory nor the plasma cell differentiation program can be initiated until expression and activity of BCL6 are extinguished by GC exit signals.BCL6 is a 95-kDa phosphoprotein with six Krüppel-type zinc fingers (ZF) at the C terminus and an N-terminal POZ/BTB domain. Our earlier work demonstrated that the maximum repression activity of BCL6 requires the entire POZ/BTB domain as well as a separate middle region, repression domain II (RDII) (7). To date, a variety of BCL6 corepressors have been described. Among the corepressors with well-documented in vivo functions, nuclear receptor coreceptor (NCoR), silencing mediator for retinoid and thyroid hormon...

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“…One of the best characterized biological functions of BCL6 in centroblasts is to facilitate simultaneous rapid proliferation and tolerance of genomic damage occurring during clonal expansion and somatic hypermutation. BCL6 mediates these effects by directly repressing DNA damage sensing and checkpoint genes such as DNA damage sensor ATR (ataxia telangiectasia and Rad3 related), TP53 (tumor protein p53) tumor suppressor and cell cycle arrest gene CDKN1A (cyclin-dependent kinase inhibitor 1A) [27][28][29]. In addition, BCL6 blocks premature activation by T cells or other soluble signals through inhibiting a number of pathways involved in B-cell activation in T-cell dependent immune [11][12][13].…”

Section: Bcl6: a Master Transcriptional Regulator Of Gc B-cell Develomentioning

confidence: 99%

Mechanisms of action of BCL6 during germinal center B cell development

Huang

Melnick

2015

Sci. China Life Sci.

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The transcriptional repressor B cell lymphoma 6 (BCL6) controls a large transcriptional network that is required for the formation and maintenance of germinal centers (GC). GC B cells represent the normal counterpart of most human B-cell lymphomas, which are often characterized by deregulated BCL6 expression or BCL6-mediated pathways. BCL6 suppresses gene transcription largely through recruitment of its co-repressors through its distinct repression domain. Understanding the precise biological roles of each repression domain in normal and malignant B cells is helpful for development of targeted inhibition of BCL6 functions that is emerging as the basis for design of anti-lymphoma therapies. This review focuses on recent progress in the molecular mechanisms of action of BCL6 in B cells and discusses remaining unresolved questions related to how these mechanisms are linked to normal and malignant B cell development. BCL6, germinal center, co-repressor, lymphoma Citation:Huang CX, Melnick A. Mechanisms of action of BCL6 during germinal center B cell development.

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Bcl-6 mediates the germinal center B cell phenotype and lymphomagenesis through transcriptional repression of the DNA-damage sensor ATR

Cited by 239 publications

References 51 publications

Alternate pathways for Bcl6‐mediated regulation of B cell to plasma cell differentiation

Alternate pathways for Bcl6‐mediated regulation of B cell to plasma cell differentiation

CtBP Is an Essential Corepressor for BCL6 Autoregulation

Mechanisms of action of BCL6 during germinal center B cell development

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