Specific peptide interference reveals BCL6 transcriptional and oncogenic mechanisms in B-cell lymphoma cells

Polo, José M.; Dell'Oso, Tania; Ranuncolo, Stella Maris; Cerchietti, Leandro; Beck, David; Silva, Gustavo F. Da; Privé, G.G.; Licht, Jonathan D.; Melnick, Ari

doi:10.1038/nm1134

Cited by 271 publications

(384 citation statements)

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“…In the BCL6 locus, the orange triangle indicates the exon 1 BCL6 binding sites studied in panel A. Opaque masking windows represent the cutoff defined as 2.5 times the standard deviation above the average relative enrichment on the entire array. (15,35). Our CtBP siRNA experiment revealed that CtBP also contributes to repression of CCL3 (Fig.…”

Section: Discussionmentioning

confidence: 71%

“…To address this issue, we evaluated the response of the endogenous BCL6 gene to the POZ lateral groove corepressor blocking peptide, BPI. We have previously shown that BPI treatment can derepress a number of BCL6 target genes in mature B cell lines (35). BCL6-positive SUDHL6 cells were treated with BPI and assayed for changes in BCL6 expression by qRT-PCR.…”

Section: Resultsmentioning

confidence: 99%

“…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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confidence: 99%

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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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Section: Discussionmentioning

confidence: 71%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…Our study suggests the possibility of disrupting the interaction between c-Myb and CBP/ p300 as an approach to targeting c-Myb. This may be achievable using small molecules or peptides, because disruption of protein-protein interactions with such agents is now considered a feasible strategy for drug development (57,58).…”

Section: Discussionmentioning

confidence: 99%

Mutations in Multiple Domains of c-Myb Disrupt Interaction with CBP/p300 and Abrogate Myeloid Transforming Ability

Pattabiraman

Sun

Dowhan

et al. 2009

Molecular Cancer Research

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The c-myb proto-oncogene is a key regulator of hematopoietic cell proliferation and differentiation. MYB mRNA is expressed at high levels in, and is required for the proliferation of, most human myeloid and acute lymphoid leukemias. Recently, chromosomal translocation and genomic duplications of c-MYB have been identified in human T-cell acute leukemia. The present work focuses on the effects of mutations in different domains of the murine c-Myb protein on its transforming ability as defined by suppression of myelomonocytic differentiation and continued proliferation. Using both a novel myeloid cell line-based assay and a primary hematopoietic cell assay, we have shown that mutation of single residues in the transactivation domain important for CBP/p300 binding leads to complete loss of transforming ability. We also simultaneously mutated residues in the DNA-binding domain and the negative regulatory domain of the protein. These double mutants, but not the corresponding single mutants, show a complete loss of transforming activity. Surprisingly, these double mutants show severely impaired transactivation and are also defective for CBP/ p300 binding. Our results imply that multiple Myb domains influence its interaction with CBP/p300, highlight the importance of this interaction for myeloid transformation, and suggest an approach for molecular targeting

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“…These different co-repressor complexes appear to suppress distinct gene sets, perhaps mediating different activities of BCL6 in various immune cells. This notion has been in part supported by studies using inhibitors that selectively disrupt the co-repressors binding to the BCL6 BTB (BR-C, ttk and bab) domain [14,15]. However, the link between the transcriptional mechanisms of action of BCL6 with its biological actions in the immune system remains to be further characterized.…”

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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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Specific peptide interference reveals BCL6 transcriptional and oncogenic mechanisms in B-cell lymphoma cells

Cited by 271 publications

References 30 publications

CtBP Is an Essential Corepressor for BCL6 Autoregulation

CtBP Is an Essential Corepressor for BCL6 Autoregulation

Mutations in Multiple Domains of c-Myb Disrupt Interaction with CBP/p300 and Abrogate Myeloid Transforming Ability

Mechanisms of action of BCL6 during germinal center B cell development

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